Chemoselective Nucleophilic Fluorination Induced by Selective

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J. Phys. Chem. B 2007, 111, 1752-1758

Chemoselective Nucleophilic Fluorination Induced by Selective Solvation of the SN2 Transition State Josefredo R. Pliego, Jr.* and Dorila Pilo´ -Veloso* Departamento de Quı´mica, UniVersidade Federal de Minas Gerais 31270-901, Belo Horizonte, MG, Brazil ReceiVed: October 6, 2006; In Final Form: December 1, 2006

Reaction of the fluoride ion with secondary alkyl halides leads to 90% of elimination reaction and only 10% of nucleophilic substitution in dipolar aprotic solvents. Adding water to the organic phase, the SN2 yield increases in the cost of decreased reactivity. Using ab initio calculations, we have shown that it is possible to increase the reaction rate and the selectivity toward the SN2 process through supramolecular organocatalysis. The catalytic concept is based on selective solvation of the transition state through two hydrogen bonds provided by the 1,4-benzenedimethanol. The two hydrogen bonds between the catalyst and the SN2 transition state favor this pathway while just one strong hydrogen bond between the catalyst and the fluoride ion leads to a lower stabilization of the nucleophile, resulting in a higher reaction rate. Our calculations predict that the substitution product increases to 40% yield because of the selective catalysis provided by the 1,4benzenedimethanol.

Introduction

SCHEME 1

Synthesis of organofluorine compounds has increased spectacularly in recent decades because of interesting and technologically useful properties obtained through introducing fluorine into organic molecules.1-5 Demand for organofluorine species has induced a noticeable development in new reagents and catalysts aimed to perform efficient and selective fluorination,6-19 and important advances have been achieved through both nucleophilic and electrophilic fluorination (Scheme 1). Nevertheless, one of the most obvious and economically viable methods, nucleophilic fluorination of alkyl halides or sulfonate esters using alkaline fluorides salts, remains as a highly utilized procedure. Indeed, direct attachment of fluorine to organic molecules via nucleophilic displacement of halide ions utilizing KF requires inexpensive and readily available reagents. Nucleophilic fluorination is usually carried out in dipolar aprotic solvents or in apolar solvents using a phase-transfer catalyst such as tetraalkylamonium cations or crown ethers. Nevertheless, fluoride ion is not only a reactive nucleophile. Gas-phase studies show that it is a powerful base,20-22 and a common side reaction of the interesting SN2 pathway is the bimolecular elimination reaction.8,14,23,24 In the liquid phase, this E2 process becomes the most important pathway when secondary alkyl halides are used and makes the SN2 process very inefficient. Thus, the search for new media, catalysts, or procedures aimed to induce chemoselective fluorination is highly desirable. In fact, emerging reaction media such as ionic liquids have also been recently studied for conducting nucleophilic fluorination but the same problem of low selectivity has also been reported.25,26 Performing the reaction under high pressure is another investigated procedure and although improved SN2 yields have been obtained, the process is not sufficiently selective.27 A new approach for catalyzing organic reactions, where purely organic molecules are utilized as catalysts,28-58 has * E-mail: [email protected] (J.P.), [email protected] (D.P-V.).

emerged in recent years. Among these molecules, hydrogen bond based organocatalysts are specially attractive for controlling ionic reactions in aprotic solvents.59-61 In this way, considering the important role that selective nucleophilic fluorination could have in the efficient and environmental friendly preparation of organofluorine compounds, we have theoretically investigated the catalysis of SN2 and E2 reactions through selective solvation of the transition state by two hydrogen bonds (Figure 1), a new concept proposed by Pliego in a recent report.61 In this approach, two hydrogen bonds between the catalyst and the center of charge of the SN2 transition state lead to rate acceleration and selectivity of the nucleophilic displacement process. The aim of the present paper is to show, via ab initio calculations, that this supramolecular organocatalytic concept can selectively induce nucleophilic fluorination. In fact, theoretical calculations are becoming powerful tools for understanding the reaction mechanism and designing new organocatalysts.62-69 The Role of Hydrogen Bond in Nucleophilic Fluorination Fluoride ion is a very reactive species in the gas phase. Because it is a small ion with high charge/volume ratio, its solubilization in aprotic solvents is very difficult, and even in highly polar aprotic solvents like dimethyl sulfoxide (DMSO), the solubility of alkaline fluoride salts is limited. Phase-transfer catalysis is an usual procedure undertaken to solubilize fluoride salts. Liotta and Harris18 have reported the use of crown ethers for solubilizing KF in acetonitrile and benzene solutions. The naked fluoride ion was utilized for nucleophilic displacement of alkyl halides. They observed that for 2-bromooctane, a high

10.1021/jp066580p CCC: $37.00 © 2007 American Chemical Society Published on Web 02/01/2007

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J. Phys. Chem. B, Vol. 111, No. 7, 2007 1753

Figure 2. Model for the hydrated fluoride ion reaction.

SCHEME 2

Figure 1. Selective solvation of the SN2 transition state.

proportion (68%) of elimination occurred, against just 8% for 1-bromooctane. Later, Cox et al.17 prepared anhydrous tetrabutylammonium fluoride, which has about 0.1-0.3 equiv of water, and conducted its reaction with 2-bromooctane without solvent. In this case, an even higher proportion (90%) of elimination reaction took place. For the 1-bromooctane, the proportion of organic fluoride was only 48%. The other products were 1-octene and 1-octanol. Very recently, Sun and DiMagno8 were able to obtain true anhydrous tetrabutylammonium fluoride in polar aprotic solvents. For the reaction with 1-bromooctane in tetrahydrofuran, although the reaction time was short and the process was conducted at room temperature, the proportion of 1-fluorooctane product was not higher than 50%. Thus, these studies show that the free fluoride ion is very reactive and has low selectivity, promoting both SN2 and E2 reactions. The competition with E2 process is much more important for secondary halides, and this fact restricts the applicability of the nucleophilic fluorination. Elimination reactions become more important in less solvating media. If a cluster of the fluoride ion with some water molecules could be generated in an aprotic solvent, the proportion of the SN2 pathway would increase while the fluoride ion reactivity would be considerably dropped. Indeed, Landini et al.16 have studied the reactivity of hexyl4N+F-‚nH2O with n-octyl methanesulfonate in chlorobenzene, for n ranging from 0.0 to 8.5. They have observed that the fluoride reactivity decreases for a factor as large as 103 with the increased hydration. On this condition, F-(H2O)n clusters should be present in solution because of strong fluoride-water interaction energy.70,71 Thus, although the fluoride ion becomes much less reactive, water molecules hydrating the fluoride ion have an important effect of inducing a greater proportion of SN2 process versus E2, as reported by Albanese et al.11 They have shown that by reacting Bu4N+F-‚nH2O with 1-bromooctane in acetonitrile or without solvent, the proportion of SN2 reaction increases with the n value. Therefore, on this condition, the reaction must proceed through a hydrated transition state as presented in Figure 2. The reaction involving the F-(H2O)n clusters with 1-bromooctane in acetonitrile is much more selective toward the SN2 process, reaching 91% yield for n ) 5, but the reaction requires 2 h at 80 °C. In addition, the hydrated fluoride ion is not sufficiently selective in the case of the reaction of the 2-bromooctane, where only 30-40% of the reaction takes place

through the SN2 pathway. New advances in selective nucleophilic fluorination are desirable. In this way, the new supramolecular organocatalytic concept proposed by Pliego,61 where the catalyst is able to selectively make two hydrogen bonds with the SN2 transition state, could be an interesting strategy for selectively accelerating the SN2 pathway.59,60 In a previous study, this selectivity was observed for the acetate ion plus ethyl chloride reaction,61 where the 1,4-benzenedimethanol organocatalyst has favored the SN2 pathway for 0.8 kcal/mol in relation to E2 in DMSO solvent. Considering that such an effect should be present in the SN2 reaction involving fluoride ion, in this paper the action of the 1,4-benzenedimethanol for inducing nucleophilic fluorination was investigated. The model system is the fluoride ion reacting with the 2-chlorobutane in the DMSO solvent (Scheme 2). There are four possible reaction channels: the SN2 pathway, leading to the 2-fluorobutane plus chloride ion (1), and three pathways through E2 reactions, generating trans-2-butene (2t), cis-2-butene (2c), and 1-butene (3), as well as the chloride ion plus hydrogen fluoride. All of these pathways were investigated using high-level theoretical calculations. Ab Initio Calculations The potential energy surface for the reaction of the fluoride ion with 2-chlorobutane, including or not including the interaction with the 1,4-benzenedimethanol, was investigated using density functional theory at B3LYP/6-31+G(d) level. Full optimization was done and the stationary points were characterized by harmonic frequency calculations. To obtain accurate energies, single-point energy calculations were performed using the ONIOM method.72-75 In this approach, the model system is treated in high level of theory, while the real system is treated in a lower level. For the model system, constituting fluoride ion plus 2-chlorobutane, the calculations were done at MP2/6311+G(2df,2p) and CCSD(T)/6-31+G(d) levels to obtain effective CCSD(T)/6-311+G(2df,2p) energies through additivity approximation. The real system was treated at MP2/6-31+G(d) level of theory. Thus, our energy calculation can be named as ONIOM[CCSD(T)/6-311+G(2df,2p):MP2/6-31+G(d)].

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Pliego and Pilo´-Veloso TABLE 1: Activation and Reaction Thermodynamic Properties Calculated for the Fluoride Ion Plus 2-Chlorobutane Reactiona Activation transition state

TS1

TS2c

TS2t

TS3

MP2/6-31+G(d) MP2/6-311+G(2df,2p) CCSD(T)/6-31+G(d) CCSD(T)/6-311+G(2df,2p)b ∆Hgqc ∆Ggqc ∆∆Gsolvqd ∆Gsolqe

-5.37 -8.81 -8.99 -12.43 -12.76 -7.81 28.15 20.34

-4.38 -10.23 -5.67 -11.52 -14.70 -10.23 30.42 20.19

-5.32 -11.30 -6.57 -12.55 -15.87 -11.38 30.56 19.18

-3.21 -9.72 -4.65 -11.17 -14.64 -10.26 30.65 20.39

1

2c

2t

3

-29.31 -33.21 -32.00 -35.89 -35.32 -35.23 19.22 -16.00

-7.99 -16.99 -10.68 -19.69 -22.87 -31.15 16.80 -14.35

-9.50 -18.11 -12.18 -20.79 -24.08 -32.01 16.84 -15.17

-7.04 -15.56 -9.85 -18.37 -21.49 -29.35 16.70 -12.65

Reaction MP2/6-31+G(d) MP2/6-311+G(2df,2p) CCSD(T)/6-31+G(d) CCSD(T)/6-311+G(2df,2p)b ∆Hgc ∆Ggc ∆∆Gsolvd ∆Gsole

Figure 3. Transition states for fluoride ion reaction with 2-chlorobutane.

The solvent effect was included through the polarizable continuum model76-81 (PCM) with the Pliego and Riveros parametrization,82,83 adequate for describing solvation in DMSO solution. The atomic radii are C(1.70), H(1.20), O(1.50), Cl(1.81), and F(1.40), and the applied scale factor is 1.35 for every atom. We have used the HF/6-31+G(d) wave function and the integral equation formalism77,78,84 routines for the PCM calculations available in the Gamess program system. Recent studies of pKa calculation85 and activation free-energy barriers for ionic SN2 reactions86,87 support the high reliability of this method for reactions in the DMSO solvent. All of the energy single-point calculations and PCM computations were done with the Gamess program,88 while the geometry optimization was performed with the Gaussian 98 package.89 The reaction and activation free energies were rigorously calculated using statistical mechanics and transition-state theory.90-98 A point which deserves attention is the role of liquid-phase optimization. Recent studies93 have suggested that the solvent effect (water solution) on the geometries of anionic SN2 reactions is usually small and that the effect on the energy is also minor. In the present study, the DMSO solvent should have even a less important effect. Reaction of the Fluoride Ion with 2-Chlorobutane The transition states for the reaction pathways studied in this work (see Scheme 2) are presented in Figure 3. The activation and reaction thermodynamic properties are available in Table 1. The TS1 structure corresponds to the SN2 pathway, leading to the formation of the 2-fluorobutane. Its energy in relation to free reactants is sensible to the level of theory and goes from -5.37 kcal/mol at MP2/6-31+G(d) level to -12.43 kcal/mol at the CCSD(T)/6-311+G(2df,2p) level. The gas-phase ∆Ggq is calculated to be -7.81 kcal mol-1. Because of high solvation of the fluoride ion in relation to TS1, the DMSO solvent induces a free-energy barrier of 28.15 kcal mol-1, resulting in a solutionphase ∆Gsolq ) 20.34 kcal mol-1. This relatively low activation barrier is compatible with the high reactivity of the fluoride

a Geometry optimization at B3LYP/6-31+G(d) level of theory. Standard state of 1 mol/L, units of kcal/mol. b Obtained by additivity approximation. c Gas-phase values. d Solvent contribution obtained at PCM/HF/6-31+G(d) level (DMSO). e Solution value (DMSO).

ion in dipolar aprotic solvent. Our previous studies86,87 of the SN2 reactions involving CH3COO- and CN- ions with ethyl chloride in DMSO solution suggest that our calculations overestimate the real barrier by 2 kcal/mol. The other three pathways are bimolecular eliminations. The TS2c structure, corresponding to the 2c pathway in Scheme 2, produces the cis-2-butene, while the TS2t structure leads to formation of the trans-2-butene. The TS3 structure corresponds to the 1-butene formation. Similarly to the SN2 process, the energy of these E2 transition states are sensible to the level of theory. The better level, CCSD(T)/6-311+G(2df,2p) calculation, predicts energies of -11.52, -12.55, and -11.17 kcal/mol, respectively, which are close to the energy of the SN2 process. The corresponding gas-phase ∆Ggq values, -10.23, -11.38, and -10.26 kcal/mol, respectively, are more negative than the free energy of the SN2 transition state. These results indicate that fluoride ion plus secondary alkyl chloride reactions are dominated by elimination reactions in low polarity solvents. When the DMSO solvent is included, we can notice that the freeenergy barrier induced by the solvent (∆∆Gsolvq) is around 30.5 kcal/mol for the E2 processes, which can be compared to 28.15 kcal/mol for the SN2 pathway. The final solution-phase ∆Gsolq barrier for TS2c, TS2t, and TS3 are 20.19, 19.18, and 20.39 kcal/mol, respectively. For both the SN2 and E2 pathways, the reaction free energies in solution are negative, ranging from -12 to -16 kcal/mol (Table 1). It should be observed that while for the nucleophilic displacement process the corresponding reaction energy is less sensible to the level of theory, the E2 process is more sensible, changing around 10 kcal/mol when going from MP2/6-31+ G(d) level to CCSD(T)/6-311+G(2df,2p) level. Comparison with Experimental Data. On the basis of our calculations, it is evident that more solvating media favors SN2 reactions versus E2, an experimentally observed effect. In this way, the fluorination reaction barrier becomes close to the elimination pathway in the DMSO solvent, resulting in the formation of the 2-fluorobutane and the alkenes. Using the theoretical ∆Gsolq and the transition-state theory, the rate

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TABLE 2: Product Ratio in the Fluoride Ion Plus 2-Chlorobutane Reaction 1 ka % product/theor

10

% (SN2 × E2)/theor % (SN2 × E2)/exptb % (SN2 × E2)/exptc

10 10 32

% alkenes/theor % alkenes/exptd

2c

2t

3

7.6 × 10-3 9.8 × 10-3 5.4 × 10-2 7.0 × 10-3 12

69

9

90 90 68 14 23

76 61

10 16

a Theoretical rate constants, DMSO, 25 °C. Units of L mol-1 s-1. Reaction of anhydrous TBAF with 2-bromooctane without solvent, 25 °C (ref 17). c Reaction of KF/(18-crown-6) with 2-bromooctane in benzene at 90 °C (ref 18). d Reaction of TBAF with 2-chlorobutane in dimethylformamide at 50 °C (ref 24).

b

constants and the product ratio for each species were calculated, which are presented in Table 2. The calculations predict that only 10% of the reaction lead to the fluorination, while the remaining 90% corresponds to the alkene mixtures. This result is in good agreement with experimental measureds17,18 for a related system, 2-bromooctane, where the fluorination takes place in a proportion ranging from 10% to 32%. Nevertheless, it is interesting to analyze such a wide range of values. Cox et al.17 have investigated the reaction of the “anhydrous” TBAF with 2-bromooctane without solvent, and they have found that the fluorination takes place in a proportion of only 10%. Liotta and Harris18 have used 18-crown-6 ether to solubilize KF in benzene solution, and the reaction with 2-bromooctane has produced 2-fluorooctane in a proportion of 32%. In the first case, about twice the amount of TBAF was used in relation to 2-bromooctane, suggesting that the fluoride ion is the reactant. Indeed, it must be observed that the elimination reaction generates HF, which interacts with the fluoride ion forming the HF2- species. Therefore, because the fluoride ion is more reactive than the HF2- species, the reaction involving the former species would predominate, leading to a small proportion of 2-fluorooctane. On the other hand, in the Liotta and Harris experiment, the crown ether is used to solubilize the KF salt in benzene, generating the fluoride ion. However, its concentration reaches only 0.05 mol/L (1 mol/L crown ether concentration). Therefore, as long as the reaction takes place, the HF2- species will be formed and the proportion of the fluoride ion will decrease. As a consequence, a large part of the reaction may take place with the HF2- species rather than with the F- ion, explaining the different product ratio experimentally observed. In addition, another event which contributes to this different behavior is the reaction temperature. While Cox et al.17 have performed the experiments at room temperature, Liotta and Harris18 have carried out the reaction at 90 °C, which decreases the selectivity of the competing SN2 and E2 reactions and produces more 2-fluorooctane. Thus, both the temperature and the HF2- species formation may explain the different observations. In this way, our analysis suggests that the naked fluoride ion reacts with 2-bromooctane in an aprotic solvent and at room temperature leading to only 10% of fluorination, in very good agreement with our theoretical calculations on a similar system. The prediction of the alkenes ratio is in Table 2. The general rules establish that the most substituted alkene is favored, as well as the trans-alkene in relation to cis-alkene. Our calculations are in agreement with this view, and we have predicted that the trans-2-butene is formed in a proportion of 76%, while the cis-2-butene and 1-butene are in the proportion of 14% and 10%, respectively. For comparison, the experimental data24 for the reaction of the tetrabutylammonium fluoride with 2-chlo-

Figure 4. Catalyst-fluoride complex and complexed transition states for fluoride ion reaction with 2-chlorobutane.

robutane has indicated a proportion of 61%, 23%, and 16%, respectively. Therefore, our theoretical values are in excellent agreement with the experimental observations, indicating the high reliability of our calculations. In this way, we are confident about predictions done in the next section on the product ratio in the catalyzed process. Organocatalyzed Reaction of the Fluoride Ion with 2-Chlorobutane Catalyst-Fluoride Complex. The interaction of the fluoride ion with the 1,4-benzenedimethanol (BDM) organocatalyst leads to the formation of a strong ion-molecule complex (Cat‚‚‚F-) presented in Figure 4. In this species, the fluoride ion has one hydrogen bond with the hydroxilic hydrogen and another with the aromatic hydrogen. Because fluoride is a small and chargeconcentrated species, it is not able to interact simultaneously with the two hydroxilic groups like the acetate61 and cyanide59 ions do. Nevertheless, its interaction energy is very high, 38.5 kcal/mol at MP2/6-31+G(d) level (Table 3), resulting in a gasphase free energy (1 mol/L standard state) of -32.8 kcal/mol for the complex formation. This value can be compared with the ∆Gg of Cat‚‚‚CH3COO- and Cat‚‚‚CN- complexes, -20.2 and -16.9 kcal/mol, respectively, indicating that the Cat‚‚‚Fcomplex has a much higher stability. In the liquid phase, the DMSO solvent considerably decreases the Cat‚‚‚F- complex stabilization, increasing its free energy by 29.4 kcal/mol in relation to the free species. The final complexation ∆G in

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Pliego and Pilo´-Veloso

TABLE 3: Thermodynamic Properties of the Transition States and Catalyst-Fluoride Complex of the System Fluoride Ion Plus 2-Chlorobutane Reaction Catalyzed by 1,4-Benzenedimethanola transition state/complex

CatF-

MP2/6-31+G(d) -38.46 ONIOMb ∆Hgc -38.69 ∆Ggc -32.75 ∆∆Gsolvd 29.44 ∆Gsole -3.31 ∆Gsolqf kg % product

TS1-cat TS2c-cat TS2t-cat TS3-cat -39.18 -46.45 -44.96 -29.90 43.19 13.28

-35.58 -42.99 -44.31 -29.45 43.21 13.76

-36.64 -44.21 -45.63 -29.95 43.24 13.28

-33.73 -42.01 -43.50 -28.05 43.34 15.28

16.59 4.3 40

17.07 1.9 18

16.59 4.3 40

18.59 0.15 2

a Geometry optimization at B3LYP/6-31+G(d) level of theory. Standard state of 1 mol/L, units of kcal/mol. Free reactants taken as the reference. b Calculation at ONIOM [CCSD(T)/6-311+G(2df,2p): MP2/6-31+G(d)] level (see text). c Gas-phase values. d Solvent contribution obtained at PCM/HF/6-31+G(d) level (DMSO). e Solution value (DMSO). f Activation free energy taking the catalyst-fluoride complex and the 2-chlorobutane as the reactants. g Bimolecular rate constant for catalyst-fluoride complex plus 2-chlorobutane reaction. Units of L mol-1 s-1.

solution is -3.3 kcal/mol. Thus, in the presence of the BDM in the DMSO solvent, the fluoride ion will be complexed. Catalyzed SN2 Pathway. We have located eight transition states for the fluoride ion reaction with 2-chlorobutane complexed with the BDM supramolecular organocatalyst. Each pathway in Scheme 2 has two complexed transition states, but we will consider only the most stable structure for each pathway, which is presented in Figure 4. The respective activation thermodynamic properties for these species are shown in Table 3. The TS1-cat structure corresponds to the catalyzed SN2 pathway, and we can notice that there is an adequate interaction via hydrogen bond between the BDM and the TS1. The complexation produces a small variation in the TS1 geometry but the interaction energy is very high, 34 kcal/mol at ONIOM[CCSD(T)/6-311+G(2df,2p):MP2/6-31+G(d)] level of theory. In free-energy terms, the TS1 is stabilized by 22.1 kcal/mol in the gas phase. It is interesting to notice that although in the TS1-cat structure there are two hydrogen bonds involving hydroxilic groups, the interaction energy is smaller than for the Cat‚‚‚F- species. An explanation for this observation is that the fluoride in the TS1 structure has a considerable charge transfer, reducing the interaction energy. When the solvent is taken into account, it induces a barrier of 43.2 kcal/mol, resulting in the free-energy barrier of 13.3 kcal/mol in relation to free reactants. This value is a substantial drop in the barrier for the uncatalyzed process, 20.3 kcal/mol. However, because the fluoride ion will be complexed with the BDM catalyst, the Cat‚‚‚F- complex plus 2-chlorobutane are the true reactants. Table 3 shows the free-energy barriers for the catalyzed processes considering the Cat‚‚‚F- complex as the reactant, instead of the free fluoride ion. For the SN2 pathway (TS1-cat), the ∆Gsolq is calculated to be 16.6 kcal/mol, which is 3.7 kcal/mol more negative than the uncatalyzed process. Therefore, our calculations predict that the SN2 reaction rate in the DMSO solvent will increase by a factor of 500 because of the action of the BDM. Catalyzed E2 Pathways. The BDM is also able to complex with the E2 transition states. Because of steric reasons, it should be expected that the TS2c structure would be more stabilized than the TS2t. Our calculations confirm this idea, predicting that the energy of the TS2c-cat structure is 31.5 kcal/mol more stable than the TS2c plus BDM in the gas phase. For the TS2t-

cat, the stabilization energy is 30.4 kcal/mol, while the TS3 is stabilized by 30.8 kcal/mol. These values can be compared with the TS1-cat stabilization energy, 34 kcal/mol. Thus, our conjecture that the BDM should favor the SN2 process has an energetic support. When we analyze the gas-phase stabilization ∆G, the values are 19.2, 18.6, and 17.8 kcal/mol, respectively. The solvent effect is very close for SN2 and E2 pathways, inducing a barrier of 43 kcal/mol. As a consequence, the BDM species determines the product ratio. The final free-energy barriers in solution, considering the Cat‚‚‚F- complex, have dropped by 1.9 to 3.1 kcal/mol and are in the range of 16.618.6 kcal/mol. In addition, although the trans-2-butene remains as the main alkene product, there is a greater proportion of cis2-butene and a substantial reduction of the 1-butene. Competition between SN2 and E2 Pathways. There are important changes in the ∆Gsolq for the catalyzed SN2 and E2 pathways that can be observed in Tables 1 and 3. While our calculations predict that the E2 pathways dominate the uncatalyzed process, generating 90% of the products, the catalyzed pathway reduces the total E2 yield to 60%. In this way, the SN2 process goes from poor 10% yield in the uncatalyzed process to moderate 40% yield in the catalyzed pathway. This is a very important result because differently from other procedures aimed to increase the SN2 product ratio, where the increased yield is followed by slower reaction rate, our calculations predict that the total reaction rate (SN2 + E2) is even increased by a factor of 100. Thus, the 1,4-benzenedimethanol in DMSO solution is able to accelerate the fluoride ion plus alkyl halide reaction rate with substantial higher SN2 yield. Role of the Solvent on Catalysis. The catalytic effect of the BDM depends on its interaction with the transition state and the solvent effect. In the case of the uncatalyzed SN2 reaction in the DMSO solvent, the solvent-induced barrier is 28.2 kcal/ mol. For the catalyzed process, the solvent effect is the difference between the solvent contribution to the TS1-cat structure formation (43.2 kcal/mol) and the Cat‚‚‚F- complex formation (29.4 kcal/mol), resulting in a value of 13.8 kcal/ mol. Thus, the solvent effect is much more positive for the uncatalyzed process. As a consequence, if the reaction is performed in a low polarity aprotic solvent like tetrahydrofuran or toluene, the barrier for the uncatalyzed process will drop considerably, while the barrier for the catalyzed pathway will decrease slowly. In this situation, the catalyzed reaction could become slower than the uncatalyzed. Nevertheless, if the 1,4benzenedimethanol is used in excess, all of the fluoride ion will be complexed and the reaction will take place through the complexed transition states. This procedure ensures that the 1,4benzenedimethanol takes the control of the reaction. To do a quantitative analysis of the role of different solvents, let us consider that the solvation free energy for each species can be written in terms of a λ parameter, defined by

∆Gsolv(λ) ) λ ∆Gsolv(DMSO) Therefore, for the DMSO solvent, the solvation free energy of any species can be obtained making λ ) 1. For less solvating medium, λ < 1, and for more solvating medium, λ > 1. Using these values of the solvation free energy in the calculation of the activation barrier for the SN2 reaction, we can draw the graphic shown in Figure 5. It can be noticed that there is a window where the catalyzed reaction dominates (0.73 < λ < 1.47). For less solvating medium (lower λ), the free fluoride ion becomes more reactive. However, in this case, the freeenergy barrier is very low and this loss of reactivity is not a

Chemoselective Nucleophilic Fluorination

Figure 5. Activation free-energy barrier for the SN2 process as a function of the solvation free energy.

problem. The reaction controlled by the 1,4-benzenedimethanol remains quick and selective while the free fluoride ion should produce an even greater proportion of the E2 products. Similarly, more solvating media like protic solvents should eliminate the catalytic activity. We can also notice that for λ ) 1.11, there is a change in the inclination. It occurs because in this point, the fluoride-catalyst complex has a positive formation free energy and the solvent effect for the direct catalyzed reaction becomes more important. Conclusion Reaction of the fluoride ion with a secondary alkyl chloride in a dipolar aprotic solvent leads to both SN2 (minor product) and E2 (major product) pathways. Our calculations are able to predict very accurately this experimental observation using 2-chloro-butane as the model. We have also explored the role of 1,4-benzenedimethanol on the product outcome of this reaction. Our ab initio calculations predict that this new catalytic concept based on the formation of selective two hydrogen bonds between the 1,4-benzenedimethanol and the SN2 transition state has an important effect on the product ratio. The catalyst is able to induce an important chemoselectivity in the reaction of the fluoride ion with secondary alkyl chlorides, decreasing the elimination products. In addition, the overall reaction rate is increased by a factor of 102 in the DMSO solvent, and even in low polarity solvents, the catalyzed reaction remains selective and fast. Therefore, the new concept explored in this work seems very promising for controlling ionic reactions in aprotic solvents. Acknowledgment. The authors thank the Brazilian Research Council (CNPq) for the support. References and Notes (1) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (2) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Boca Raton, FL, 2004. (3) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2003, 104, 1. (4) Mann, J. Chem. Soc. ReV. 1987, 16, 381. (5) Welch, J. T. Tetrahedron 1987, 43, 3123. (6) Sun, H. R.; DiMagno, S. G. Angew. Chem., Int. Ed. 2006, 45, 2720. (7) Rozen, S. Acc. Chem. Res. 2005, 38, 803. (8) Sun, H. R.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050. (9) Ma, J.; Cahard, D. Chem. ReV. 2004, 104, 6119. (10) Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett. 2004, 6, 1465. (11) Albanese, D.; Landini, D.; Penso, M. J. Org. Chem. 1998, 63, 9587. (12) Moughamir, K.; Atmani, A.; Mestdagh, H.; Rolando, C.; Francesch, C. Tetrahedron Lett. 1998, 39, 7305. (13) Pilcher, A. S.; Ammon, H. L.; Deshong, P. J. Am. Chem. Soc. 1995, 117, 5166. (14) Wilkinson, J. A. Chem. ReV. 1992, 92, 505.

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