DOI: 10.1002/chem.201404004
Full Paper
& Organic Synthesis
Alkali-Metal Ion Catalysis and Inhibition in SNAr Displacement: Relative Stabilization of Ground State and Transition State Determines Catalysis and Inhibition in SNAr Reactivity Ik-Hwan Um,*[a] Hyo-Jin Cho,[b] Min-Young Kim,[a] and Erwin Buncel*[c]
Abstract: We report here the first observation of alkali-metal ion catalysis and inhibition in SNAr reactions. The plot of kobsd versus [alkali-metal ethoxide] exhibits downward curvature for the reactions of 1-(4-nitrophenoxy)-2,4-dinitrobenzene with EtOLi, EtONa, and EtOK, but upward curvature for the corresponding reaction with EtOK in the presence of 18crown-6-ether (18C6). Dissection of kobsd into the secondorder rate constants for the reactions with the dissociated EtO and the ion-paired EtOM (i.e., kEtO and kEtOM, respectively) has revealed that the reactivity increases in the order EtOLi < EtONa < EtOK < EtO < EtOK/18C6. This indicates that the reaction is inhibited by Li + , Na + , and K + ions but is cata-
Introduction Metal ions (as Lewis acids) have often been reported to catalyze nucleophilic substitution reactions of esters bearing various electrophilic centers.[1–9] Since Lewis acidity increases with increasing charge density of metal ions, studies have focused mostly on reactions involving multivalent metal ions (e.g., La3 + , Eu3 + , Co3 + , Zn2 + , Cu2 + , etc.).[1–5] It is well known that alkalimetal ions are ubiquitous in nature and play important roles in biological processes (e.g., a Na + pump to maintain high K + and low Na + concentrations in mammalian cells).[10] Nevertheless, studies on alkali-metal ions have been sparingly carried out.[6–9] Our group has initiated a systematic study of nucleophilic substitution reactions of 4-nitrophenyl diphenylphosphinate (1, see Figure 1) with alkali-metal ethoxides (EtOM, M = Li, Na and K) in anhydrous ethanol.[6] This study has revealed that M + ions catalyze the reaction and the catalytic effect increases
lyzed by 18C6 K + ion. The reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes have been proposed to proceed through a stepwise mechanism, in which expulsion of the leaving group occurs after the rate-determining step based on the kinetic result that so constants exhibit a much better Hammett correlation than s constants. Alkali-metal ion catalysis or inhibition has been discussed in terms of differential stabilization of ground-state and transition-state complexes through a qualitative energy profile. A p-complexed transition-state structure is proposed to account for the kinetic results.
with decreasing size of M + ions, that is, K + < Na + < Li + .[6] However, the catalytic effect exerted by M + ions disappeared in the presence of complexing agents such as 18-crown-6 ether (18C6) for K + ion, 15-crown-5-ether (15C5) for Na + ion and [2,1,1]-cryptand for Li + ion.[6] In contrast, we have found that the corresponding reaction of 4-nitrophenyl diphenylphosphinothioate (2) is inhibited by Li + ion but is catalyzed by Na + and K + ions.[7] More interestingly, 18C6-crowned K + ion exhibited a stronger catalytic effect than Na + and K + ions, indicating that the M + ion effect is dependent on the nature of the electrophilic center (e.g., P=O vs. P=S).[7]
[a] Prof. I.-H. Um, M.-Y. Kim Department of Chemistry and Nano Science, Ewha Womans University Seoul 120-750 (Korea) E-mail: [email protected] [b] H.-J. Cho Department of Chemistry, Ducksung Women’s University Seoul 132-714 (Korea) [c] Prof. E. Buncel Department of Chemistry, Queen’s University Kingston, Ontario K7L 3N6 (Canada) Fax: (+ 1) 613-533-6669 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404004. Chem. Eur. J. 2014, 20, 13337 – 13344
Figure 1. Order of M + ion effects.
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Full Paper A similar result has been found for the alkaline ethanolysis of paraoxon and its methyl counterpart (3 a and 3 b) and parathion with its methyl analogue (4 a and 4 b), that is,1) the reaction of the P=O compounds (3 a and 3 b) is catalyzed by M + ions with a catalytic order K + < Na + < Li + ; 2) contrastingly, the reaction of the P=S compounds (4 a and 4 b, Figure 1) is inhibited by Na + and Li + ions but is catalyzed by K + ion; and 3) the reaction of the P=S compound 4 b is strongly catalyzed by 18C6-crowned K + ion.[8b] The contrasting M + ion effects were discussed on the basis of competing electrostatic effects and solvational requirements as a function of anionic electrophilic field strength and cationic size (Eisenman’s theory).[11] The effect of M + ions has also been investigated on two series of sulfonyl-transfer reactions, that is, alkaline ethanolyses of 2,4-dinitrophenyl X-substituted-benzenesulfonates (5 a–5 f) and Y-substituted-phenyl benzenesulfonates (6 a–6 k, Figure 1).[9] The reaction of 4-nitrophenyl benzenesulfonate (6 c) with EtOM was catalyzed by M + ions in the order K + > Na + > Li + .[9a] Furthermore, the catalytic effect exerted by K + ion increased linearly on changing the substituent X in the benzenesulfonyl moiety from a strong electron-withdrawing group (EWG) to an electron-donating group (EDG), but was independent of the electronic nature of the substituent Y in the leaving group.[9b] Thus, it has been concluded that the K + ion catalyzes the sulfonyl-transfer reaction by increasing electrophilicity of the reaction center through TSI rather than by enhancing nucleofugality of the leaving group via TSII.[9b] Nucleophilic reaction at a carbonyl center, as a model for the reactions shown in Figure 1, involves formation of an sp3-hybridized intermediate (or TS modeled such an intermediate). The process requires rehybridization from sp2 C=O carbon to sp3 (Scheme 1 A). Similarly, in SNAr displacements nucleophilic attack at substituted ring carbon results in the same rehybridization (Scheme 1B). Therefore, in principle, there is a bridge linking carbonyl displacements to P=O, P=S and O=S=O displacements and to SNAr reactions. Thus, our study has now been extended to the SNAr reaction of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (7 a–7 g) with EtOM (M = Li, Na, K, and K/18C6) as shown in Scheme 2 in order to obtain further information on the role of M + ions in-
Scheme 2. SNAr reaction of 7 a–7 g with EtOM.
cluding the reaction mechanism. Although numerous studies on SNAr reactions of activated aromatic or heteroaromatic compounds have been carried out,[12–17] the effect of M + ions on SNAr reactions has not been investigated systematically. We report in this paper that the reactions of 7 a–7 g with EtOM proceed through a stepwise mechanism in which expulsion of the leaving group occurs after the rate-determining step (RDS) and that M + ions behave as catalyst or inhibitor depending on the relative stabilization of the ground state (GS) and transition state (TS). The results are discussed in light of a possible novel p-complexed TS and by comparison with the systems given in Figure 1.
Results and Discussion The kinetic study was carried out spectrophotometrically under pseudo-first-order conditions in which the EtOM concentration was in large excess over the substrate concentration. All the reactions in this study obeyed pseudo-first-order kinetics and proceeded with quantitative liberation of Y-substituted-phenoxide ion. Pseudo-first-order rate constants (kobsd) were calculated from Equation (1). lnðA1 At Þ ¼ kobsd t þ C
ð1Þ
The uncertainty in the kobsd values was estimated to be less than 3 % from replicate runs. The second-order rate constants for the reactions with the dissociated EtO and ionpaired EtOM (i.e., kEtO and kEtOM, respectively) were calculated from the ion-pairing treatment of the kinetic data, and are summarized in Table 1 for the reactions of 1-(4-nitrophenoxy)2,4-dinitrobenzene (7 a) with EtOM (M = Li, Na, K, and K/18C6) and in Table 2 for the reactions of 1-(Y-substituted-phenoxy)2,4-dinitrobenzenes (7 a–7 g) with EtOK in the presence of 18C6. Detailed kinetic conditions and results (i.e., the kobsd data
Table 1. Summary of second-order rate constants (kEtO and kEtOM) calculated from ion-pairing treatment of the kinetic data for the reaction of 1(4-nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOM in anhydrous EtOH at (25.0 0.1) 8C.
Scheme 1. Chem. Eur. J. 2014, 20, 13337 – 13344
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EtOM
kEtOM [M1 s1]
kEtO [M1 s1]
kEtOM/kEtO
EtOLi EtONa EtOK EtOK/18C6
0.103 0.002 0.225 0.002 0.281 0.003 0.568 0.008
0.314 0.005 0.307 0.003 0.295 0.005 0.286 0.004
0.33 0.73 0.95 1.99
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Full Paper Table 2. Summary of second-order rate constants calculated from ionpairing treatment of the kinetic data for the reaction of 1-(Y-substitutedphenoxy)-2,4-dinitrobenzenes (7 a–7 g) with EtOK in the presence of 18C6 in anhydrous EtOH at (25.0 0.1) 8C.[a, b]
7a 7b 7c 7d 7e 7f 7g
Y
pK Ya -PhOH kEtOK/18C6 [M1 s1] kEtO [M1 s1]
4-NO2 4-CN 4-COCH3 3-Cl 4-Cl H 4-CH3
11.98 13.04 13.26 14.47 14.90 15.76 15.99
0.568 0.008 0.490 0.005 0.231 0.002 0.133 0.001 0.120 0.001 0.0311 0.0003 0.0233 0.0004
0.286 0.004 0.209 0.003 0.092 0.001 0.0470 0.0007 0.0380 0.0008 0.0092 0.0001 0.0062 0.0001
kEtOK/18C6/kEtO 1.99 2.34 2.51 2.83 3.16 3.38 3.76
[a] [18C6]/[EtOK] = 2.0. [b] The pKa data in anhydrous ethanol were taken from ref. [22].
as a function of [EtOM]) are summarized in Tables S1–S10 and in Figure S1–S6 in the Supporting Information (SI). Curvature of rate plots and role of M + ions As shown in Figure 2, the plots of kobsd versus [EtOM] for the reaction of 7 a with EtOM are not uniformly linear. Such curved
Figure 3. Effects of added A) LiSCN and B) 18C6 on reactivity of EtOK for the SNAr reaction of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOK in anhydrous EtOH at (25.0 0.1) 8C. [EtOK] = 30.2 mm.
with varying concentrations of LiSCN (Figure 3 A) and 18C6 (Figure 3 B). As shown in Figure 3 A, the kobsd value at [EtOK] = 30.2 mm decreases rapidly on addition of LiSCN up to [LiSCN]/[ EtOK] 6, indicating that Li + ion strongly inhibits the reaction. In contrast, the kobsd for the same reaction increases on addition of 18C6 up to [18C6]/[EtOK] 1, indicating that the reaction is catalyzed by 18C6-crowned K + ion.
Figure 2. Plots of kobsd versus [EtOM] for the SNAr reaction of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOK/18C6(~), EtOK(*), EtONa(*) and EtOLi(&) in anhydrous EtOH at 25.0 0.1 8C. [18C6]/[EtOK] = 2.0.
plots are typical for reactions of esters with EtOM, in which the M + ion behaves as a catalyst or an inhibitor depending on the type of the curvature. For example, the downward curvature for the reactions with EtOLi and EtONa indicates that Li + and Na + ions inhibit the reaction while the upward curvature for the reaction with EtOK in the presence of 18C6 demonstrates that the 18C6-crowned K + ion acts as a catalyst.[6–9] The catalytic effect exerted by 18C6-crowned K + ion is quite unusual, but was reported previously for the reactions of the P=S centered substrates 2 and 4 b (Figure 1).[8] To probe the above idea that the reaction is inhibited by Li + ion but is catalyzed by 18C6-crowned K + ion, the reaction of 7 a with EtOK at a fixed concentration has been carried out Chem. Eur. J. 2014, 20, 13337 – 13344
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Dissection of kobsd into kEtO and kEtOM To quantify the catalytic or inhibitory effect shown by M + ions, the kobsd values have been dissected into the second-order rate constants for the reactions with the dissociated EtO ion and ion-paired EtOM (i.e., kEtO and kEtOM, respectively). EtOM was reported to exist as dimers or higher order aggregates in highly concentrated solutions (e.g., [EtOM] > 0.1 m) but mainly as the dissociated and ion-paired species in low concentration range as used in the current study (e.g., [EtOM] < 0.1 m).[18] Since both the dissociated EtO and ion-paired EtOM would react with substrate 7 a, as shown in Scheme 3, one can derive a rate equation as in Equation (2).
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Scheme 3. Reactions of 7 a with the dissociated EtO and ion-paired EtOM.
Under pseudo-first-order kinetic conditions (i.e., [EtOM] @ [7 a]), kobsd can be expressed as Equation (3). Since the association constant K EtOM = [EtOM]eq/[EtO]eq[M+]eq, and [EtO]eq = [M + a ]eq at equilibrium, Equation (3) can be converted to Equation (4). The [EtO]eq and [EtOM]eq values can be calculated values for EtOM (i.e., K EtOM = 16.6, 90.1, from the reported K EtOM a a 1 102, and 212 m for EtOK/18C6, EtOK, EtONa and EtOLi, in turn)[19] and the initial concentration of EtOM using Equations (5) and (6). Rate ¼ kEtO ½EtO eq ½7 a þ kEtOM ½EtOMeq ½7 a
ð2Þ
kobsd ¼ kEtO ½EtO eq þ kEtOM ½EtOMeq
ð3Þ
kEtOM½EtO eq kobsd =½EtO eq ¼ kEtO þ K EtOM a
ð4Þ
½EtOM ¼ ½EtO eq þ ½EtOMeq
ð5Þ
½EtO eq ¼ ½1 þ ð1 þ 4 K EtOM ½EtOMÞ1=2 =2 K EtOM a a
ð6Þ
The plot of kobsd/[EtO]eq versus [EtO]eq should be linear if the reaction of 7 a with EtOM proceeds as proposed in Scheme 3. In fact, the plots shown in Figure 4 exhibit excellent linear correlations (R2 0.999). Furthermore, the intercepts of the linear plots are almost identical, regardless of the size of M + ions; this is consistent with the derived equations based on the reactions proposed in Scheme 3. Accordingly, the kEtO and K EtOM kEtOM values were determined from the intercept and a the slope of the linear plots, respectively. The kEtOM values were calculated from the above K EtOM kEtOM values and the reported a
values.[19] The kEtO and kEtOM values calculated in this way K EtOM a are summarized in Table 1 for the reactions of 7 a with EtOM and in Table 2 for the reactions of 7 a–7 g with EtOK in the presence of 18C6. As shown in Table 1, the kEtOM value for the reaction of 7 a increases in the order kEtOLi < kEtONa < kEtOK < kEtOK/18C6. The reactivity order observed in the current SNAr reaction is opposite to that reported previously for the corresponding reactions of the P= O centered electrophiles (e.g., 1, 3 a, and 3 b, Figure 1) but is similar to that reported for the reactions of the P=S centered electrophile (4 b).[6, 8] It is also shown that dissociated EtO is more reactive toward 7 a than the ion-paired EtOLi, EtONa, and EtOK, indicating that the current SNAr reaction is inhibited by M + ions (except 18C6-complexed K + ion). Importantly, the smallest ion, Li + , exhibits the strongest inhibition. This accounts for the result that kobsd decreases rapidly on addition of LiSCN, as shown in Figure 3 A, for the reaction mixture of 7 a and EtOK.
Comparison to computational study In a pertinent study, Jones et al. have recently carried out computations on SNAr reactions of mono-, di-, and triactivated fluorobenzenes (8) with alkali-metal cresolates (Scheme 4).[20] Their calculations using DFT methods have shown that M + ions
Scheme 4. SNAr reaction of fluorobenzenes with alkali-metal cresolates.
(M + = Li + , Na + , and K + ) complex the fluoride leaving group and facilitate expulsion of the leaving group as modeled by TSIII in Scheme 4.[20] However, their calculations revealed that presence of M + ions increases the barrier height due to formation of stable reactant complexes upon interaction with the fluorobenzenes.[20] They also found that the activation energy decreases as the size of M + ions increases, due to the fact that phenoxide becomes less distorted in the TS as the size of M + ions increases.[20] Our experimental results, shown in Table 1, appear to be consistent with the computational results reported by Jones et al., since M + ions (except 18C6-crowned K + ion) inhibit the reaction of 7 a and the inhibitory effect increases as the size of
Figure 4. Plots of kobsd/[EtO]eq versus [EtO]eq for the SNAr reaction of 1-(4nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOK/18C6(~), EtOK(*), EtONa(*) and EtOLi(&) in anhydrous EtOH at (25.0 0.1) 8C. Chem. Eur. J. 2014, 20, 13337 – 13344
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Full Paper M + ions decreases. On this basis, one can propose TSIV as a plausible TS structure for the current reaction of 7 a with EtOM. It is noted that TSIV is similar to TSIII suggested by Jones et al., except alkali-metal cresolates and fluoride in TSIII are replaced by alkali-metal ethoxides and 4-nitrophenoxide in TSIV, respectively. It is apparent that the M + ions in TSIII and TSIV could accelerate expulsion of the leaving groups (i.e., fluoride in TSIII and 4-nitrophenoxide in TSIV). However, the enhanced nucleofugality through TSIII or TSIV would not increase the overall reaction rate, if the reaction proceeds through a stepwise mechanism in which expulsion of the leaving group occurs after the RDS. In other words, in the RDS the nucleophile, EtOM here, attacks at the ring C bearing the 4-nitrophenoxyl leaving group, proceeding via TSIV to give the alkali-metal associated anionic s-adduct (Meisenheimer complex). This twostep mechanism is typical in SNAr reactions.[13a, 21] Effect of leaving-group substituents on reactivity To further elucidate the TS structure, rate constants for the reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (7 a– 7 g) with EtOK in the presence of 18C6 ([18C6]/[EtOK] = 2.0) have been measured. As shown in Table 2, the second-order rate constant for the reaction with EtOK in the presence of 18C6 (i.e., kEtOK/18C6) decreases as the substituent Y changes from a strong EWG to an EDG, for example, kEtOK/18C6 decreases from 0.566 to 0.133 and 0.0233 m1 s1, an approximately 25fold decrease in rate constant, as Y changes from 4-NO2 to 3-Cl and 4-CH3, in turn. A similar result is shown for the reaction with the dissociated EtO . However, the kEtO value is smaller than the kEtOK/18C6 value in all cases, indicating that the 18C6crowned K + ion catalyzes the reaction regardless of the electronic nature of the substituent Y. It is also notable that the catalytic effect shown by the 18C6-crowned K + ion (i.e., kEtOK/ 18C6/kEtO ratio) increases as the substituent Y changes from 4NO2 to 4-CH3. The effects of leaving-group basicity on the rate constants are illustrated in Figure 5. The Brønsted-type plots are linear with some scattered points (R2 = 0.962 0.972). Importantly, the bLg values are very small (e.g., 0.35 for the reaction with EtOK/18C6 and 0.41 for that with the dissociated EtO). Such small bLg values are typical for reactions reported previously to proceed through a stepwise mechanism in which expulsion of the leaving group occurs after the RDS (e.g., aminolysis of aryl benzoates, aryl phenyl carbonates, and related esters).[23–25] One can therefore suggest that the SNAr reaction in this case also proceeds through a stepwise mechanism in which expulsion of the leaving group occurs after RDS on the basis of the small bLg value. Note the implications for TSIV (vide supra). Hammett plots and reaction mechanism Hammett plots for the reactions of 7 a–7 g with EtOK in the presence of 18C6 have been constructed using so and s constants. If expulsion of the leaving group is involved in the RDS, a partial negative charge would develop on the O atom of the leaving group. Since such a negative charge can be delocalized Chem. Eur. J. 2014, 20, 13337 – 13344
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Figure 5. Brønsted-type plots for the reactions of 1-(Y-substituted-phenoxy)2,4-dinitrobenzenes (7 a–7 g) with A) the ion-paired EtOK/18C6 and B) dissociated EtO in anhydrous EtOH at (25.0 0.1) 8C.
to the substituent Y, one might expect that s constants would result in a much better Hammett correlation than so constants. In contrast, if expulsion of the leaving group occurs after the RDS, no negative charge would develop on the O atom of the leaving group. In this case, so constants would result in a better correlation than s constants. In fact, as shown in Figure 6 for the reactions of 7 a–7 g with the dissociated EtO , the Hammett plot using so constants results in an excellent linear correlation (R2 = 0.995). In contrast, the corresponding plot constructed with s constants is linear but exhibits highly scattered points (R2 = 0.975). A similar result is shown in Figure S7 (Supporting Information) for the corresponding reactions with EtOK/18C6. The fact that so constants result in a better Hammett correlation than s constants is a clear indication that no negative charge develops on the O atom of the leaving group in the rate-determining TS. Therefore, one can conclude that the reactions of 7 a–7 g proceed through a stepwise mechanism in which expulsion of the leaving group occurs after RDS. This idea can be further supported by the fact that the EtO ion is much more basic and is, therefore, a poorer nucleofuge than all the Y-substituted-phenoxide ions used in this study.
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Full Paper (HSAB) principle.[26] This idea is consistent with the kinetic result that the reaction of 7 a is catalyzed by a 18C6-crowned K + ion but is strongly inhibited by a Li + ion (Table 1). The TS structure modeled by TSV also accounts for the fact that the catalytic effect shown by 18C6-crowned K + ion (i.e., the kEtOK/ 18C6/kEtO ratio) decreases as the substituent Y in the leaving group becomes a stronger EWG (Table 2). Changing the substituent Y from 4-CH3 to 4-NO2 would reduce the interaction between the p-electrons and 18C6-crowned K + ions in the TS by diminishing the p-electron density. As we have shown, the TS for catalysis of the aromatic displacement involves complexation of the alkali-metal ions (or 18C6-crowned K + ion) with the delocalized p-system (TSV). It is well known that transition metals form stable p-adducts with such delocalized systems (e.g., ferrocene, uranocene, etc.).[27] To the best of our knowledge, this is the first indication that a similar complex with alkali-metal ions or an 18C6-crowned K + ion, albeit as a model TSV, takes part in nucleophilic aromatic substitution. Thus, the role of alkali-metal ions in catalysis is expanded by their interaction not only with single nucleophilic or leaving group centers[20] but also with p-systems in rate-determining TSs. GS and TS stabilization by M + ions
Figure 6. Hammett plots correlated with A) so and B) s constants for the reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (7 a–7 g) with dissociated EtO in anhydrous EtOH at (25.0 0.1) 8C.
TS structure and role of M + ions Since expulsion of the leaving group has been shown to occur after the RDS for the current SNAr reactions, the reactivity of 7 a–7 g toward EtOM would not be governed by nucleofugality of the leaving group. Accordingly, the enhanced nucleofugality afforded by the putative TSIV cannot be the origin of the catalysis shown by the 18C6-crowned K + ion in the current SNAr system. We propose that the SNAr reaction with EtOM in this study proceeds through a stepwise mechanism via a p-complexed TS as modeled by TSV (crown-ether omitted for clarity, Scheme 5). One might expect that the polarizable p-electrons in the benzene ring of TSV would interact strongly with the large 18C6-crowned K + ion but not with a small M + ion (e.g., Li + ion) on the basis of the hard and soft acids and bases
Scheme 5. SNAr reaction of 7 a–7 g with EtOM. Chem. Eur. J. 2014, 20, 13337 – 13344
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M + ion catalysis and inhibition found in the current reactions of 7 a with EtOM can be expressed generally, by Figure 7. In both types of processes, the reaction pathway follows initial complex formation by the reactants, followed by formation of the rate-determining TS and product formation. The relative magnitude of the GS stabilization term (dGGS) and the TS stabilization term (dGTS) determines catalysis or inhibition, that is, dGTS > dGGS corresponds to catalysis and dGGS > dGTS to inhibition.
Figure 7. Qualitative free energies involved in the uncatalyzed and M + ioncatalyzed reactions of 7 a with EtOM. DGu and DGc are the activation energies for the uncatalyzed and catalyzed reactions, respectively, while dGGS and dGTS refer respectively to stabilization of GS and TS by an M + ion.
Since no evidence for complexation of M + ions with the substrate 7 a in the GS has been found in the current or previous studies, GS stabilization would be achieved mainly through ion-pairing between M + and EtO ions. Differential stabilization of TS and GS can be evaluated using a method developed 13342
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Scheme 6. Reactions of 7 a with dissociated EtO and ion-paired EtOM.
by Kurz[28] and in different forms by Mandolini[29] and Tee.[30] Scheme 6 describes a set of equilibria among the reactants and TSs for the catalyzed and uncatalyzed pathways. In Scheme 6, Ku and Kc represent the equilibrium constants for formation of the uncatalyzed and catalyzed TSs, while K EtOM a + and K TS a are the association constants for ion-pairing of M TS with EtO and the TS, respectively. K a can be calculated from EtOM kEtOM/kEtO together with the rethe relationship,[31] K TS a = Ka [13] EtOM ported K a values and the respective rate constants. K EtOM a and K TS a can also be expressed in terms of free energies of stabilization by an M + ion, i.e., dGGS and dGTS, respectively. The dGGS and dGTS values determined for the current reactions are summarized in Table 3. The dGGS value is more nega-
Table 3. Free energies of stabilization of ground state (dGGS) and transition state (dGTS) for the reactions of 7 a with EtOM in anhydrous EtOH at (25.0 0.1) 8C. M+
dGGS [kcal mol1]
dGTS [kcal mol1]
Li + Na + K+ 18C6-K +
3.16 2.73 2.65 1.66
2.50 2.55 2.63 2.06
tive than the dGTS value for the reactions of 7a with EtOLi, EtONa, and EtOK, indicating that the GS stabilization through ion-pairing of EtOM is more significant than the TS stabilization through the p-complexed TSV. This is consistent with the kinetic results that Li + , Na + , and K + ions act as inhibitors. In contrast, the dGGS value is less negative than the dGTS value for the reaction with EtOK/18C6, indicating that the TS stabilization through TSV is more significant than the GS stabilization provided by ion-pairing of EtOK/18C6. This is in accord with the HSAB principle,[26] since the large 18C6-crowned K + ion would interact strongly with the polarizable p-electrons in the TS but weakly with the hard EtO ion in the GS.
3) Brønsted-type plots for the reactions of 7 a–7 g with EtOK/ 18C6 are linear with bLg = 0.35 0.41, indicating that expulsion of the leaving group is not advanced in the rate-determining TS. 4) The fact that so constants result in a better Hammett correlation than s constants is clear indication that expulsion of the leaving group occurs after the RDS. 5) 18C6-Crowned K + ion catalyzes the reaction by stabilizing the TS through the p-complex (i.e., TSV as the novel TS in this study). 6) Li + ion inhibits the SNAr reaction, since it forms a strong ion-pair with EtO in the GS but interacts weakly with the polarizable p-electrons of the aromatic ring in TSV.
Experimental Section Materials 1-(Y-Substituted-phenoxy)-2,4-dinitrobenzenes (7 a–7 g) were readily prepared from the reaction of 1-fluoro-2,4-dinitrobenzene with the respective Y-substituted phenol under the presence of triethylamine in anhydrous ether as reported previously.[17] The crude products were purified by column chromatography and the purity was checked by their melting points and spectral data such as 1 H NMR spectra. Other chemicals were of the highest quality available. The solutions of EtOM were prepared by dissolving the respective alkali metal in anhydrous ethanol under N2 and stored in the refrigerator. The concentrations of EtOM were determined by titration with standard HCl solution. 18-Crown-6-ether was recrystallized from acetonitrile and dried over P2O5 in vacuo. The anhydrous ethanol was further dried over magnesium and distilled under N2 just before use.
Kinetics Kinetic study was performed using a UV/Vis spectrophotometer equipped with a constant-temperature circulating bath. The reactions were followed by monitoring the appearance of Y-substituted-phenoxide ion at a fixed wavelength corresponding to the maximum absorption (lmax, e.g., 400 nm for 4-nitrophenoxide ion). Pseudo-first-order conditions with EtOM at least 20 times greater than substrate concentration were used. Generally, reactions were followed for 9–10 half-lives and kobsd were calculated using the equation, ln (A1 At) vs. t. The conditions and the kobsd values are summarized in Tables S1 – S10 in the Supporting Information (SI).
Product analysis
Conclusion Our study on the SNAr reactions of 7 a–7 g with EtOM has allowed us to conclude the following:
Y-Substituted-phenoxide ion was liberated quantitatively and identified as one of the products by comparison of the UV/Vis spectra under the same kinetic conditions.
Acknowledgements 1) Alkali-metal ions catalyze or inhibit SNAr reactivity depending on the relative stabilization of the GS and TS complexes. 2) The SNAr reaction of 7 a is catalyzed by an 18C6-crowned K + ion but is inhibited by Li + , Na + , and K + ions in the order K + < Na + < Li + . Chem. Eur. J. 2014, 20, 13337 – 13344
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This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), and funded by the Ministry of Education (2012-R1 A1B-3001637). Grateful acknowledgment is also given to the Natural Sciences and Engineering Research Council of Canada (NSERC) for re-
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Full Paper search support and useful discussions on host-guest interactions with Prof. D. McCartney at Queen’s University (E.B.). Keywords: alkali metals · catalysis · inhibition · nucleofugality · SNAr reaction · Pi-complex [1] a) I. F. Barrera, C. I. Maxwell, A. A. Neverov, R. S. Brown, J. Org. Chem. 2012, 77, 4156 – 4160; b) R. S. Brown, Prog. Inorg. Chem. 2012, 57, 55 – 117; c) R. S. Brown, A. A. Neverov, Adv. Phys. Org. Chem. 2007, 42, 271 – 331. [2] a) G. K. Smith, Z. Ke, H. Guo, A. C. Hengge, J. Phys. Chem. B 2011, 115, 13713 – 13722; b) N. Mitic, K. S. Hadler, L. R. Gahan, A. C. Hengge, G. Schenk, J. Am. Chem. Soc. 2010, 132, 7049 – 7054; c) G. Feng, E. A. Tanifum, H. Adams, A. C. Hengge, J. Am. Chem. Soc. 2009, 131, 12771 – 12779; d) A. G. Davies, J. Chem. Res. 2008, 361 – 375; e) A. G. Davies, Perkin 1 2000, 1997 – 2010. [3] a) W. S. Chei, H. Ju, J. Suh, Bioorg. Med. Chem. Lett. 2012, 22, 1533 – 1537; b) W. S. Chei, H. Ju, J. Suh, J. Biol. Inorg. Chem. 2011, 16, 511 – 519; c) W. S. Chei, J. Suh, Prog. Inorg. Chem. 2007, 55, 79 – 142. [4] a) J. H. Lee, J. Park, M. S. Lah, J. Chin, J. I. Hong, Org. Lett. 2007, 9, 3729 – 3731; b) M. Livieri, F. Manicin, G. Saielli, J. Chin, U. Tonellato, Chem. Eur. J. 2007, 13, 2246 – 2256; c) N. H. Williams, B. Takasaki, M. Wall, J. Chin, Acc. Chem. Res. 1999, 32, 485 – 493. [5] a) T. H. Fife, L. Chauffe, Bioorg. Chem. 2000, 28, 357 – 373; b) T. H. Fife, R. Bembi, J. Am. Chem. Soc. 1993, 115, 11358 – 11363; c) T. H. Fife, M. P. Pujari, J. Am. Chem. Soc. 1990, 112, 5551 – 5557. [6] a) E. Buncel, E. J. Dunn, R. B. Bannard, J. G. Purdon, J. Chem. Soc. Chem. Commun. 1984, 162 – 163; b) E. J. Dunn, E. Buncel, Can. J. Chem. 1989, 67, 1440 – 1448. [7] I. H. Um, Y. H. Shin, J. E. Park, J. S. Kang, E. Buncel, Chem. Eur. J. 2012, 18, 961 – 968. [8] a) I. H. Um, S. E. Jeon, M. H. Baek, H. R. Park, Chem. Commun. 2003, 3016 – 3017; b) I. H. Um, Y. H. Shin, S. E. Lee, K. Y. Yang, E. Buncel, J. Org. Chem. 2008, 73, 923 – 930. [9] a) M. J. Pregel, E. J. Dunn, E. Buncel, J. Am. Chem. Soc. 1991, 113, 3545 – 3550; b) I. H. Um, J. S. Kang, Y. H. Shin; E. Buncel, J. Org. Chem. 2013, 78, 490 – 497; E. Buncel, J. Org. Chem. 2013, 78, 490 – 497. [10] a) D. W. Martin, P. A. Mayes, V. W. Rodwell, D. K. Granner, in Harper’s Review of Biochemistry, Lange Medical Publications, Los Altos, 1985, p. 630; b) H. Dugas, Bioorganic Chemistry, Springer, New York, 1989. p. 284. [11] G. Eisenman, Biophys. J. 1962, 2, 259 – 323. [12] a) J. F. Burnett, R. E. Zahler, Chem. Rev. 1951, 49, 273 – 412; b) J. F. Bunnett, J. Chem. Educ. 1974, 51, 312 – 315. [13] a) F. Terrier, Modern Nucleophilic Aromatic Substitutions; Wiley-VCH, Weinheim, 2013, Ch. 1; b) F. Terrier, Nucleophilic Aromatic Displacement: The Influence of the Nitro Group, (Ed.: H. Feuer), Organic Nitro Chem. Ser., VCH, Weinheim, 1991; c) E. Buncel, F. Terrier, J. M. Dust, Chem. Rev. 1995, 95, 2261 – 2280; d) F. Terrier, E. Magnier, E. Kizilian, C. Wakselman, E. Buncel, J. Am. Chem. Soc. 2005, 127, 5563 – 5571; e) N. El Guesmi, T. Boubaker, F. Goumont, F. Terrier, Org. Biomol. Chem. 2008, 6, 4041 – 4052.
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Received: June 17, 2014 Published online on August 29, 2014
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& Organic Synthesis
Alkali-Metal Ion Catalysis and Inhibition in SNAr Displacement: Relative Stabilization of Ground State and Transition State Determines Catalysis and Inhibition in SNAr Reactivity Ik-Hwan Um,*[a] Hyo-Jin Cho,[b] Min-Young Kim,[a] and Erwin Buncel*[c]
Abstract: We report here the first observation of alkali-metal ion catalysis and inhibition in SNAr reactions. The plot of kobsd versus [alkali-metal ethoxide] exhibits downward curvature for the reactions of 1-(4-nitrophenoxy)-2,4-dinitrobenzene with EtOLi, EtONa, and EtOK, but upward curvature for the corresponding reaction with EtOK in the presence of 18crown-6-ether (18C6). Dissection of kobsd into the secondorder rate constants for the reactions with the dissociated EtO and the ion-paired EtOM (i.e., kEtO and kEtOM, respectively) has revealed that the reactivity increases in the order EtOLi < EtONa < EtOK < EtO < EtOK/18C6. This indicates that the reaction is inhibited by Li + , Na + , and K + ions but is cata-
Introduction Metal ions (as Lewis acids) have often been reported to catalyze nucleophilic substitution reactions of esters bearing various electrophilic centers.[1–9] Since Lewis acidity increases with increasing charge density of metal ions, studies have focused mostly on reactions involving multivalent metal ions (e.g., La3 + , Eu3 + , Co3 + , Zn2 + , Cu2 + , etc.).[1–5] It is well known that alkalimetal ions are ubiquitous in nature and play important roles in biological processes (e.g., a Na + pump to maintain high K + and low Na + concentrations in mammalian cells).[10] Nevertheless, studies on alkali-metal ions have been sparingly carried out.[6–9] Our group has initiated a systematic study of nucleophilic substitution reactions of 4-nitrophenyl diphenylphosphinate (1, see Figure 1) with alkali-metal ethoxides (EtOM, M = Li, Na and K) in anhydrous ethanol.[6] This study has revealed that M + ions catalyze the reaction and the catalytic effect increases
lyzed by 18C6 K + ion. The reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes have been proposed to proceed through a stepwise mechanism, in which expulsion of the leaving group occurs after the rate-determining step based on the kinetic result that so constants exhibit a much better Hammett correlation than s constants. Alkali-metal ion catalysis or inhibition has been discussed in terms of differential stabilization of ground-state and transition-state complexes through a qualitative energy profile. A p-complexed transition-state structure is proposed to account for the kinetic results.
with decreasing size of M + ions, that is, K + < Na + < Li + .[6] However, the catalytic effect exerted by M + ions disappeared in the presence of complexing agents such as 18-crown-6 ether (18C6) for K + ion, 15-crown-5-ether (15C5) for Na + ion and [2,1,1]-cryptand for Li + ion.[6] In contrast, we have found that the corresponding reaction of 4-nitrophenyl diphenylphosphinothioate (2) is inhibited by Li + ion but is catalyzed by Na + and K + ions.[7] More interestingly, 18C6-crowned K + ion exhibited a stronger catalytic effect than Na + and K + ions, indicating that the M + ion effect is dependent on the nature of the electrophilic center (e.g., P=O vs. P=S).[7]
[a] Prof. I.-H. Um, M.-Y. Kim Department of Chemistry and Nano Science, Ewha Womans University Seoul 120-750 (Korea) E-mail: [email protected] [b] H.-J. Cho Department of Chemistry, Ducksung Women’s University Seoul 132-714 (Korea) [c] Prof. E. Buncel Department of Chemistry, Queen’s University Kingston, Ontario K7L 3N6 (Canada) Fax: (+ 1) 613-533-6669 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404004. Chem. Eur. J. 2014, 20, 13337 – 13344
Figure 1. Order of M + ion effects.
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Full Paper A similar result has been found for the alkaline ethanolysis of paraoxon and its methyl counterpart (3 a and 3 b) and parathion with its methyl analogue (4 a and 4 b), that is,1) the reaction of the P=O compounds (3 a and 3 b) is catalyzed by M + ions with a catalytic order K + < Na + < Li + ; 2) contrastingly, the reaction of the P=S compounds (4 a and 4 b, Figure 1) is inhibited by Na + and Li + ions but is catalyzed by K + ion; and 3) the reaction of the P=S compound 4 b is strongly catalyzed by 18C6-crowned K + ion.[8b] The contrasting M + ion effects were discussed on the basis of competing electrostatic effects and solvational requirements as a function of anionic electrophilic field strength and cationic size (Eisenman’s theory).[11] The effect of M + ions has also been investigated on two series of sulfonyl-transfer reactions, that is, alkaline ethanolyses of 2,4-dinitrophenyl X-substituted-benzenesulfonates (5 a–5 f) and Y-substituted-phenyl benzenesulfonates (6 a–6 k, Figure 1).[9] The reaction of 4-nitrophenyl benzenesulfonate (6 c) with EtOM was catalyzed by M + ions in the order K + > Na + > Li + .[9a] Furthermore, the catalytic effect exerted by K + ion increased linearly on changing the substituent X in the benzenesulfonyl moiety from a strong electron-withdrawing group (EWG) to an electron-donating group (EDG), but was independent of the electronic nature of the substituent Y in the leaving group.[9b] Thus, it has been concluded that the K + ion catalyzes the sulfonyl-transfer reaction by increasing electrophilicity of the reaction center through TSI rather than by enhancing nucleofugality of the leaving group via TSII.[9b] Nucleophilic reaction at a carbonyl center, as a model for the reactions shown in Figure 1, involves formation of an sp3-hybridized intermediate (or TS modeled such an intermediate). The process requires rehybridization from sp2 C=O carbon to sp3 (Scheme 1 A). Similarly, in SNAr displacements nucleophilic attack at substituted ring carbon results in the same rehybridization (Scheme 1B). Therefore, in principle, there is a bridge linking carbonyl displacements to P=O, P=S and O=S=O displacements and to SNAr reactions. Thus, our study has now been extended to the SNAr reaction of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (7 a–7 g) with EtOM (M = Li, Na, K, and K/18C6) as shown in Scheme 2 in order to obtain further information on the role of M + ions in-
Scheme 2. SNAr reaction of 7 a–7 g with EtOM.
cluding the reaction mechanism. Although numerous studies on SNAr reactions of activated aromatic or heteroaromatic compounds have been carried out,[12–17] the effect of M + ions on SNAr reactions has not been investigated systematically. We report in this paper that the reactions of 7 a–7 g with EtOM proceed through a stepwise mechanism in which expulsion of the leaving group occurs after the rate-determining step (RDS) and that M + ions behave as catalyst or inhibitor depending on the relative stabilization of the ground state (GS) and transition state (TS). The results are discussed in light of a possible novel p-complexed TS and by comparison with the systems given in Figure 1.
Results and Discussion The kinetic study was carried out spectrophotometrically under pseudo-first-order conditions in which the EtOM concentration was in large excess over the substrate concentration. All the reactions in this study obeyed pseudo-first-order kinetics and proceeded with quantitative liberation of Y-substituted-phenoxide ion. Pseudo-first-order rate constants (kobsd) were calculated from Equation (1). lnðA1 At Þ ¼ kobsd t þ C
ð1Þ
The uncertainty in the kobsd values was estimated to be less than 3 % from replicate runs. The second-order rate constants for the reactions with the dissociated EtO and ionpaired EtOM (i.e., kEtO and kEtOM, respectively) were calculated from the ion-pairing treatment of the kinetic data, and are summarized in Table 1 for the reactions of 1-(4-nitrophenoxy)2,4-dinitrobenzene (7 a) with EtOM (M = Li, Na, K, and K/18C6) and in Table 2 for the reactions of 1-(Y-substituted-phenoxy)2,4-dinitrobenzenes (7 a–7 g) with EtOK in the presence of 18C6. Detailed kinetic conditions and results (i.e., the kobsd data
Table 1. Summary of second-order rate constants (kEtO and kEtOM) calculated from ion-pairing treatment of the kinetic data for the reaction of 1(4-nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOM in anhydrous EtOH at (25.0 0.1) 8C.
Scheme 1. Chem. Eur. J. 2014, 20, 13337 – 13344
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EtOM
kEtOM [M1 s1]
kEtO [M1 s1]
kEtOM/kEtO
EtOLi EtONa EtOK EtOK/18C6
0.103 0.002 0.225 0.002 0.281 0.003 0.568 0.008
0.314 0.005 0.307 0.003 0.295 0.005 0.286 0.004
0.33 0.73 0.95 1.99
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Full Paper Table 2. Summary of second-order rate constants calculated from ionpairing treatment of the kinetic data for the reaction of 1-(Y-substitutedphenoxy)-2,4-dinitrobenzenes (7 a–7 g) with EtOK in the presence of 18C6 in anhydrous EtOH at (25.0 0.1) 8C.[a, b]
7a 7b 7c 7d 7e 7f 7g
Y
pK Ya -PhOH kEtOK/18C6 [M1 s1] kEtO [M1 s1]
4-NO2 4-CN 4-COCH3 3-Cl 4-Cl H 4-CH3
11.98 13.04 13.26 14.47 14.90 15.76 15.99
0.568 0.008 0.490 0.005 0.231 0.002 0.133 0.001 0.120 0.001 0.0311 0.0003 0.0233 0.0004
0.286 0.004 0.209 0.003 0.092 0.001 0.0470 0.0007 0.0380 0.0008 0.0092 0.0001 0.0062 0.0001
kEtOK/18C6/kEtO 1.99 2.34 2.51 2.83 3.16 3.38 3.76
[a] [18C6]/[EtOK] = 2.0. [b] The pKa data in anhydrous ethanol were taken from ref. [22].
as a function of [EtOM]) are summarized in Tables S1–S10 and in Figure S1–S6 in the Supporting Information (SI). Curvature of rate plots and role of M + ions As shown in Figure 2, the plots of kobsd versus [EtOM] for the reaction of 7 a with EtOM are not uniformly linear. Such curved
Figure 3. Effects of added A) LiSCN and B) 18C6 on reactivity of EtOK for the SNAr reaction of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOK in anhydrous EtOH at (25.0 0.1) 8C. [EtOK] = 30.2 mm.
with varying concentrations of LiSCN (Figure 3 A) and 18C6 (Figure 3 B). As shown in Figure 3 A, the kobsd value at [EtOK] = 30.2 mm decreases rapidly on addition of LiSCN up to [LiSCN]/[ EtOK] 6, indicating that Li + ion strongly inhibits the reaction. In contrast, the kobsd for the same reaction increases on addition of 18C6 up to [18C6]/[EtOK] 1, indicating that the reaction is catalyzed by 18C6-crowned K + ion.
Figure 2. Plots of kobsd versus [EtOM] for the SNAr reaction of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOK/18C6(~), EtOK(*), EtONa(*) and EtOLi(&) in anhydrous EtOH at 25.0 0.1 8C. [18C6]/[EtOK] = 2.0.
plots are typical for reactions of esters with EtOM, in which the M + ion behaves as a catalyst or an inhibitor depending on the type of the curvature. For example, the downward curvature for the reactions with EtOLi and EtONa indicates that Li + and Na + ions inhibit the reaction while the upward curvature for the reaction with EtOK in the presence of 18C6 demonstrates that the 18C6-crowned K + ion acts as a catalyst.[6–9] The catalytic effect exerted by 18C6-crowned K + ion is quite unusual, but was reported previously for the reactions of the P=S centered substrates 2 and 4 b (Figure 1).[8] To probe the above idea that the reaction is inhibited by Li + ion but is catalyzed by 18C6-crowned K + ion, the reaction of 7 a with EtOK at a fixed concentration has been carried out Chem. Eur. J. 2014, 20, 13337 – 13344
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Dissection of kobsd into kEtO and kEtOM To quantify the catalytic or inhibitory effect shown by M + ions, the kobsd values have been dissected into the second-order rate constants for the reactions with the dissociated EtO ion and ion-paired EtOM (i.e., kEtO and kEtOM, respectively). EtOM was reported to exist as dimers or higher order aggregates in highly concentrated solutions (e.g., [EtOM] > 0.1 m) but mainly as the dissociated and ion-paired species in low concentration range as used in the current study (e.g., [EtOM] < 0.1 m).[18] Since both the dissociated EtO and ion-paired EtOM would react with substrate 7 a, as shown in Scheme 3, one can derive a rate equation as in Equation (2).
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Scheme 3. Reactions of 7 a with the dissociated EtO and ion-paired EtOM.
Under pseudo-first-order kinetic conditions (i.e., [EtOM] @ [7 a]), kobsd can be expressed as Equation (3). Since the association constant K EtOM = [EtOM]eq/[EtO]eq[M+]eq, and [EtO]eq = [M + a ]eq at equilibrium, Equation (3) can be converted to Equation (4). The [EtO]eq and [EtOM]eq values can be calculated values for EtOM (i.e., K EtOM = 16.6, 90.1, from the reported K EtOM a a 1 102, and 212 m for EtOK/18C6, EtOK, EtONa and EtOLi, in turn)[19] and the initial concentration of EtOM using Equations (5) and (6). Rate ¼ kEtO ½EtO eq ½7 a þ kEtOM ½EtOMeq ½7 a
ð2Þ
kobsd ¼ kEtO ½EtO eq þ kEtOM ½EtOMeq
ð3Þ
kEtOM½EtO eq kobsd =½EtO eq ¼ kEtO þ K EtOM a
ð4Þ
½EtOM ¼ ½EtO eq þ ½EtOMeq
ð5Þ
½EtO eq ¼ ½1 þ ð1 þ 4 K EtOM ½EtOMÞ1=2 =2 K EtOM a a
ð6Þ
The plot of kobsd/[EtO]eq versus [EtO]eq should be linear if the reaction of 7 a with EtOM proceeds as proposed in Scheme 3. In fact, the plots shown in Figure 4 exhibit excellent linear correlations (R2 0.999). Furthermore, the intercepts of the linear plots are almost identical, regardless of the size of M + ions; this is consistent with the derived equations based on the reactions proposed in Scheme 3. Accordingly, the kEtO and K EtOM kEtOM values were determined from the intercept and a the slope of the linear plots, respectively. The kEtOM values were calculated from the above K EtOM kEtOM values and the reported a
values.[19] The kEtO and kEtOM values calculated in this way K EtOM a are summarized in Table 1 for the reactions of 7 a with EtOM and in Table 2 for the reactions of 7 a–7 g with EtOK in the presence of 18C6. As shown in Table 1, the kEtOM value for the reaction of 7 a increases in the order kEtOLi < kEtONa < kEtOK < kEtOK/18C6. The reactivity order observed in the current SNAr reaction is opposite to that reported previously for the corresponding reactions of the P= O centered electrophiles (e.g., 1, 3 a, and 3 b, Figure 1) but is similar to that reported for the reactions of the P=S centered electrophile (4 b).[6, 8] It is also shown that dissociated EtO is more reactive toward 7 a than the ion-paired EtOLi, EtONa, and EtOK, indicating that the current SNAr reaction is inhibited by M + ions (except 18C6-complexed K + ion). Importantly, the smallest ion, Li + , exhibits the strongest inhibition. This accounts for the result that kobsd decreases rapidly on addition of LiSCN, as shown in Figure 3 A, for the reaction mixture of 7 a and EtOK.
Comparison to computational study In a pertinent study, Jones et al. have recently carried out computations on SNAr reactions of mono-, di-, and triactivated fluorobenzenes (8) with alkali-metal cresolates (Scheme 4).[20] Their calculations using DFT methods have shown that M + ions
Scheme 4. SNAr reaction of fluorobenzenes with alkali-metal cresolates.
(M + = Li + , Na + , and K + ) complex the fluoride leaving group and facilitate expulsion of the leaving group as modeled by TSIII in Scheme 4.[20] However, their calculations revealed that presence of M + ions increases the barrier height due to formation of stable reactant complexes upon interaction with the fluorobenzenes.[20] They also found that the activation energy decreases as the size of M + ions increases, due to the fact that phenoxide becomes less distorted in the TS as the size of M + ions increases.[20] Our experimental results, shown in Table 1, appear to be consistent with the computational results reported by Jones et al., since M + ions (except 18C6-crowned K + ion) inhibit the reaction of 7 a and the inhibitory effect increases as the size of
Figure 4. Plots of kobsd/[EtO]eq versus [EtO]eq for the SNAr reaction of 1-(4nitrophenoxy)-2,4-dinitrobenzene (7 a) with EtOK/18C6(~), EtOK(*), EtONa(*) and EtOLi(&) in anhydrous EtOH at (25.0 0.1) 8C. Chem. Eur. J. 2014, 20, 13337 – 13344
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Full Paper M + ions decreases. On this basis, one can propose TSIV as a plausible TS structure for the current reaction of 7 a with EtOM. It is noted that TSIV is similar to TSIII suggested by Jones et al., except alkali-metal cresolates and fluoride in TSIII are replaced by alkali-metal ethoxides and 4-nitrophenoxide in TSIV, respectively. It is apparent that the M + ions in TSIII and TSIV could accelerate expulsion of the leaving groups (i.e., fluoride in TSIII and 4-nitrophenoxide in TSIV). However, the enhanced nucleofugality through TSIII or TSIV would not increase the overall reaction rate, if the reaction proceeds through a stepwise mechanism in which expulsion of the leaving group occurs after the RDS. In other words, in the RDS the nucleophile, EtOM here, attacks at the ring C bearing the 4-nitrophenoxyl leaving group, proceeding via TSIV to give the alkali-metal associated anionic s-adduct (Meisenheimer complex). This twostep mechanism is typical in SNAr reactions.[13a, 21] Effect of leaving-group substituents on reactivity To further elucidate the TS structure, rate constants for the reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (7 a– 7 g) with EtOK in the presence of 18C6 ([18C6]/[EtOK] = 2.0) have been measured. As shown in Table 2, the second-order rate constant for the reaction with EtOK in the presence of 18C6 (i.e., kEtOK/18C6) decreases as the substituent Y changes from a strong EWG to an EDG, for example, kEtOK/18C6 decreases from 0.566 to 0.133 and 0.0233 m1 s1, an approximately 25fold decrease in rate constant, as Y changes from 4-NO2 to 3-Cl and 4-CH3, in turn. A similar result is shown for the reaction with the dissociated EtO . However, the kEtO value is smaller than the kEtOK/18C6 value in all cases, indicating that the 18C6crowned K + ion catalyzes the reaction regardless of the electronic nature of the substituent Y. It is also notable that the catalytic effect shown by the 18C6-crowned K + ion (i.e., kEtOK/ 18C6/kEtO ratio) increases as the substituent Y changes from 4NO2 to 4-CH3. The effects of leaving-group basicity on the rate constants are illustrated in Figure 5. The Brønsted-type plots are linear with some scattered points (R2 = 0.962 0.972). Importantly, the bLg values are very small (e.g., 0.35 for the reaction with EtOK/18C6 and 0.41 for that with the dissociated EtO). Such small bLg values are typical for reactions reported previously to proceed through a stepwise mechanism in which expulsion of the leaving group occurs after the RDS (e.g., aminolysis of aryl benzoates, aryl phenyl carbonates, and related esters).[23–25] One can therefore suggest that the SNAr reaction in this case also proceeds through a stepwise mechanism in which expulsion of the leaving group occurs after RDS on the basis of the small bLg value. Note the implications for TSIV (vide supra). Hammett plots and reaction mechanism Hammett plots for the reactions of 7 a–7 g with EtOK in the presence of 18C6 have been constructed using so and s constants. If expulsion of the leaving group is involved in the RDS, a partial negative charge would develop on the O atom of the leaving group. Since such a negative charge can be delocalized Chem. Eur. J. 2014, 20, 13337 – 13344
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Figure 5. Brønsted-type plots for the reactions of 1-(Y-substituted-phenoxy)2,4-dinitrobenzenes (7 a–7 g) with A) the ion-paired EtOK/18C6 and B) dissociated EtO in anhydrous EtOH at (25.0 0.1) 8C.
to the substituent Y, one might expect that s constants would result in a much better Hammett correlation than so constants. In contrast, if expulsion of the leaving group occurs after the RDS, no negative charge would develop on the O atom of the leaving group. In this case, so constants would result in a better correlation than s constants. In fact, as shown in Figure 6 for the reactions of 7 a–7 g with the dissociated EtO , the Hammett plot using so constants results in an excellent linear correlation (R2 = 0.995). In contrast, the corresponding plot constructed with s constants is linear but exhibits highly scattered points (R2 = 0.975). A similar result is shown in Figure S7 (Supporting Information) for the corresponding reactions with EtOK/18C6. The fact that so constants result in a better Hammett correlation than s constants is a clear indication that no negative charge develops on the O atom of the leaving group in the rate-determining TS. Therefore, one can conclude that the reactions of 7 a–7 g proceed through a stepwise mechanism in which expulsion of the leaving group occurs after RDS. This idea can be further supported by the fact that the EtO ion is much more basic and is, therefore, a poorer nucleofuge than all the Y-substituted-phenoxide ions used in this study.
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Full Paper (HSAB) principle.[26] This idea is consistent with the kinetic result that the reaction of 7 a is catalyzed by a 18C6-crowned K + ion but is strongly inhibited by a Li + ion (Table 1). The TS structure modeled by TSV also accounts for the fact that the catalytic effect shown by 18C6-crowned K + ion (i.e., the kEtOK/ 18C6/kEtO ratio) decreases as the substituent Y in the leaving group becomes a stronger EWG (Table 2). Changing the substituent Y from 4-CH3 to 4-NO2 would reduce the interaction between the p-electrons and 18C6-crowned K + ions in the TS by diminishing the p-electron density. As we have shown, the TS for catalysis of the aromatic displacement involves complexation of the alkali-metal ions (or 18C6-crowned K + ion) with the delocalized p-system (TSV). It is well known that transition metals form stable p-adducts with such delocalized systems (e.g., ferrocene, uranocene, etc.).[27] To the best of our knowledge, this is the first indication that a similar complex with alkali-metal ions or an 18C6-crowned K + ion, albeit as a model TSV, takes part in nucleophilic aromatic substitution. Thus, the role of alkali-metal ions in catalysis is expanded by their interaction not only with single nucleophilic or leaving group centers[20] but also with p-systems in rate-determining TSs. GS and TS stabilization by M + ions
Figure 6. Hammett plots correlated with A) so and B) s constants for the reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (7 a–7 g) with dissociated EtO in anhydrous EtOH at (25.0 0.1) 8C.
TS structure and role of M + ions Since expulsion of the leaving group has been shown to occur after the RDS for the current SNAr reactions, the reactivity of 7 a–7 g toward EtOM would not be governed by nucleofugality of the leaving group. Accordingly, the enhanced nucleofugality afforded by the putative TSIV cannot be the origin of the catalysis shown by the 18C6-crowned K + ion in the current SNAr system. We propose that the SNAr reaction with EtOM in this study proceeds through a stepwise mechanism via a p-complexed TS as modeled by TSV (crown-ether omitted for clarity, Scheme 5). One might expect that the polarizable p-electrons in the benzene ring of TSV would interact strongly with the large 18C6-crowned K + ion but not with a small M + ion (e.g., Li + ion) on the basis of the hard and soft acids and bases
Scheme 5. SNAr reaction of 7 a–7 g with EtOM. Chem. Eur. J. 2014, 20, 13337 – 13344
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M + ion catalysis and inhibition found in the current reactions of 7 a with EtOM can be expressed generally, by Figure 7. In both types of processes, the reaction pathway follows initial complex formation by the reactants, followed by formation of the rate-determining TS and product formation. The relative magnitude of the GS stabilization term (dGGS) and the TS stabilization term (dGTS) determines catalysis or inhibition, that is, dGTS > dGGS corresponds to catalysis and dGGS > dGTS to inhibition.
Figure 7. Qualitative free energies involved in the uncatalyzed and M + ioncatalyzed reactions of 7 a with EtOM. DGu and DGc are the activation energies for the uncatalyzed and catalyzed reactions, respectively, while dGGS and dGTS refer respectively to stabilization of GS and TS by an M + ion.
Since no evidence for complexation of M + ions with the substrate 7 a in the GS has been found in the current or previous studies, GS stabilization would be achieved mainly through ion-pairing between M + and EtO ions. Differential stabilization of TS and GS can be evaluated using a method developed 13342
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Scheme 6. Reactions of 7 a with dissociated EtO and ion-paired EtOM.
by Kurz[28] and in different forms by Mandolini[29] and Tee.[30] Scheme 6 describes a set of equilibria among the reactants and TSs for the catalyzed and uncatalyzed pathways. In Scheme 6, Ku and Kc represent the equilibrium constants for formation of the uncatalyzed and catalyzed TSs, while K EtOM a + and K TS a are the association constants for ion-pairing of M TS with EtO and the TS, respectively. K a can be calculated from EtOM kEtOM/kEtO together with the rethe relationship,[31] K TS a = Ka [13] EtOM ported K a values and the respective rate constants. K EtOM a and K TS a can also be expressed in terms of free energies of stabilization by an M + ion, i.e., dGGS and dGTS, respectively. The dGGS and dGTS values determined for the current reactions are summarized in Table 3. The dGGS value is more nega-
Table 3. Free energies of stabilization of ground state (dGGS) and transition state (dGTS) for the reactions of 7 a with EtOM in anhydrous EtOH at (25.0 0.1) 8C. M+
dGGS [kcal mol1]
dGTS [kcal mol1]
Li + Na + K+ 18C6-K +
3.16 2.73 2.65 1.66
2.50 2.55 2.63 2.06
tive than the dGTS value for the reactions of 7a with EtOLi, EtONa, and EtOK, indicating that the GS stabilization through ion-pairing of EtOM is more significant than the TS stabilization through the p-complexed TSV. This is consistent with the kinetic results that Li + , Na + , and K + ions act as inhibitors. In contrast, the dGGS value is less negative than the dGTS value for the reaction with EtOK/18C6, indicating that the TS stabilization through TSV is more significant than the GS stabilization provided by ion-pairing of EtOK/18C6. This is in accord with the HSAB principle,[26] since the large 18C6-crowned K + ion would interact strongly with the polarizable p-electrons in the TS but weakly with the hard EtO ion in the GS.
3) Brønsted-type plots for the reactions of 7 a–7 g with EtOK/ 18C6 are linear with bLg = 0.35 0.41, indicating that expulsion of the leaving group is not advanced in the rate-determining TS. 4) The fact that so constants result in a better Hammett correlation than s constants is clear indication that expulsion of the leaving group occurs after the RDS. 5) 18C6-Crowned K + ion catalyzes the reaction by stabilizing the TS through the p-complex (i.e., TSV as the novel TS in this study). 6) Li + ion inhibits the SNAr reaction, since it forms a strong ion-pair with EtO in the GS but interacts weakly with the polarizable p-electrons of the aromatic ring in TSV.
Experimental Section Materials 1-(Y-Substituted-phenoxy)-2,4-dinitrobenzenes (7 a–7 g) were readily prepared from the reaction of 1-fluoro-2,4-dinitrobenzene with the respective Y-substituted phenol under the presence of triethylamine in anhydrous ether as reported previously.[17] The crude products were purified by column chromatography and the purity was checked by their melting points and spectral data such as 1 H NMR spectra. Other chemicals were of the highest quality available. The solutions of EtOM were prepared by dissolving the respective alkali metal in anhydrous ethanol under N2 and stored in the refrigerator. The concentrations of EtOM were determined by titration with standard HCl solution. 18-Crown-6-ether was recrystallized from acetonitrile and dried over P2O5 in vacuo. The anhydrous ethanol was further dried over magnesium and distilled under N2 just before use.
Kinetics Kinetic study was performed using a UV/Vis spectrophotometer equipped with a constant-temperature circulating bath. The reactions were followed by monitoring the appearance of Y-substituted-phenoxide ion at a fixed wavelength corresponding to the maximum absorption (lmax, e.g., 400 nm for 4-nitrophenoxide ion). Pseudo-first-order conditions with EtOM at least 20 times greater than substrate concentration were used. Generally, reactions were followed for 9–10 half-lives and kobsd were calculated using the equation, ln (A1 At) vs. t. The conditions and the kobsd values are summarized in Tables S1 – S10 in the Supporting Information (SI).
Product analysis
Conclusion Our study on the SNAr reactions of 7 a–7 g with EtOM has allowed us to conclude the following:
Y-Substituted-phenoxide ion was liberated quantitatively and identified as one of the products by comparison of the UV/Vis spectra under the same kinetic conditions.
Acknowledgements 1) Alkali-metal ions catalyze or inhibit SNAr reactivity depending on the relative stabilization of the GS and TS complexes. 2) The SNAr reaction of 7 a is catalyzed by an 18C6-crowned K + ion but is inhibited by Li + , Na + , and K + ions in the order K + < Na + < Li + . Chem. Eur. J. 2014, 20, 13337 – 13344
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This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), and funded by the Ministry of Education (2012-R1 A1B-3001637). Grateful acknowledgment is also given to the Natural Sciences and Engineering Research Council of Canada (NSERC) for re-
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Received: June 17, 2014 Published online on August 29, 2014
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