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Dividing a Complex Reaction Involving a Hypervalent Iodine Reagent into Three Limiting Mechanisms by Ab Initio Molecular Dynamics €thi,*[a] Antonio Togni,[a] Marcella Iannuzzi,[b] and Ju €rg Hutter[b] Oliver Sala,[a] Hans Peter Lu The electrophilic N-trifluoromethylation of MeCN with a hypervalent iodine reagent to form a nitrilium ion, that is rapidly trapped by an azole nucleophile, is thought to occur via reductive elimination (RE). A recent study showed that, depending on the solvent representation, the SN2 is favoured to a different extent over the RE. However, there is a discriminative solvent effect present, which calls for a statistical mechanics approach to fully account for the entropic contributions. In this study, we perform metadynamic simulations for two trifluoromethylation reactions (with N- and S-nucleophiles), showing that the RE mechanism is always favoured in MeCN solution. These computations also indicate that a radical
mechanism (single electron transfer) may play an important role. The computational protocol based on accelerated molecular dynamics for the exploration of the free energy surface is transferable and will be applied to similar reactions to investigate other electrophiles on the reagent. Based on the activation parameters determined, this approach also gives insight into the mechanistic details of the trifluoromethylation and shows that these commonly known mechanisms mark the limits within C 2015 Wiley Periodicals, Inc. which the reaction proceeds. V
Introduction
calculations—were shown to work in favour of the RE mechanism. The observation that an increasing level of sophistication of the solvent goes in parallel with a decreasing dominance of the SN2 mechanism, makes a fully explicit representation of the solvent indispensable to determine which mechanism is ultimately favored. To account for the entropic contributions to the solvent effect, namely electrostriction and dielectric saturation, the solvent (MeCN) is treated explicitly by means of ab initio molecular dynamics (AIMD) in condensed phase. Electrostriction describes the local density change of the solvent in the vicinity of the solute, that is, the change of the radius of the solute’s cavity. The orientational ordering of the polar solvent molecules, induced by the solute dipole, is expressed by the dielectric saturation.[9] In apolar solvents, these two effects have a farther reaching impact on the solvation shell(s) than in polar solvents, which are already electrostricted. To investigate the reaction mechanisms we use ab initio metadynamics. This method allows the reconstruction of the underlying free energy surface (FES) as a function of a few, properly selected, collective variables (CVs).[10,11]. To describe the generalized nucleophilic substitution (SN2 as well as SN1;
Over the years, trifluoromethylation has emerged to be an important reaction, as trifluoromethylated compounds became increasingly attractive, in particular for medicinal chemistry.[1] In general, fluorine-containing species are among other aspects more difficult to oxidize and, hence, more stable under metabolic conditions. In addition, the lipophilicity is increased. Trifluoromethylated compounds can be obtained by reaction with 3,3-dimethyl-1-(trifluoromethyl)-1k3,2-benziodoxol (unprotonated 1) through electrophilic transfer of the CF3 group bound to the hypervalent iodine reagent (a k3-iodane) to a vast array of nucleophiles, such as C-, O-, P-, N-, and S-centered ones.[2] In this study, the focus is on the reaction of acetonitrile (MeCN) and thiophenol (PhSH) (4) acting as N- and S-nucleophile, respectively (Fig. 1). The electronic and structural properties leading to the distinct reactivity of reagent 1 have been the topic of earlier studies.[4–7] The trifluoromethylation reaction with reagent 1 is assumed to occur via a reductive elimination (RE)[7,8] of the electrophilic CF3 ligand and the nucleophile coordinated to the iodine atom. However, contrary to expectations, RE was shown to be challenged by an SN2 mechanism on the basis of stationary computations in the gas phase.[5,6] Furthermore, a recent study has shown that the solvent effect reduces the gap between the activation energies (DDG‡) significantly, but that, depending on the solvent representation, the SN2 reaction mechanism is still favoured over RE.[4] The difference in activation energies DDG‡ (DG‡RE 2 DG‡SN 2 ) amounts to roughly 15 kcal mol21 in the gas phase and to as little as 2 kcal mol21 in condensed phase (MeCN), depending on the solvent model. The entropic contributions to the solvent effect—within the limits of stationary
DOI: 10.1002/jcc.23857
[a] O. Sala, H. P. L€ uthi, A. Togni ETH Zurich, Laboratorium f€ ur Physikalische Chemie, Vladimir–Prelog–Weg 2, 8093, Zurich, Switzerland E-mail: [email protected] [b] M. Iannuzzi, J€ urg Hutter University of Zurich, Department of Chemistry, Winterthurerstrasse 190, 8057, Zurich, Switzerland Contract grant sponsor: Swiss National Science Foundation; Contract grant number: 200020-146230 and 200020-137712 C 2015 Wiley Periodicals, Inc. V
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Figure 1. These trifluoromethylation reaction pathways are investigated in this study. The reactive intermediate 2 and the trifluoromethyl phenyl thioether 7, obtained by the two reactions, are the main products. The first step (1 ! 2) in the formation of 9 represents the rate-determining step. Therefore, the reactive intermediate 2, which is essential in a newly discovered Ritter-type reaction, is the species of interest.[3]
leftmost reaction pathway in Fig. 2), two CVs are chosen: the interatomic distance between the nucleophile and the electrophile and the interatomic distance between the electrophile and the nucleofuge. As for the RE mechanism (Fig. 2, middle reaction pathway) coordination of the nucleophile to the reagent 1 is crucial, an additional CV is introduced, describing the coordination number (cn) of the nucleophile to the electrondeficient iodine atom. To extend the scope of nucleophiles we further consider thiophenol 4, or its deprotonated form 6, in the same solvent. Experiments have indicated that the trifluoromethylation of Snucleophiles most likely occurs via single electron transfer (SET).[12,13] The possibility of an SET mechanism is explored also for the trifluoromethylation of MeCN. Unlike the product of the first step of MeCN-trifluoromethylation, 2, phenyl trifluoromethyl thioether (7) does not represent a reactive intermediate. In this study, the solvent effect on three limiting reaction mechanisms is investigated. First, the two polar reaction mechanisms (SN and RE) are evaluated for the trifluoromethylation of MeCN in MeCN (solvolysis) by reagent 1 [reaction (1), Fig. 1]. The trifluoromethylation by reagent 1 of thiophenol and thiophenolate, 4 and 6, is studied subsequently [reactions (2) and (3), Fig. 1]. Much of the focus will be on the contribution of entropy, the activation parameters (including the free energy, enthalpy, entropy, and volume of activation) and the structure of the transition states (TSs). The evaluation of the entropy and volume of activation can be used to determine whether the SN mechanism is unimolecular or bimolecular. In addition, the two polar mechanisms are investigated for the reaction yielding 2 and 3, but with model reagent 10. The free energies of activation are compared to the ones obtained by stationary calculations using continuum solvent models. Finally, we will also explore radical (SET) mechanisms for which experimental evidence was found.[12]
Computational Details All simulations are based on density functional theory electronic structure calculations based on the generalized gradient 786
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Figure 2. The three mechanisms shown define the boundaries of the possible reaction pathways (i.e., limiting mechanisms) for the electrophilic trifluoromethylation of nucleophile 11 by means of reagent 1, all leading to the same products 3 and 20. Coordination of 11 to the k3-iodane 1 (resulting in k4-iodane 14) precedes the elimination of product 20 and the formation of the reduced iodoalcohol 3. In contrast to the RE mechanism, no coordination of 11 to the iodine atom of 1 is required for the nucleophilic substitution (SN) to reach the transition state TS-13. The SN mechanism can proceed unimolecularly or bimolecularly. In the former case the I–CF3 bond is first cleaved (see structure 12), followed by the attack of 11 to the cationic CF3-group. This process occurs concertedly in the latter case (bimolecular) forming the new Nu–CF3 bond while breaking the I–CF3 bond (TS13). During the SET mechanism, 11 reduces 1 by one electron (SET-16), yielding radical cation 17 and the neutral radical species 18. Through homolytic I–CF3 bond cleavage the CF3 radical 19 is formed, which recombines with 17 to yield the products 20 and 3.
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approximation, specifically with the BLYP[14,15] functional. The Kohn–Sham[16] (KS) equations are solved according to the Gaussian and plane wave (GPW) formalism[17] as implemented in the CP2K program package.[18–20] The GPW uses Goedecker–Teter–Hutter pseudo potentials[21] to describe the interactions between core and valence electrons, while the valence electron density is represented in terms of Gaussian type orbital (GTO) basis set functions. In particular, we use molecularly optimized (MOLOP)[17] basis sets. The auxiliary PW basis set, which is needed for the efficient solution of the Poisson’s equation in reciprocal space, is truncated at 500 Ry. For the exploration of the SET mechanism, spin polarized KS is used to allow configurations with unpaired electrons. Relaxing the multiplicity constraint (S 5 0 for the initial state) will make spin flips possible. (See Supporting Information section 6.) The solution is modelled by a cubic simulation cell with periodic boundary conditions. The simulation box contains between 40 and 60 solvent molecules, in a volume that corresponds to the solvent density at the simulation temperature. Initial equilibration runs are carried out at constant volume. However, to allow volume fluctuations when reactions occur, AIMD simulations at variable volume are needed, which is achieved by coupling the simulation cell to a barostat. As we are dealing with an isotropic system, only isotropic volume changes are permitted. The temperature of the system is always controlled by a thermostat,[22–24] to keep it around 300 K. For all Born–Oppenheimer AIMD simulations, we use a time step of 0.5 fs. Metadynamic simulations are used to accelerate the exploration of the FES.[10,11] The typical procedure consists of a first equilibration AIMD of the solvent in the canonical ensemble (constant volume and temperature) for a simulation time of 50–100 ps. The substrate(s) is then introduced in the simulation cell by replacing some of the solvent molecules. After the exchange, a further equilibration is needed for another 50–120 ps, where the volume is also equilibrated to obtain the equilibrium density of the solution (constant pressure, constant temperature ensemble). The metadynamic simulation is started from the equilibrated structure of the solution, by properly selecting two or three CVs. The choice of CVs is not always trivial, as they need to describe the reaction mechanism of interest, distinguishing the different stages of the process and possible intermediates. Ideally, they should also be able to describe alternative processes. However, in this work we prefer to select CVs that specifically address only one type of mechanism at a time, in order to be able to separately investigate all the proposed mechanisms and to compare them. The specific choices of CVs for the different metadynamic simulations reported here are discussed in the respective sections of the results. Details on the preliminary studies needed to determine the optimal choice of CVs are reported in the Supporting Information section 4. In general, the metadynamic simulations are extended until the FES is properly explored, that is, after several recrossing of the transition regions are observed. However, in certain cases the process is observed only once, as a very stable intermediate is reached and the selected CVs are not adequate to describe a further development to other products or back to
reactants. In these circumstances, if the reaction mechanisms of interest has been properly sampled, the metadynamic simulation is interrupted once no more relevant structural changes are observed. The estimate of the underlying FES is directly determined from the spawned metadynamic potential along the sampling. The resulting FES is defined in the reduced space of the CVs and it is a direct measurement of the probability distribution of the states of the system in this space. The visualisation and interpretation of multidimensional probability distributions require some care in order not to discard important information. One common procedure is to identify possible minimum energy pathways on the FES and study the mechanism along these pathways. For our analysis, we did obtain estimates of enthalpic and entropic contributions to the free energy along the identified minimal energy pathways (MEPs) by post processing. In particular, we selected a set of sample configurations along the pathway. Each configuration is obtained by setting the corresponding values to the CVs as determined from the FES. These configurations are used as starting structure for constrained molecular dynamic simulations, where the constraints keep the values of the CVs fixed. Each of these runs, of about 35 ps, provides a sampling of the system state at the specific point on the FES and therefore an evaluation of the corresponding enthalpic contribution. The entropic term is then obtained by difference. The volume of activation characterizing a TS structure was obtained by calculation of the difference between the average volume of the simulation cell in the initial minimum state, and the average volume of the system at the TS. The first average volume is easily obtained by an equilibration of the initial state (substrates in the solvent) without any constraints. The volume at the TS is obtained from a simulation where selected coordinates of the substrates are constrained in order to preserve the TS structure. Obviously, both simulations are performed at constant pressure to allow volume equilibration. For the investigation of the solvent effect applying stationary quantum chemical calculations using polarizable continuum (PCM) based solvent models for these same reactions, we refer to our previous work.[4]
Results and Discussion The summary of results obtained for the ab initio metadynamic simulations of the trifluoromethylation of MeCN and PhSH presented in Table 1 shows that RE is favoured over the SN mechanism. This observation is in line with the results of the static quantum chemical calculations, which indicate that the solvent effect will favour the RE mechanism.[4] The simulations also show the emergence of a radical mechanism, comparable to the RE in terms of the reaction barrier heights and stereochemical outcome. The details of the metadynamic simulations of the two polar mechanisms (RE, SN) for the trifluoromethylation of MeCN [reaction (1) in Fig. 1] and of thiophenol [reaction (2) & (3)] are thoroughly discussed with particular attention on TS structures and the activation parameters (e.g. entropy of activation (DS‡), Journal of Computational Chemistry 2015, 36, 785–794
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Table 1. Overview of all reactions investigated in this study with the corresponding free energies of activation DF‡ in kcal mol21, the simulation temperature, and the sets of CVs used. Reaction
Mechanism
N-nucleophile (MeCN) 1 !2 SN 1 !2 RE 1 !2 SET 10 !2 SN 10 !2 RE S-nucleophile (PhSH or PhS--) 1 !7 via 5 SN2 1 !7 via 5 RE 1 !7 via 5 non-conc. RE 1 !7 using 6 RE
DF‡
T/K
CV 1
31.4 20.1 19.9 24.9 16.6
220 300 350 300 300
rCF3 2I rCF3 2I rCF3 2I rCF3 2I rCF3 2I
CV 2
CV 3
rNprox 2CF3 [a] – rNprox 2CF3 cn(N,I)[b] rNprox 2CF3 – rNprox 2CF3 – rNprox 2CF3 cn (N,I)
17.6 250 rCF3 2I 15.7 250 rCF3 2I 15.5 250 rCF3 2I
rS2CF3 rS2CF3 rS2CF3
cn(S,I) – –
15.0 193 rCF3 2I
rS2CF3
cn (S,I)
[a] Interatomic distance between the nitrogen atom of the acetonitrile and the CF3-carbon, where “prox” stands for proximal. [b] Coordination of MeCN to the hypervalent iodine atom.
DV‡ ). Finally, the trifluoromethylation of MeCN following an SET mechanism is investigated, also in view of the high probability of a radical mechanism involving S-nucleophiles. Further details, e.g. the free energies of reaction DRF, are listed in the Supporting Information section 3. N-Trifluoromethylation of MeCN in MeCN as Solvent To clearly distinguish between the two competing polar mechanisms for the trifluoromethylation of MeCN in MeCN solvent, RE and SN, we performed two independent metadynamic simulations: the SN mechanism can be followed in the phase space defined by the CF3-carbon–iodine interatomic distance (rCF3 2I ) and by the interatomic distance between the nitrogen atom of the acetonitrile and the CF3-carbon (rNprox 2CF3 , where “prox” stands for proximal). The proper description of the RE mechanism requires the introduction of an additional variable, namely the coordination of MeCN to the hypervalent iodine atom (cn(N,I)). Preliminary studies revealed that this coordinate is important prior to reaching the RE TS. The coordination number[25] is defined as: " #21 X rN2I nn rN2I nd 12 12 cnðN; IÞ5 r0 r0 N ˚ , nn 5 10 and nd 5 16. After obtaining the where r0 5 3 A reactive intermediate 2 along the metadynamics trajectory, the set of CVs might not be suitable anymore for recrossing events (see Supporting Information section 2 for more details). The solvent is represented by 39 MeCN molecules in a cubic cell ˚ length. with 16.7 A Figure 3 shows the two resulting FESs for the SN (left side) and the RE (right) together with the corresponding contour plot maps (from top to bottom) as a function of the first two CVs only. Transition State Structure and Energy The simulations show that the RE mechanism is favoured over the SN pathway by as much as 11.3 kcal mol21 (DDF‡) (Table 788
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1). This is also evident by comparing the two contour plots of the FESs (panels C and F in Fig. 3), showing the two different MEPs connecting the well of substrates with the well of products. The TS marks the point of highest energy on the MEP of this exergonic reaction. The TS region, that is, the area around the maximum on the MEP (Fig. 3 panels C & F) for the SN mechanism is characterized by an rCF3 2I much larger than rN2CF3 pointing to a (rather) late TS geometry, resembling the products more than the substrates. In contrast, the RE TS occurs rather early, being structurally more similar to the substrates (Fig. 4). The lower energy TS observed for the RE is in line with the Hammond postulate, which states that the structure of the RE TS is thus closer to the substrates. As expected for ionogenic reactions, entropy effects, in particular dielectric saturation and electrostriction,[26] contribute significantly to the free energy of activation DF‡. These effects can be quantitatively assessed by the activation entropy DS‡ and by the activation volume DV‡, which takes into account environmental volume changes arising from solute–solvent interactions (electrostriction) as well as structural volume changes from the bond-forming and -breaking processes. The difference in enthalpies of activation DDU‡ between the two polar mechanisms (RE and SN) amounts to 25.0 kcal mol21 (Table 2). Entropy and Volume of Activation The difference between the entropies of activation D(TDS‡) amounts to 16.3 kcal mol21 (or DDS‡ 5 124.2 e.u.) in favour of the RE mechanism (e.u.: entropy units, cal mol21 K21). The positive entropy of activation for the RE (112.0 e.u., Table 2) points to a unimolecular reaction mechanism with a (rather) loose TS. A large and negative entropy of activation would be indicative of a tight TS, as observed in a bimolecular reaction mechanism. From this perspective, no clear statement can be made for the SN with respect to the molecularity (DS‡SN 5212.2 e.u.). It appears that the TS can be viewed as a combination of both, uni- and bimolecular. In Figure 5, the evolution of the entropy DS from the substrates to the TS region is shown for both polar mechanisms. For the SN mechanism (panel A, Fig. 5) the entropy DS evolves between 237 and 212 e.u. along the MEP from the substrates to the TS. Note that the DS ordinate is not scaled with the temperature, that is, higher amplitudes are obtained. In the TS region DS‡ is negative (212.2 e.u., Table 2). Thus, it is difficult to make any clear statements, other than that the molecularity must lie between uni- and bimolecular. For the RE pathway (panel B) DS remains negative until, by approaching the RE TS region, it turns positive (112.0 e.u., Table 2), pointing at a unimolecular mechanism. Contrary to the SN mechanism, an entropy gain is observed for the RE by reaching the TS region. Therefore, the RE TS is less rigid than the SN TS. Given the large difference in the volumes of activation (DDV‡ 5 2114 cm3 mol21), the change in mechanism is a logical consequence (SN1/SN2 $ RE). The large and positive DV‡ of the nucleophilic substitution (SN) mechanism (1189 cm3 mol21) points WWW.CHEMISTRYVIEWS.COM
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Figure 3. The FESs of the SN (panels A–C) and the RE (panels D–F) are shown. Panel A) displays the FES with the contour map. The MEP in red connects the substrate with the product well. Panel B) shows the contour plot with the MEP and the TS marked as X. The energy scale is in kcal mol21. The isoenergy contours increment correspond to 3 kcal mol21. Panel C) is a magnification of the TS region with an isoenergy contours increment corresponding to 2 kcal mol21. Panel D) shows the FES together with the contour map as a function of the CVs 1 and 2 in Table 1. In panel E) the contour plot is shown with the MEP and the TS marked with X. The isoenergy contours increment correspond to 3 kcal mol21. Panel F) is a magnification of the TS region (isoenergy contours increment: 2 kcal mol21). Note the different location of the TS compared to panel C.
clearly at a unimolecular mechanism (SN1), confirming the findings from the entropy of activation (Table 2). Therefore, the ratedetermining step in the SN1 is the IACF3 bond cleavage, giving rise to a cationic CF3-group, which interacts more strongly with the (polar) solvent than during RE. This larger solvent effect (in general) is expressed by the larger volume of activation for the SN1 mechanism compared to RE (1189 vs. 175 cm3 mol21, respectively). To put the DV‡ values in relation, the group contribution to the Van der Waals volume is reported to be 21.3 for the ACF3 group, 19.6 for the iodine atom (AI) and 13.7 cm3 mol21 for the methyl group (ACH3).[27,28]
The formation of an intermediate in a unimolecular mechanism goes along with additional creation of (highly) localized charges, which leads to an enhanced solute–solvent interaction, and thus to higher electrostriction. Clearly, these effects are more pronounced in the SN1 mechanism (compared to the RE), which is expressed by both the lower entropy of activation and the higher volume of activation. The probability of encountering a solvated, free CF3 cation is higher for the SN mechanism, as seen in Figure 3 (panel B). Therefore, both mechanisms (SN and RE) are unimolecular in 1 and the RE TS charge is distributed more uniformly, conversely leading to a Journal of Computational Chemistry 2015, 36, 785–794
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Figure 4. Left side: The structure of the SN2/SN1 TS is shown, which corresponds to the maximum on the MEP on the FES in Figure 3 (B,C, crosses). Note ˚ larger than rCF3 2N and that the I–C–N geometry does not need to be necessarily colinearly. Right side: A trithat the interatomic distance rCF3 2I is by 0.7 A angular I–C–N geometry is obtained for the RE-TS structure (compare TS-15 in Fig. 2). Additionally, one MeCN solvent is coordinated to the iodine atom (its nitrogen atom is marked orange).
stronger solvent effect for the SN1 mechanism. This solvent effect is known to be more pronounced in apolar solvents, where the effect of electrostriction is larger, in contrast to already electrostricted polar solvents. In summary, the difference in the free energy of activation DDF‡ (211.3 kcal mol21) in favour of RE is enhanced by entropy, as DDU‡ amounts to 25.0 kcal mol21. Concerning the entropy of activation, particularly DDS‡, these findings are qualitatively in line with the estimation of entropies obtained by means of the cluster-continuum model (as described by Riveros and coworkers).[4,29]
simultaneously establish hydrogen-bonding to the OH-group and coordination to the iodine atom. In gas phase, the progress of coordination, starting at the free energy minimum with nearly no coordination (cn(N,I) 5
Coordination of MeCN to the Reagent: Entropic Considerations The electron-deficient iodine atom in reagent 1 allows for multiple coordination of ligands.[4] To explore the development of the entropy in the coordination process that leads to the RE TS (Fig. 2: 1 ! 14), we selected the coordination number cn(N,I) and the potential energy U as CVs. This approach, introduced by Milet et al., [30] allows to directly obtain an estimate of the entropic contribution. We compare a simulation of the solvated system with a simulation in gas phase with just two ligands. These allow to Table 2. Activation parameters[a] for the two polar reaction mechanisms depicted in Figure 2. Mechanism
DF‡
DU‡
DS‡
DV‡
Molecularity
1 !2
SN1/SN2
131.4
128.7
212.2
1189
1 !2
RE
120.1
123.7
112.0
175
Unimolecular/ bimolecular Unimolecular
25.0
124.2
2114
Reaction
DDX‡
211.3
[a] DF and DU in kcal mol DV ‡ in cm3 mol21
790
21
‡
, DS in entropy units (e.u.) cal mol21 K21,
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Figure 5. Panel A shows the thermodynamic state functions for the SN mechanism (panel B for the RE): The black line corresponds to the free energy DF along the MEP from the substrates to the TS as obtained from the FES (Fig. 3), projected on the rCF3 2I coordinate (CV). The red line is the enthalpy DU. Plotting the difference between DF and DU results in the entropy DS in e.u. (cal mol21 K21, scale on the right).
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Figure 6. Panel A, gas phase: The FES of the coordination process of the two available MeCN to the iodine atom of reagent 1 is shown as a function of the two CVs, cn(N,I) and enthalpy U. The blue line corresponds to the MEP starting from the free energy minimum towards higher coordination numbers. In the inlet, the evolution of the free energy F and enthalpy U along the MEP are opposed, showing the loss of entropy towards higher coordination number. Panel B, solvated system: The coordination behaviour of MeCN to the iodine atom of 1 in solution is shown here. For both panels, the isoenergy contours increment correspond to 1 kcal mol21.
0.25) to the coordination of one MeCN within a distance of 3 ˚ (cn(N,I) 5 1), is entropically disfavoured by DS 5 2191 e.u. A (Fig. 6, panel A). Further coordination (to cn(N,I) 5 1.6) leads to DS 5 2273 e.u. or TDS 5260 kcal mol21. Obviously, the increase in free energy upon coordination is lead by the loss in entropy, overcompensating the enthalpic stabilization of 228 kcal mol21. In the solvated system, the coordination number of cn(N,I) 5 0.7 represents the minimum on the FES. However, escaping the shallow region between cn(N,I) 5 0.4 and 1.6 leads to a significant increase of the free energy (Fig. 6, panel B). In solution, relative to gas phase, the coordination process necessary for an RE mechanism becomes entropically less unfavourable, because of the larger number of configurations having higher coordination. Thus, the statistical probability of such a state increases.
assume that the SN mechanism is more appropriately described as rather unimolecular also in this case. In gas phase, the SN2 reaction mechanism is dominant over the RE, as shown by stationary quantum chemical calculations (e.g., B3LYP/aug-cc-pVDZ-pp).[4–6] The metadynamic
Comparison to the Static Calculations (Applying the Model Reagent 10) The validity of model reagent 10 (Fig. 2) replacing 1 was confirmed in an earlier study.[4] Using 10 as trifluoromethylation reagent for MeCN, the two polar reaction mechanisms are investigated, again in MeCN solution. The same sets of CVs were applied for the metadynamic simulations as for the SN1 and the RE with reagent 1 (see Table 1). As in the case of the trifluoromethylation of MeCN with reagent 1, RE is favoured over SN1 by as much as 8.3 kcal mol21 using reagent 10 (Table 3). In absolute terms, both reaction barriers are lower, meaning that, with 10 as reagent, the reaction would proceed more quickly. The TS region of the RE mechanism on the FES is the same as by applying reagent 1. However, for the SN1 pathway the TS region is located towards shorter interatomic distances (by approximatively 0.5 A˚) (Fig. 7). Following the argumentation for the nucleophilic substitution reaction involving reagent 1, and given the similarity (electronically and geometrically) between model reagent 10 and 1, we strongly
Figure 7. FES contour maps obtained from metadynamics for SN1 (upper panel) and RE. The red lines represent the MEP calculated on the resulting FES. The isoenergy contours increment correspond to 3 kcal mol21.
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Table 3. Comparison between the free energies of activation DF‡ and reaction DRF in kcal mol21 for the trifluoromethylation of MeCN in MeCN with reagent 10 applying metadynamics and two PCM-based representations of the solvent in stationary quantum chemistry. Mechanism
DF‡
SN2
RE
DDF‡
DRF
T/K
Method[a]
24.9
245
300
Metadynamics
25.1
215.7
298
37.1
215.7
298
IEF-PCM B3LYP/ aug-cc-pVDZ CC B3LYP/ aug-cc-pVDZ Metadynamics
16.6
28.3
292
300
34.1
9.0
215.7
298
40.8
3.7
215.7
298
IEF-PCM B3LYP/ aug-cc-pVDZ CC B3LYP/aug-cc-pVDZ
This work [4] [4] This work [4] [4]
[a] CC: Cluster-continuum with 3 MeCN. Details in the lit. [4], using also M06-2X, BP86, and MP2.
simulations, instead, suggest that the SN becomes unfavourable in MeCN solution. This observation can be attributed to entropic effects (vide supra), which are not fully accounted for in stationary calculations. The necessity for an explicit representation of the solvent by AIMD to properly account for the entropic contributions, which discriminate clearly between the two mechanisms, is therefore essential. S-Trifluoromethylation of Thiophenol in MeCN as Solvent Trifluoromethylation of thiopenol (4) or thiophenolate (6) yields thioether 7 as a stable product, in contrast to the reactive intermediate 2, obtained from MeCN as reactant (Fig. 1). To discriminate between the reaction mechanisms discussed so far, the same CVs are applied as for the reaction (1) (Fig. 1, Table 1). Two parameters for the CV cn(S,I) were slightly modi˚ and nd 5 12. The solvent is fied, namely: rN–I ! rS–I, r0 5 4 A represented by 39 MeCN molecules in a cubic cell of 17.5 A˚ side length. The activation energy DF‡ for the RE mechanism amounts to 15.7 kcal mol21 and to 17.6 kcal mol21 for the SN2, this being 13.8 kcal mol21 lower than the DF‡ for the SN with MeCN as nucleophile (Table 4 and 1). The difference between the activation barriers (DDF‡) becomes smaller compared to the formation of the reactive intermediate 2 by reagent 1 (21.9 vs. 211.3 kcal mol21). Therefore, during trifluoromethylation of 4 both mechanisms are likely to occur, RE being slightly favoured. The SN appears to be bimolecular: The bond breaking (IACF3) and formation (SACF3) processes are taking place simultaneously (MEP in Fig. 8, panel A), as opposed to the deferred formation of the new NACF3 bond in MeCN trifluoromethylation (Fig. 3, panel B). However, this assumption should be refined by taking into consideration DS‡ and DV‡. The obtained RE FES is characterized by a large shallow region, where several local minima are found. In this region, the CF3 group is dissociated from reagent 1, but not yet bound to the substrate 4. A second pathway (Fig. 8, panel B, right line) is therefore possible, describing a non-concerted RE. As a result of a partial reduction of the iodine atom (before reaching the TS), the IACF3 bond is significantly elongated at 792
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˚ . After the reaction with thia very early stage to around 3.5 A openol (4) the proton is abstracted from the resulting protonated thioether 5 by MeCN solvent molecule giving 8 (Fig. 1). The activation energy for this alternative nonconcerted reaction pathway is slightly lower than for the RE mechanism (right MEP, panel B Fig. 8) and is mainly attributed to the elongation of the IACF3 bond (Table 4). Both polar mechanisms were also investigated in dichloromethane as a solvent. However, the formation of side products, e.g. intramolecular trifluoromethylation of the reagent or the formation of CF3OH and CF3Cl after the reaction, disabled the formation of the product or the recrossing of the TS region. The use of thiophenolate (6) as nucleophile further lowers DF‡ to 15 kcal mol21 (Table 4). The lack of a distinct substrate well, as it has been always observed previously with a local ˚ IACF3 bond length, points at a minimum at around 2.1 A spontaneous reaction beginning with an immediate cleavage of the IACF3 bond. Nonetheless, the reaction resembles a RE mechanism without inversion of CF3 configuration. (More detail in the Supporting Information section 5.) SET as Third Limiting Reaction Mechanism Applying the same set of CVs as for the RE (Table 1), the metadynamics with spin polarized orbitals revealed an SET mechanism during the reaction of reagent 1 with MeCN, involving a CF3 radical. The activation barrier of 19.9 kcal mol21 is competitive with the non radical barrier (RE), which amounts to 20.1 kcal mol21. This metadynamics confirms that an open shell mechanism is possible. Investigation of the trajectory showed a retention of the CF3 pseudo configuration during the reaction.[31,32] Apparently, the CF3 radical is relatively stable in MeCN solution, that is, no further initiation of radical species is triggered by the CF3 radical, until the recombination takes place (right reaction pathway in Fig. 2). This finding is deduced from the shallow region on the FES shown in Figure 9. A spin density plot from the region of the TS can be found in the Supporting Information section 6. The first TS region of the SET mechanism lies between the ones of the RE and the SN. Following the MEP in Figure 9, the formation and stabilization of a free CF3 radical is observable on the FES at the local minimum at around rCF3 2I 58.3 and rN2CF3 56.1 bohr. The shallow region at higher CV values—consisting of two further local minima—confirms the stability of the Table 4. Free energy of activation DF‡ and reaction DRF in kcal mol21 for the trifluoromethylation of thiophenol(-ate) in MeCN by reagent 1. Mechanism
DF‡
PhSH (4) as nucleophile SN2 17.6 RE 15.7 non-conc. RE 15.5 PhS– (6) as nucleophile RE 15.0
DRF
T/K
CV 1
CV 2
CV 3
288 237 237
250 250 250
rCF3 2I rCF3 2I rCF3 2I
rS2CF3 rS2CF3 rS2CF3
cn (S,I) – –
2109
193
rCF3 2I
rS2CF3
cn (S,I)
The nonconcerted RE is described in the third from last paragraph of this section.
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Figure 8. Panel A: The FES of the SN2 mechanism is shown with the MEP (yellow line) and the TS point (cross) (in kcal mol21). The isoenergy contours increment is 3 kcal mol21 in both panels. Panel B: Two MEPs are shown on the FES of the RE mechanism: the first MEP (left) resembles a RE (concerted) and the second one a non-concerted RE. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
CF3 radical during the reaction. The mechanism can be therefore described as follows: Homolytic IACF3 bond cleavage is induced by a one electron reduction of 1 from the solvent, for which no experimental evidence exists so far. This CF3 radical is stabilized by the solvent before recombination with the MeCN solvent molecule that reduced reagent 1 in the first place.
Conclusions The present study shows that for both reactions, (1) and (2), the RE mechanism is favoured over the nucleophilic substitution in acetonitrile. This is in contrast to the results of the static calculations, at least for reaction (1).[4] The AIMD simulations reveal a substantial solvent effect, in particular a contribution of the solvent to entropy, which is not present in the nucleophilic substitution. Depending on the nucleophile, the RE preference is more or less pronounced. While N-nucleophiles (MeCN) clearly prefer the RE mechanism, the two mechanisms can be considered competitive in the case of the S-
nucleophile (PhSH), due to the reduced difference between the activation barriers. Still, the trifluoromethylation reactions with alcohol reagent 1 can not be attributed to a single clearly defined reaction mechanism. Instead, this study shows that the reaction might proceed through several concomitant mechanisms, of similar probability. In other words, the reaction pathways explored here define the mechanistic limits in which the reaction takes place, that is, the limiting mechanisms as introduced in the title of this work. Furthermore, the consideration of the entropy and volume of activation reveals that the SN mechanism during MeCN trifluoromethylation is more likely to be unimolecular rather than bimolecular, that is, SN1 rather than SN2. This is even more pronounced for the RE, which implies that the mechanism is not strictly concerted. We have also extended our investigation to radical mechanisms. Such mechanisms are considered to be likely for Snucleophiles[12] or trifluoromethylation reactions including e.g. copper-, rhenium-, zinc- [33] or vanadium-based catalysts.[34] Our results suggest indeed that the SET mechanism follows a
Figure 9. The FES is shown together with the contour plot and the MEP (green and red lines) describing the SET mechanism. The isoenergy contours increment correspond to 3 kcal mol21. The first (and energetically highest lying) TS is marked with a cross. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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pathway energetically not very different from the non radical one. SET mechanisms are currently being explored using the same approach presented here. In summary, we elaborated a computational protocol that facilitates a thorough investigation of complex chemical systems (hypervalent bonding, multiple reaction mechanisms) in terms of kinetic and thermodynamic considerations in condensed phase. In particular, we thereby provide an evaluation of the nature of the mechanism and the TSs based on a comprehensive estimation of the entropic contribution to the free energy changes. This protocol can be extended to other reactions, which might also imply more than one clearly defined limiting reaction mechanism, as it appears to be the case for a variety of reactions involving reagents of type 1 that have been reported in recent years.[33]
Acknowledgment The authors would like to thank Julie Charpentier and Halua Pinto de Magalha~es for their valuable comments. Keywords: hypervalency iodanes reaction mechanisms solvent effect trifluoromethylation ab initio molecular dynamics metadynamics activation parameters entropy single electron transfer
How to cite this article: O. Sala, H. P. L€ uthi, A. Togni, M. Iannuzzi, J. Hutter J. Comput. Chem. 2015, 36, 785–794. DOI: 10.1002/jcc.23857
]
Additional Supporting Information may be found in the online version of this article.
[1] K. M€ uller, C. Faeh, F. Diederich, Science 2007, 317, 1881. [2] T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. Engl. 2013, 52, 8214. [3] K. Niedermann, N. Fr€ uh, E. Vinogradova, M. S. Wiehn, A. Moreno, A. Togni Angew. Chem. Int. Ed. Engl. 2011, 50, 1059. [4] O. Sala, H. P. L€ uthi, A. Togni, J. Comput. Chem. 2014, 35, 2122.
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[5] H. Pinto de Magalh~aes, Reactivity of electrophillic trifluoromethylating hypervalent lambda-3-iodane reagents, Master’s Thesis, ETH Z€ urich, Z€ urich, 2011. [6] O. Sala, Quantum chemical investigation of the solvent effect on two competing trifluoromethylation reaction mechanisms involving lambda-3-iodane reagents, Master’s Thesis, ETH Z€ urich, Z€ urich, 2012. [7] H. Pinto de Magalh~aes, H. P. L€ uthi, A. Togni, J. Organic Chem. 2014, 79, 8374. [8] A recent computational work concerned with the reaction of alkynyl iodanes with thiols seems to indicate a concerted pathway for the CAS bond forming process resembling a RE. R. Frei, M. D. Wodrich, D. P. Hari, P.-A. Borin, C. Chauvier, J. Waser, J. Am. Chem. Soc. 2014, 136, 16563. [9] A. Milischuk, D. V. Matyushov, J. Phys. Chem. A 2002, 106, 2146. [10] L. Sutto, S. Marsili, F. L. Gervasio, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 771. [11] A. Barducci, M. Bonomi, and M. Parrinello, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2011, 1, 826. [12] N. Santschi, Hypervalent Iodine Trifluoromethylating Agents at Work. PhD Thesis, ETH Z€ urich, Z€ urich, 2013. [13] O. Sala, S. Jungen, H. P. L€ uthi, M. Iannuzzi, A. Togni (in preparation). [14] Becke, Phys. Rev. A 1988, 38, 3098. [15] C. Lee, W. Yang, R. Parr, Phys. Rev. B 1988, 37, 785. [16] W. Kohn, L. Sham, Phys. Rev. 1965, 140, A1133. [17] J. VandeVondele, J. Hutter, J. Chem. Phys. 2007, 127, 114105. [18] J. VandeVondele, M. Krack, F. Mohamed, M. Parrinello, T. Chassaing, J. Hutter, Comput. Phys. Commun. 2005, 167, 103. [19] The CP2K developers group, http://www.cp2k.org, 2013 Version 2.5. [20] J. Hutter, M. Iannuzzi, F. Schiffmann, and J. VandeVondele, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2014, 4, 15. [21] S. Goedecker, M. Teter, J. Hutter, Phys. Rev. B 1996, 54, 1703. [22] S. Nos e, J. Chem. Phys. 1984, 81, 511. [23] W. G. Hoover, Phys. Rev. A 1985, 31, 1695. [24] G. Bussi, D. Donadio, M. Parrinello, J. Chem. Phys. 2007, 126, 014101. [25] M. Iannuzzi, A. Laio, M. Parrinello, Phys. Rev. Lett. 2003, 90, 238302. [26] G. Jenner, J. Phys. Organic Chem. 2002, 15, 1. [27] A. Bondi, J. Phys. Chem. 1964, 68, 441. [28] D. E. Williams, D. J. Houpt Acta Crystallograph Section B 1986, 42, 286. [29] J. R. Pliego, J. M. Riveros J. Phys. Chem. A 2001, 105, 7241. [30] C. Michel, A. Laio, A. Milet, J. Chem. Theory Comput. 2009, 5, 2193. [31] W. R. Dolbier, Chem. Rev. 1996, 96, 1557. PMID: 11848804. [32] C. Yamada, E. Hirota, J. Chem. Phys. 1983, 78, 1703. [33] J. Charpentier, N. Fr€ uh, A. Togni, Chem. Rev. 2015, 115, 650. [34] N. Fr€ uh, A. Togni, Angew. Chem. Int. Ed. 2014, 53, 10813.
Received: 3 December 2014 Revised: 23 January 2015 Accepted: 25 January 2015 Published online on 12 March 2015
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Dividing a Complex Reaction Involving a Hypervalent Iodine Reagent into Three Limiting Mechanisms by Ab Initio Molecular Dynamics €thi,*[a] Antonio Togni,[a] Marcella Iannuzzi,[b] and Ju €rg Hutter[b] Oliver Sala,[a] Hans Peter Lu The electrophilic N-trifluoromethylation of MeCN with a hypervalent iodine reagent to form a nitrilium ion, that is rapidly trapped by an azole nucleophile, is thought to occur via reductive elimination (RE). A recent study showed that, depending on the solvent representation, the SN2 is favoured to a different extent over the RE. However, there is a discriminative solvent effect present, which calls for a statistical mechanics approach to fully account for the entropic contributions. In this study, we perform metadynamic simulations for two trifluoromethylation reactions (with N- and S-nucleophiles), showing that the RE mechanism is always favoured in MeCN solution. These computations also indicate that a radical
mechanism (single electron transfer) may play an important role. The computational protocol based on accelerated molecular dynamics for the exploration of the free energy surface is transferable and will be applied to similar reactions to investigate other electrophiles on the reagent. Based on the activation parameters determined, this approach also gives insight into the mechanistic details of the trifluoromethylation and shows that these commonly known mechanisms mark the limits within C 2015 Wiley Periodicals, Inc. which the reaction proceeds. V
Introduction
calculations—were shown to work in favour of the RE mechanism. The observation that an increasing level of sophistication of the solvent goes in parallel with a decreasing dominance of the SN2 mechanism, makes a fully explicit representation of the solvent indispensable to determine which mechanism is ultimately favored. To account for the entropic contributions to the solvent effect, namely electrostriction and dielectric saturation, the solvent (MeCN) is treated explicitly by means of ab initio molecular dynamics (AIMD) in condensed phase. Electrostriction describes the local density change of the solvent in the vicinity of the solute, that is, the change of the radius of the solute’s cavity. The orientational ordering of the polar solvent molecules, induced by the solute dipole, is expressed by the dielectric saturation.[9] In apolar solvents, these two effects have a farther reaching impact on the solvation shell(s) than in polar solvents, which are already electrostricted. To investigate the reaction mechanisms we use ab initio metadynamics. This method allows the reconstruction of the underlying free energy surface (FES) as a function of a few, properly selected, collective variables (CVs).[10,11]. To describe the generalized nucleophilic substitution (SN2 as well as SN1;
Over the years, trifluoromethylation has emerged to be an important reaction, as trifluoromethylated compounds became increasingly attractive, in particular for medicinal chemistry.[1] In general, fluorine-containing species are among other aspects more difficult to oxidize and, hence, more stable under metabolic conditions. In addition, the lipophilicity is increased. Trifluoromethylated compounds can be obtained by reaction with 3,3-dimethyl-1-(trifluoromethyl)-1k3,2-benziodoxol (unprotonated 1) through electrophilic transfer of the CF3 group bound to the hypervalent iodine reagent (a k3-iodane) to a vast array of nucleophiles, such as C-, O-, P-, N-, and S-centered ones.[2] In this study, the focus is on the reaction of acetonitrile (MeCN) and thiophenol (PhSH) (4) acting as N- and S-nucleophile, respectively (Fig. 1). The electronic and structural properties leading to the distinct reactivity of reagent 1 have been the topic of earlier studies.[4–7] The trifluoromethylation reaction with reagent 1 is assumed to occur via a reductive elimination (RE)[7,8] of the electrophilic CF3 ligand and the nucleophile coordinated to the iodine atom. However, contrary to expectations, RE was shown to be challenged by an SN2 mechanism on the basis of stationary computations in the gas phase.[5,6] Furthermore, a recent study has shown that the solvent effect reduces the gap between the activation energies (DDG‡) significantly, but that, depending on the solvent representation, the SN2 reaction mechanism is still favoured over RE.[4] The difference in activation energies DDG‡ (DG‡RE 2 DG‡SN 2 ) amounts to roughly 15 kcal mol21 in the gas phase and to as little as 2 kcal mol21 in condensed phase (MeCN), depending on the solvent model. The entropic contributions to the solvent effect—within the limits of stationary
DOI: 10.1002/jcc.23857
[a] O. Sala, H. P. L€ uthi, A. Togni ETH Zurich, Laboratorium f€ ur Physikalische Chemie, Vladimir–Prelog–Weg 2, 8093, Zurich, Switzerland E-mail: [email protected] [b] M. Iannuzzi, J€ urg Hutter University of Zurich, Department of Chemistry, Winterthurerstrasse 190, 8057, Zurich, Switzerland Contract grant sponsor: Swiss National Science Foundation; Contract grant number: 200020-146230 and 200020-137712 C 2015 Wiley Periodicals, Inc. V
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Figure 1. These trifluoromethylation reaction pathways are investigated in this study. The reactive intermediate 2 and the trifluoromethyl phenyl thioether 7, obtained by the two reactions, are the main products. The first step (1 ! 2) in the formation of 9 represents the rate-determining step. Therefore, the reactive intermediate 2, which is essential in a newly discovered Ritter-type reaction, is the species of interest.[3]
leftmost reaction pathway in Fig. 2), two CVs are chosen: the interatomic distance between the nucleophile and the electrophile and the interatomic distance between the electrophile and the nucleofuge. As for the RE mechanism (Fig. 2, middle reaction pathway) coordination of the nucleophile to the reagent 1 is crucial, an additional CV is introduced, describing the coordination number (cn) of the nucleophile to the electrondeficient iodine atom. To extend the scope of nucleophiles we further consider thiophenol 4, or its deprotonated form 6, in the same solvent. Experiments have indicated that the trifluoromethylation of Snucleophiles most likely occurs via single electron transfer (SET).[12,13] The possibility of an SET mechanism is explored also for the trifluoromethylation of MeCN. Unlike the product of the first step of MeCN-trifluoromethylation, 2, phenyl trifluoromethyl thioether (7) does not represent a reactive intermediate. In this study, the solvent effect on three limiting reaction mechanisms is investigated. First, the two polar reaction mechanisms (SN and RE) are evaluated for the trifluoromethylation of MeCN in MeCN (solvolysis) by reagent 1 [reaction (1), Fig. 1]. The trifluoromethylation by reagent 1 of thiophenol and thiophenolate, 4 and 6, is studied subsequently [reactions (2) and (3), Fig. 1]. Much of the focus will be on the contribution of entropy, the activation parameters (including the free energy, enthalpy, entropy, and volume of activation) and the structure of the transition states (TSs). The evaluation of the entropy and volume of activation can be used to determine whether the SN mechanism is unimolecular or bimolecular. In addition, the two polar mechanisms are investigated for the reaction yielding 2 and 3, but with model reagent 10. The free energies of activation are compared to the ones obtained by stationary calculations using continuum solvent models. Finally, we will also explore radical (SET) mechanisms for which experimental evidence was found.[12]
Computational Details All simulations are based on density functional theory electronic structure calculations based on the generalized gradient 786
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Figure 2. The three mechanisms shown define the boundaries of the possible reaction pathways (i.e., limiting mechanisms) for the electrophilic trifluoromethylation of nucleophile 11 by means of reagent 1, all leading to the same products 3 and 20. Coordination of 11 to the k3-iodane 1 (resulting in k4-iodane 14) precedes the elimination of product 20 and the formation of the reduced iodoalcohol 3. In contrast to the RE mechanism, no coordination of 11 to the iodine atom of 1 is required for the nucleophilic substitution (SN) to reach the transition state TS-13. The SN mechanism can proceed unimolecularly or bimolecularly. In the former case the I–CF3 bond is first cleaved (see structure 12), followed by the attack of 11 to the cationic CF3-group. This process occurs concertedly in the latter case (bimolecular) forming the new Nu–CF3 bond while breaking the I–CF3 bond (TS13). During the SET mechanism, 11 reduces 1 by one electron (SET-16), yielding radical cation 17 and the neutral radical species 18. Through homolytic I–CF3 bond cleavage the CF3 radical 19 is formed, which recombines with 17 to yield the products 20 and 3.
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approximation, specifically with the BLYP[14,15] functional. The Kohn–Sham[16] (KS) equations are solved according to the Gaussian and plane wave (GPW) formalism[17] as implemented in the CP2K program package.[18–20] The GPW uses Goedecker–Teter–Hutter pseudo potentials[21] to describe the interactions between core and valence electrons, while the valence electron density is represented in terms of Gaussian type orbital (GTO) basis set functions. In particular, we use molecularly optimized (MOLOP)[17] basis sets. The auxiliary PW basis set, which is needed for the efficient solution of the Poisson’s equation in reciprocal space, is truncated at 500 Ry. For the exploration of the SET mechanism, spin polarized KS is used to allow configurations with unpaired electrons. Relaxing the multiplicity constraint (S 5 0 for the initial state) will make spin flips possible. (See Supporting Information section 6.) The solution is modelled by a cubic simulation cell with periodic boundary conditions. The simulation box contains between 40 and 60 solvent molecules, in a volume that corresponds to the solvent density at the simulation temperature. Initial equilibration runs are carried out at constant volume. However, to allow volume fluctuations when reactions occur, AIMD simulations at variable volume are needed, which is achieved by coupling the simulation cell to a barostat. As we are dealing with an isotropic system, only isotropic volume changes are permitted. The temperature of the system is always controlled by a thermostat,[22–24] to keep it around 300 K. For all Born–Oppenheimer AIMD simulations, we use a time step of 0.5 fs. Metadynamic simulations are used to accelerate the exploration of the FES.[10,11] The typical procedure consists of a first equilibration AIMD of the solvent in the canonical ensemble (constant volume and temperature) for a simulation time of 50–100 ps. The substrate(s) is then introduced in the simulation cell by replacing some of the solvent molecules. After the exchange, a further equilibration is needed for another 50–120 ps, where the volume is also equilibrated to obtain the equilibrium density of the solution (constant pressure, constant temperature ensemble). The metadynamic simulation is started from the equilibrated structure of the solution, by properly selecting two or three CVs. The choice of CVs is not always trivial, as they need to describe the reaction mechanism of interest, distinguishing the different stages of the process and possible intermediates. Ideally, they should also be able to describe alternative processes. However, in this work we prefer to select CVs that specifically address only one type of mechanism at a time, in order to be able to separately investigate all the proposed mechanisms and to compare them. The specific choices of CVs for the different metadynamic simulations reported here are discussed in the respective sections of the results. Details on the preliminary studies needed to determine the optimal choice of CVs are reported in the Supporting Information section 4. In general, the metadynamic simulations are extended until the FES is properly explored, that is, after several recrossing of the transition regions are observed. However, in certain cases the process is observed only once, as a very stable intermediate is reached and the selected CVs are not adequate to describe a further development to other products or back to
reactants. In these circumstances, if the reaction mechanisms of interest has been properly sampled, the metadynamic simulation is interrupted once no more relevant structural changes are observed. The estimate of the underlying FES is directly determined from the spawned metadynamic potential along the sampling. The resulting FES is defined in the reduced space of the CVs and it is a direct measurement of the probability distribution of the states of the system in this space. The visualisation and interpretation of multidimensional probability distributions require some care in order not to discard important information. One common procedure is to identify possible minimum energy pathways on the FES and study the mechanism along these pathways. For our analysis, we did obtain estimates of enthalpic and entropic contributions to the free energy along the identified minimal energy pathways (MEPs) by post processing. In particular, we selected a set of sample configurations along the pathway. Each configuration is obtained by setting the corresponding values to the CVs as determined from the FES. These configurations are used as starting structure for constrained molecular dynamic simulations, where the constraints keep the values of the CVs fixed. Each of these runs, of about 35 ps, provides a sampling of the system state at the specific point on the FES and therefore an evaluation of the corresponding enthalpic contribution. The entropic term is then obtained by difference. The volume of activation characterizing a TS structure was obtained by calculation of the difference between the average volume of the simulation cell in the initial minimum state, and the average volume of the system at the TS. The first average volume is easily obtained by an equilibration of the initial state (substrates in the solvent) without any constraints. The volume at the TS is obtained from a simulation where selected coordinates of the substrates are constrained in order to preserve the TS structure. Obviously, both simulations are performed at constant pressure to allow volume equilibration. For the investigation of the solvent effect applying stationary quantum chemical calculations using polarizable continuum (PCM) based solvent models for these same reactions, we refer to our previous work.[4]
Results and Discussion The summary of results obtained for the ab initio metadynamic simulations of the trifluoromethylation of MeCN and PhSH presented in Table 1 shows that RE is favoured over the SN mechanism. This observation is in line with the results of the static quantum chemical calculations, which indicate that the solvent effect will favour the RE mechanism.[4] The simulations also show the emergence of a radical mechanism, comparable to the RE in terms of the reaction barrier heights and stereochemical outcome. The details of the metadynamic simulations of the two polar mechanisms (RE, SN) for the trifluoromethylation of MeCN [reaction (1) in Fig. 1] and of thiophenol [reaction (2) & (3)] are thoroughly discussed with particular attention on TS structures and the activation parameters (e.g. entropy of activation (DS‡), Journal of Computational Chemistry 2015, 36, 785–794
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Table 1. Overview of all reactions investigated in this study with the corresponding free energies of activation DF‡ in kcal mol21, the simulation temperature, and the sets of CVs used. Reaction
Mechanism
N-nucleophile (MeCN) 1 !2 SN 1 !2 RE 1 !2 SET 10 !2 SN 10 !2 RE S-nucleophile (PhSH or PhS--) 1 !7 via 5 SN2 1 !7 via 5 RE 1 !7 via 5 non-conc. RE 1 !7 using 6 RE
DF‡
T/K
CV 1
31.4 20.1 19.9 24.9 16.6
220 300 350 300 300
rCF3 2I rCF3 2I rCF3 2I rCF3 2I rCF3 2I
CV 2
CV 3
rNprox 2CF3 [a] – rNprox 2CF3 cn(N,I)[b] rNprox 2CF3 – rNprox 2CF3 – rNprox 2CF3 cn (N,I)
17.6 250 rCF3 2I 15.7 250 rCF3 2I 15.5 250 rCF3 2I
rS2CF3 rS2CF3 rS2CF3
cn(S,I) – –
15.0 193 rCF3 2I
rS2CF3
cn (S,I)
[a] Interatomic distance between the nitrogen atom of the acetonitrile and the CF3-carbon, where “prox” stands for proximal. [b] Coordination of MeCN to the hypervalent iodine atom.
DV‡ ). Finally, the trifluoromethylation of MeCN following an SET mechanism is investigated, also in view of the high probability of a radical mechanism involving S-nucleophiles. Further details, e.g. the free energies of reaction DRF, are listed in the Supporting Information section 3. N-Trifluoromethylation of MeCN in MeCN as Solvent To clearly distinguish between the two competing polar mechanisms for the trifluoromethylation of MeCN in MeCN solvent, RE and SN, we performed two independent metadynamic simulations: the SN mechanism can be followed in the phase space defined by the CF3-carbon–iodine interatomic distance (rCF3 2I ) and by the interatomic distance between the nitrogen atom of the acetonitrile and the CF3-carbon (rNprox 2CF3 , where “prox” stands for proximal). The proper description of the RE mechanism requires the introduction of an additional variable, namely the coordination of MeCN to the hypervalent iodine atom (cn(N,I)). Preliminary studies revealed that this coordinate is important prior to reaching the RE TS. The coordination number[25] is defined as: " #21 X rN2I nn rN2I nd 12 12 cnðN; IÞ5 r0 r0 N ˚ , nn 5 10 and nd 5 16. After obtaining the where r0 5 3 A reactive intermediate 2 along the metadynamics trajectory, the set of CVs might not be suitable anymore for recrossing events (see Supporting Information section 2 for more details). The solvent is represented by 39 MeCN molecules in a cubic cell ˚ length. with 16.7 A Figure 3 shows the two resulting FESs for the SN (left side) and the RE (right) together with the corresponding contour plot maps (from top to bottom) as a function of the first two CVs only. Transition State Structure and Energy The simulations show that the RE mechanism is favoured over the SN pathway by as much as 11.3 kcal mol21 (DDF‡) (Table 788
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1). This is also evident by comparing the two contour plots of the FESs (panels C and F in Fig. 3), showing the two different MEPs connecting the well of substrates with the well of products. The TS marks the point of highest energy on the MEP of this exergonic reaction. The TS region, that is, the area around the maximum on the MEP (Fig. 3 panels C & F) for the SN mechanism is characterized by an rCF3 2I much larger than rN2CF3 pointing to a (rather) late TS geometry, resembling the products more than the substrates. In contrast, the RE TS occurs rather early, being structurally more similar to the substrates (Fig. 4). The lower energy TS observed for the RE is in line with the Hammond postulate, which states that the structure of the RE TS is thus closer to the substrates. As expected for ionogenic reactions, entropy effects, in particular dielectric saturation and electrostriction,[26] contribute significantly to the free energy of activation DF‡. These effects can be quantitatively assessed by the activation entropy DS‡ and by the activation volume DV‡, which takes into account environmental volume changes arising from solute–solvent interactions (electrostriction) as well as structural volume changes from the bond-forming and -breaking processes. The difference in enthalpies of activation DDU‡ between the two polar mechanisms (RE and SN) amounts to 25.0 kcal mol21 (Table 2). Entropy and Volume of Activation The difference between the entropies of activation D(TDS‡) amounts to 16.3 kcal mol21 (or DDS‡ 5 124.2 e.u.) in favour of the RE mechanism (e.u.: entropy units, cal mol21 K21). The positive entropy of activation for the RE (112.0 e.u., Table 2) points to a unimolecular reaction mechanism with a (rather) loose TS. A large and negative entropy of activation would be indicative of a tight TS, as observed in a bimolecular reaction mechanism. From this perspective, no clear statement can be made for the SN with respect to the molecularity (DS‡SN 5212.2 e.u.). It appears that the TS can be viewed as a combination of both, uni- and bimolecular. In Figure 5, the evolution of the entropy DS from the substrates to the TS region is shown for both polar mechanisms. For the SN mechanism (panel A, Fig. 5) the entropy DS evolves between 237 and 212 e.u. along the MEP from the substrates to the TS. Note that the DS ordinate is not scaled with the temperature, that is, higher amplitudes are obtained. In the TS region DS‡ is negative (212.2 e.u., Table 2). Thus, it is difficult to make any clear statements, other than that the molecularity must lie between uni- and bimolecular. For the RE pathway (panel B) DS remains negative until, by approaching the RE TS region, it turns positive (112.0 e.u., Table 2), pointing at a unimolecular mechanism. Contrary to the SN mechanism, an entropy gain is observed for the RE by reaching the TS region. Therefore, the RE TS is less rigid than the SN TS. Given the large difference in the volumes of activation (DDV‡ 5 2114 cm3 mol21), the change in mechanism is a logical consequence (SN1/SN2 $ RE). The large and positive DV‡ of the nucleophilic substitution (SN) mechanism (1189 cm3 mol21) points WWW.CHEMISTRYVIEWS.COM
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Figure 3. The FESs of the SN (panels A–C) and the RE (panels D–F) are shown. Panel A) displays the FES with the contour map. The MEP in red connects the substrate with the product well. Panel B) shows the contour plot with the MEP and the TS marked as X. The energy scale is in kcal mol21. The isoenergy contours increment correspond to 3 kcal mol21. Panel C) is a magnification of the TS region with an isoenergy contours increment corresponding to 2 kcal mol21. Panel D) shows the FES together with the contour map as a function of the CVs 1 and 2 in Table 1. In panel E) the contour plot is shown with the MEP and the TS marked with X. The isoenergy contours increment correspond to 3 kcal mol21. Panel F) is a magnification of the TS region (isoenergy contours increment: 2 kcal mol21). Note the different location of the TS compared to panel C.
clearly at a unimolecular mechanism (SN1), confirming the findings from the entropy of activation (Table 2). Therefore, the ratedetermining step in the SN1 is the IACF3 bond cleavage, giving rise to a cationic CF3-group, which interacts more strongly with the (polar) solvent than during RE. This larger solvent effect (in general) is expressed by the larger volume of activation for the SN1 mechanism compared to RE (1189 vs. 175 cm3 mol21, respectively). To put the DV‡ values in relation, the group contribution to the Van der Waals volume is reported to be 21.3 for the ACF3 group, 19.6 for the iodine atom (AI) and 13.7 cm3 mol21 for the methyl group (ACH3).[27,28]
The formation of an intermediate in a unimolecular mechanism goes along with additional creation of (highly) localized charges, which leads to an enhanced solute–solvent interaction, and thus to higher electrostriction. Clearly, these effects are more pronounced in the SN1 mechanism (compared to the RE), which is expressed by both the lower entropy of activation and the higher volume of activation. The probability of encountering a solvated, free CF3 cation is higher for the SN mechanism, as seen in Figure 3 (panel B). Therefore, both mechanisms (SN and RE) are unimolecular in 1 and the RE TS charge is distributed more uniformly, conversely leading to a Journal of Computational Chemistry 2015, 36, 785–794
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Figure 4. Left side: The structure of the SN2/SN1 TS is shown, which corresponds to the maximum on the MEP on the FES in Figure 3 (B,C, crosses). Note ˚ larger than rCF3 2N and that the I–C–N geometry does not need to be necessarily colinearly. Right side: A trithat the interatomic distance rCF3 2I is by 0.7 A angular I–C–N geometry is obtained for the RE-TS structure (compare TS-15 in Fig. 2). Additionally, one MeCN solvent is coordinated to the iodine atom (its nitrogen atom is marked orange).
stronger solvent effect for the SN1 mechanism. This solvent effect is known to be more pronounced in apolar solvents, where the effect of electrostriction is larger, in contrast to already electrostricted polar solvents. In summary, the difference in the free energy of activation DDF‡ (211.3 kcal mol21) in favour of RE is enhanced by entropy, as DDU‡ amounts to 25.0 kcal mol21. Concerning the entropy of activation, particularly DDS‡, these findings are qualitatively in line with the estimation of entropies obtained by means of the cluster-continuum model (as described by Riveros and coworkers).[4,29]
simultaneously establish hydrogen-bonding to the OH-group and coordination to the iodine atom. In gas phase, the progress of coordination, starting at the free energy minimum with nearly no coordination (cn(N,I) 5
Coordination of MeCN to the Reagent: Entropic Considerations The electron-deficient iodine atom in reagent 1 allows for multiple coordination of ligands.[4] To explore the development of the entropy in the coordination process that leads to the RE TS (Fig. 2: 1 ! 14), we selected the coordination number cn(N,I) and the potential energy U as CVs. This approach, introduced by Milet et al., [30] allows to directly obtain an estimate of the entropic contribution. We compare a simulation of the solvated system with a simulation in gas phase with just two ligands. These allow to Table 2. Activation parameters[a] for the two polar reaction mechanisms depicted in Figure 2. Mechanism
DF‡
DU‡
DS‡
DV‡
Molecularity
1 !2
SN1/SN2
131.4
128.7
212.2
1189
1 !2
RE
120.1
123.7
112.0
175
Unimolecular/ bimolecular Unimolecular
25.0
124.2
2114
Reaction
DDX‡
211.3
[a] DF and DU in kcal mol DV ‡ in cm3 mol21
790
21
‡
, DS in entropy units (e.u.) cal mol21 K21,
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Figure 5. Panel A shows the thermodynamic state functions for the SN mechanism (panel B for the RE): The black line corresponds to the free energy DF along the MEP from the substrates to the TS as obtained from the FES (Fig. 3), projected on the rCF3 2I coordinate (CV). The red line is the enthalpy DU. Plotting the difference between DF and DU results in the entropy DS in e.u. (cal mol21 K21, scale on the right).
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Figure 6. Panel A, gas phase: The FES of the coordination process of the two available MeCN to the iodine atom of reagent 1 is shown as a function of the two CVs, cn(N,I) and enthalpy U. The blue line corresponds to the MEP starting from the free energy minimum towards higher coordination numbers. In the inlet, the evolution of the free energy F and enthalpy U along the MEP are opposed, showing the loss of entropy towards higher coordination number. Panel B, solvated system: The coordination behaviour of MeCN to the iodine atom of 1 in solution is shown here. For both panels, the isoenergy contours increment correspond to 1 kcal mol21.
0.25) to the coordination of one MeCN within a distance of 3 ˚ (cn(N,I) 5 1), is entropically disfavoured by DS 5 2191 e.u. A (Fig. 6, panel A). Further coordination (to cn(N,I) 5 1.6) leads to DS 5 2273 e.u. or TDS 5260 kcal mol21. Obviously, the increase in free energy upon coordination is lead by the loss in entropy, overcompensating the enthalpic stabilization of 228 kcal mol21. In the solvated system, the coordination number of cn(N,I) 5 0.7 represents the minimum on the FES. However, escaping the shallow region between cn(N,I) 5 0.4 and 1.6 leads to a significant increase of the free energy (Fig. 6, panel B). In solution, relative to gas phase, the coordination process necessary for an RE mechanism becomes entropically less unfavourable, because of the larger number of configurations having higher coordination. Thus, the statistical probability of such a state increases.
assume that the SN mechanism is more appropriately described as rather unimolecular also in this case. In gas phase, the SN2 reaction mechanism is dominant over the RE, as shown by stationary quantum chemical calculations (e.g., B3LYP/aug-cc-pVDZ-pp).[4–6] The metadynamic
Comparison to the Static Calculations (Applying the Model Reagent 10) The validity of model reagent 10 (Fig. 2) replacing 1 was confirmed in an earlier study.[4] Using 10 as trifluoromethylation reagent for MeCN, the two polar reaction mechanisms are investigated, again in MeCN solution. The same sets of CVs were applied for the metadynamic simulations as for the SN1 and the RE with reagent 1 (see Table 1). As in the case of the trifluoromethylation of MeCN with reagent 1, RE is favoured over SN1 by as much as 8.3 kcal mol21 using reagent 10 (Table 3). In absolute terms, both reaction barriers are lower, meaning that, with 10 as reagent, the reaction would proceed more quickly. The TS region of the RE mechanism on the FES is the same as by applying reagent 1. However, for the SN1 pathway the TS region is located towards shorter interatomic distances (by approximatively 0.5 A˚) (Fig. 7). Following the argumentation for the nucleophilic substitution reaction involving reagent 1, and given the similarity (electronically and geometrically) between model reagent 10 and 1, we strongly
Figure 7. FES contour maps obtained from metadynamics for SN1 (upper panel) and RE. The red lines represent the MEP calculated on the resulting FES. The isoenergy contours increment correspond to 3 kcal mol21.
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Table 3. Comparison between the free energies of activation DF‡ and reaction DRF in kcal mol21 for the trifluoromethylation of MeCN in MeCN with reagent 10 applying metadynamics and two PCM-based representations of the solvent in stationary quantum chemistry. Mechanism
DF‡
SN2
RE
DDF‡
DRF
T/K
Method[a]
24.9
245
300
Metadynamics
25.1
215.7
298
37.1
215.7
298
IEF-PCM B3LYP/ aug-cc-pVDZ CC B3LYP/ aug-cc-pVDZ Metadynamics
16.6
28.3
292
300
34.1
9.0
215.7
298
40.8
3.7
215.7
298
IEF-PCM B3LYP/ aug-cc-pVDZ CC B3LYP/aug-cc-pVDZ
This work [4] [4] This work [4] [4]
[a] CC: Cluster-continuum with 3 MeCN. Details in the lit. [4], using also M06-2X, BP86, and MP2.
simulations, instead, suggest that the SN becomes unfavourable in MeCN solution. This observation can be attributed to entropic effects (vide supra), which are not fully accounted for in stationary calculations. The necessity for an explicit representation of the solvent by AIMD to properly account for the entropic contributions, which discriminate clearly between the two mechanisms, is therefore essential. S-Trifluoromethylation of Thiophenol in MeCN as Solvent Trifluoromethylation of thiopenol (4) or thiophenolate (6) yields thioether 7 as a stable product, in contrast to the reactive intermediate 2, obtained from MeCN as reactant (Fig. 1). To discriminate between the reaction mechanisms discussed so far, the same CVs are applied as for the reaction (1) (Fig. 1, Table 1). Two parameters for the CV cn(S,I) were slightly modi˚ and nd 5 12. The solvent is fied, namely: rN–I ! rS–I, r0 5 4 A represented by 39 MeCN molecules in a cubic cell of 17.5 A˚ side length. The activation energy DF‡ for the RE mechanism amounts to 15.7 kcal mol21 and to 17.6 kcal mol21 for the SN2, this being 13.8 kcal mol21 lower than the DF‡ for the SN with MeCN as nucleophile (Table 4 and 1). The difference between the activation barriers (DDF‡) becomes smaller compared to the formation of the reactive intermediate 2 by reagent 1 (21.9 vs. 211.3 kcal mol21). Therefore, during trifluoromethylation of 4 both mechanisms are likely to occur, RE being slightly favoured. The SN appears to be bimolecular: The bond breaking (IACF3) and formation (SACF3) processes are taking place simultaneously (MEP in Fig. 8, panel A), as opposed to the deferred formation of the new NACF3 bond in MeCN trifluoromethylation (Fig. 3, panel B). However, this assumption should be refined by taking into consideration DS‡ and DV‡. The obtained RE FES is characterized by a large shallow region, where several local minima are found. In this region, the CF3 group is dissociated from reagent 1, but not yet bound to the substrate 4. A second pathway (Fig. 8, panel B, right line) is therefore possible, describing a non-concerted RE. As a result of a partial reduction of the iodine atom (before reaching the TS), the IACF3 bond is significantly elongated at 792
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˚ . After the reaction with thia very early stage to around 3.5 A openol (4) the proton is abstracted from the resulting protonated thioether 5 by MeCN solvent molecule giving 8 (Fig. 1). The activation energy for this alternative nonconcerted reaction pathway is slightly lower than for the RE mechanism (right MEP, panel B Fig. 8) and is mainly attributed to the elongation of the IACF3 bond (Table 4). Both polar mechanisms were also investigated in dichloromethane as a solvent. However, the formation of side products, e.g. intramolecular trifluoromethylation of the reagent or the formation of CF3OH and CF3Cl after the reaction, disabled the formation of the product or the recrossing of the TS region. The use of thiophenolate (6) as nucleophile further lowers DF‡ to 15 kcal mol21 (Table 4). The lack of a distinct substrate well, as it has been always observed previously with a local ˚ IACF3 bond length, points at a minimum at around 2.1 A spontaneous reaction beginning with an immediate cleavage of the IACF3 bond. Nonetheless, the reaction resembles a RE mechanism without inversion of CF3 configuration. (More detail in the Supporting Information section 5.) SET as Third Limiting Reaction Mechanism Applying the same set of CVs as for the RE (Table 1), the metadynamics with spin polarized orbitals revealed an SET mechanism during the reaction of reagent 1 with MeCN, involving a CF3 radical. The activation barrier of 19.9 kcal mol21 is competitive with the non radical barrier (RE), which amounts to 20.1 kcal mol21. This metadynamics confirms that an open shell mechanism is possible. Investigation of the trajectory showed a retention of the CF3 pseudo configuration during the reaction.[31,32] Apparently, the CF3 radical is relatively stable in MeCN solution, that is, no further initiation of radical species is triggered by the CF3 radical, until the recombination takes place (right reaction pathway in Fig. 2). This finding is deduced from the shallow region on the FES shown in Figure 9. A spin density plot from the region of the TS can be found in the Supporting Information section 6. The first TS region of the SET mechanism lies between the ones of the RE and the SN. Following the MEP in Figure 9, the formation and stabilization of a free CF3 radical is observable on the FES at the local minimum at around rCF3 2I 58.3 and rN2CF3 56.1 bohr. The shallow region at higher CV values—consisting of two further local minima—confirms the stability of the Table 4. Free energy of activation DF‡ and reaction DRF in kcal mol21 for the trifluoromethylation of thiophenol(-ate) in MeCN by reagent 1. Mechanism
DF‡
PhSH (4) as nucleophile SN2 17.6 RE 15.7 non-conc. RE 15.5 PhS– (6) as nucleophile RE 15.0
DRF
T/K
CV 1
CV 2
CV 3
288 237 237
250 250 250
rCF3 2I rCF3 2I rCF3 2I
rS2CF3 rS2CF3 rS2CF3
cn (S,I) – –
2109
193
rCF3 2I
rS2CF3
cn (S,I)
The nonconcerted RE is described in the third from last paragraph of this section.
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Figure 8. Panel A: The FES of the SN2 mechanism is shown with the MEP (yellow line) and the TS point (cross) (in kcal mol21). The isoenergy contours increment is 3 kcal mol21 in both panels. Panel B: Two MEPs are shown on the FES of the RE mechanism: the first MEP (left) resembles a RE (concerted) and the second one a non-concerted RE. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
CF3 radical during the reaction. The mechanism can be therefore described as follows: Homolytic IACF3 bond cleavage is induced by a one electron reduction of 1 from the solvent, for which no experimental evidence exists so far. This CF3 radical is stabilized by the solvent before recombination with the MeCN solvent molecule that reduced reagent 1 in the first place.
Conclusions The present study shows that for both reactions, (1) and (2), the RE mechanism is favoured over the nucleophilic substitution in acetonitrile. This is in contrast to the results of the static calculations, at least for reaction (1).[4] The AIMD simulations reveal a substantial solvent effect, in particular a contribution of the solvent to entropy, which is not present in the nucleophilic substitution. Depending on the nucleophile, the RE preference is more or less pronounced. While N-nucleophiles (MeCN) clearly prefer the RE mechanism, the two mechanisms can be considered competitive in the case of the S-
nucleophile (PhSH), due to the reduced difference between the activation barriers. Still, the trifluoromethylation reactions with alcohol reagent 1 can not be attributed to a single clearly defined reaction mechanism. Instead, this study shows that the reaction might proceed through several concomitant mechanisms, of similar probability. In other words, the reaction pathways explored here define the mechanistic limits in which the reaction takes place, that is, the limiting mechanisms as introduced in the title of this work. Furthermore, the consideration of the entropy and volume of activation reveals that the SN mechanism during MeCN trifluoromethylation is more likely to be unimolecular rather than bimolecular, that is, SN1 rather than SN2. This is even more pronounced for the RE, which implies that the mechanism is not strictly concerted. We have also extended our investigation to radical mechanisms. Such mechanisms are considered to be likely for Snucleophiles[12] or trifluoromethylation reactions including e.g. copper-, rhenium-, zinc- [33] or vanadium-based catalysts.[34] Our results suggest indeed that the SET mechanism follows a
Figure 9. The FES is shown together with the contour plot and the MEP (green and red lines) describing the SET mechanism. The isoenergy contours increment correspond to 3 kcal mol21. The first (and energetically highest lying) TS is marked with a cross. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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pathway energetically not very different from the non radical one. SET mechanisms are currently being explored using the same approach presented here. In summary, we elaborated a computational protocol that facilitates a thorough investigation of complex chemical systems (hypervalent bonding, multiple reaction mechanisms) in terms of kinetic and thermodynamic considerations in condensed phase. In particular, we thereby provide an evaluation of the nature of the mechanism and the TSs based on a comprehensive estimation of the entropic contribution to the free energy changes. This protocol can be extended to other reactions, which might also imply more than one clearly defined limiting reaction mechanism, as it appears to be the case for a variety of reactions involving reagents of type 1 that have been reported in recent years.[33]
Acknowledgment The authors would like to thank Julie Charpentier and Halua Pinto de Magalha~es for their valuable comments. Keywords: hypervalency iodanes reaction mechanisms solvent effect trifluoromethylation ab initio molecular dynamics metadynamics activation parameters entropy single electron transfer
How to cite this article: O. Sala, H. P. L€ uthi, A. Togni, M. Iannuzzi, J. Hutter J. Comput. Chem. 2015, 36, 785–794. DOI: 10.1002/jcc.23857
]
Additional Supporting Information may be found in the online version of this article.
[1] K. M€ uller, C. Faeh, F. Diederich, Science 2007, 317, 1881. [2] T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. Engl. 2013, 52, 8214. [3] K. Niedermann, N. Fr€ uh, E. Vinogradova, M. S. Wiehn, A. Moreno, A. Togni Angew. Chem. Int. Ed. Engl. 2011, 50, 1059. [4] O. Sala, H. P. L€ uthi, A. Togni, J. Comput. Chem. 2014, 35, 2122.
794
Journal of Computational Chemistry 2015, 36, 785–794
[5] H. Pinto de Magalh~aes, Reactivity of electrophillic trifluoromethylating hypervalent lambda-3-iodane reagents, Master’s Thesis, ETH Z€ urich, Z€ urich, 2011. [6] O. Sala, Quantum chemical investigation of the solvent effect on two competing trifluoromethylation reaction mechanisms involving lambda-3-iodane reagents, Master’s Thesis, ETH Z€ urich, Z€ urich, 2012. [7] H. Pinto de Magalh~aes, H. P. L€ uthi, A. Togni, J. Organic Chem. 2014, 79, 8374. [8] A recent computational work concerned with the reaction of alkynyl iodanes with thiols seems to indicate a concerted pathway for the CAS bond forming process resembling a RE. R. Frei, M. D. Wodrich, D. P. Hari, P.-A. Borin, C. Chauvier, J. Waser, J. Am. Chem. Soc. 2014, 136, 16563. [9] A. Milischuk, D. V. Matyushov, J. Phys. Chem. A 2002, 106, 2146. [10] L. Sutto, S. Marsili, F. L. Gervasio, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 771. [11] A. Barducci, M. Bonomi, and M. Parrinello, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2011, 1, 826. [12] N. Santschi, Hypervalent Iodine Trifluoromethylating Agents at Work. PhD Thesis, ETH Z€ urich, Z€ urich, 2013. [13] O. Sala, S. Jungen, H. P. L€ uthi, M. Iannuzzi, A. Togni (in preparation). [14] Becke, Phys. Rev. A 1988, 38, 3098. [15] C. Lee, W. Yang, R. Parr, Phys. Rev. B 1988, 37, 785. [16] W. Kohn, L. Sham, Phys. Rev. 1965, 140, A1133. [17] J. VandeVondele, J. Hutter, J. Chem. Phys. 2007, 127, 114105. [18] J. VandeVondele, M. Krack, F. Mohamed, M. Parrinello, T. Chassaing, J. Hutter, Comput. Phys. Commun. 2005, 167, 103. [19] The CP2K developers group, http://www.cp2k.org, 2013 Version 2.5. [20] J. Hutter, M. Iannuzzi, F. Schiffmann, and J. VandeVondele, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2014, 4, 15. [21] S. Goedecker, M. Teter, J. Hutter, Phys. Rev. B 1996, 54, 1703. [22] S. Nos e, J. Chem. Phys. 1984, 81, 511. [23] W. G. Hoover, Phys. Rev. A 1985, 31, 1695. [24] G. Bussi, D. Donadio, M. Parrinello, J. Chem. Phys. 2007, 126, 014101. [25] M. Iannuzzi, A. Laio, M. Parrinello, Phys. Rev. Lett. 2003, 90, 238302. [26] G. Jenner, J. Phys. Organic Chem. 2002, 15, 1. [27] A. Bondi, J. Phys. Chem. 1964, 68, 441. [28] D. E. Williams, D. J. Houpt Acta Crystallograph Section B 1986, 42, 286. [29] J. R. Pliego, J. M. Riveros J. Phys. Chem. A 2001, 105, 7241. [30] C. Michel, A. Laio, A. Milet, J. Chem. Theory Comput. 2009, 5, 2193. [31] W. R. Dolbier, Chem. Rev. 1996, 96, 1557. PMID: 11848804. [32] C. Yamada, E. Hirota, J. Chem. Phys. 1983, 78, 1703. [33] J. Charpentier, N. Fr€ uh, A. Togni, Chem. Rev. 2015, 115, 650. [34] N. Fr€ uh, A. Togni, Angew. Chem. Int. Ed. 2014, 53, 10813.
Received: 3 December 2014 Revised: 23 January 2015 Accepted: 25 January 2015 Published online on 12 March 2015
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