Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202102250 Origin of the Rate Acceleration in the C C Reductive Elimination from Pt(IV)-complex in a [Ga4L6]12 Supramolecular Metallocage Gantulga Norjmaa,[a] Jean-Didier Maréchal,*[a] and Gregori Ujaque*[a] Abstract: The reductive elimination on [(Me3P)2Pt- experimental values for both environments. The effect of (MeOH)(CH3)3] +, 2P, complex performed in MeOH solution microsolvation and encapsulation on the rate acceleration are and inside a [Ga4L6]12 metallocage are computationally evaluated and shows that the latter is far more relevant, analysed by mean of QM and MD simulations and compared conversely to 2Au. Energy decomposition analysis indicates with the mechanism of gold parent systems previously that the encapsulation is the main responsible for most of the reported [Et3PAu(MeOH)(CH3)2] +, 2Au. The comparative analy- energy barrier reduction. Microsolvation and encapsulation sis between the encapsulated Au(III) and Pt(IV)-counterparts effects are not equally contributing for both metal systems shows that there are no additional solvent MeOH molecules and consequently, the reasons of the rate acceleration are not inside the cavity of the metallocage for both systems. The the same for both metallic systems despite the similarity Gibbs energy barriers for the 2P reductive elimination between them. calculated at DFT level are in good agreement with the Introduction complexes (Au(III) and Pt(IV) complexes) by Bergman, Raymond and Toste groups.[22,29] The reaction from Au(III) complexes was Supramolecular catalysis is an interesting discipline that also computationally investigated by us,[30,31] and by Head- combines catalysis and supramolecular chemistry.[1–8] In the last Gordon group.[32,33] For the case of Pt(IV) a computational few decades, several supramolecules have been designed as mechanistic analysis on the origin of rate enhancement is microenvironments for chemical reactions and applied to the missing. A general scheme on the processes here investigated host-guest catalysis, with metal–organic cages (MOCs) playing a are shown in Scheme 1. prominent role.[9–12] Metal–organic cages (MxLy), also named Theoretical studies are essential to understand catalytic supramolecular organometallic cages (SOCs) or metallocages,[13] processes;[34–37] however, computational works on are prepared from metal ions and organic ligands and have well supramolecular catalysis are still scarce.[38–47] In the case of defined cavities in size and shape; they are able to host highly anionic hosts, as the [Ga4L6]12 metallocage, all computa- molecules or ions and chemical reactions.[14,15] Examples are tional studies show that electrostatic effects are crucial for the Raymond’s Ga4L6,[16] Fujita’s Pd6L4,[17] Nitschke’s Fe4L6,[18] Lusby’s rate acceleration.[30–33,48,49] In our previous works, we studied the Pd2L4,[19] among others.[20,21] reductive eliminations from the Au(III) complexes, [R3PAu The metallocage K12[Ga4L6] developed by Raymond and (MeOH)(CH3)2] +, in the [Ga4L6]12 and showed that not only coworkers has been successfully applied to accelerate many encapsulation by the host, but also microsolvation plays an reactions: alkyl-alkyl reductive elimination,[22] orthoformate important role for lowering the Gibbs energy barrier of the hydrolysis,[23] Nazarov cyclization,[24] hydroalkylation,[25] etc.[26–28] reductive elimination from the Au(III) complexes inside Among these reactions, the alkyl-alkyl reductive elimination has [Ga4L6]12 .[30,31] been studied in detail for high valent transition metal In the present study, we investigate computationally the origin of the catalysis observed for alkyl-alkyl reductive [a] G. Norjmaa, Dr. J.-D. Maréchal, Dr. G. Ujaque elimination from the Pt(IV)-complex, [trans-(Me3P)2Pt- Departament de Química and Centro de Innovación en Química Avanzada (MeOH)(CH3)3] +, 2P. The analysis is performed first in solution (ORFEO-CINQA) and then inside the metallocage, [Ga4L6]12 , 3, (Scheme 1). Universitat Autònoma de Barcelona Microsolvation and encapsulation effects on the reduction of 08193 Cerdanyola del Valles, Barcelona, Catalonia (Spain) E-mail: jeandidier.marechal@uab.cat the Gibbs energy barrier in the metallocage are analysed. gregori.ujaque@uab.cat Moreover, comparisons of the encapsulation effects of the Supporting information for this article is available on the WWW under [Ga4L6]12 metallocage on the Au(III) and the Pt(IV) reductive https://doi.org/10.1002/chem.202102250 elimination processes are performed. This could lead to © 2021 The Authors. Chemistry - A European Journal published by Wiley- significant contribution in both understanding and developing VCH GmbH. This is an open access article under the terms of the Creative chemical reactions in confined space. Commons Attribution Non-Commercial License, which permits use, dis- tribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Chem. Eur. J. 2021, 27, 15973 – 15980 15973 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202102250 Scheme 1. Schematic representation of reductive elimination from [trans-(Me3P)2Pt(I)(CH3)3] complex, 1P. Reaction in MeOH solution (blue arrow) and inside [Ga4L6]12 metallocage 3, (orange arrow). Results and Discussion The alkyl-alkyl reductive elimination from the Pt(IV) complexes provide a rich ensemble of experimental data. First, in terms of catalysis, the reaction is highly accelerated in the presence of metallocage, [Ga4L6]12 , 3 although the catalytic profile is function of the isomer. For cis-[(Me3P)2PtI(CH3)3], the measured rate constant, kcat, is 2.4 × 10 2 s 1, with an acceleration (kcat/ kuncat) of 2.6 × 104 for the encapsulated system.[22] For trans- [(Me3P)2PtI(CH3)3] complex, the process inside the [Ga4L6]12 was Figure 1. Cis- and trans- isomers of cationic Pt(IV) complex, [(Me3P)2Pt(MeOH)(CH3)3] +. too fast at the catalytically relevant temperature (45 °C) for accurate monitoring by 1H NMR; nevertheless, at 25 °C the measured rate constant was 2.0 × 10 2 s 1.[29] Experiments also Reaction in solution indicate that the complex needs to become positively charged, thus losing the iodide ligand, to be encapsulated by the To investigate the catalytic properties of the metallocage, the metallocage 3. Such phenomenon is not observed in the reaction was initially evaluated in solution. The reaction inside absence of the metallocage. Finally, experimental observations the metallocage takes place through the cationic complex once also suggest that the trans-isomer of the Pt(IV) cationic the iodide is released. For the sake of comparison, the reaction complex, 2P, is the one involved in the catalytic cycle for is solution was analysed for both the neutral and cationic generating the C C bond, whereas the cis-isomer, cis2P, is an complexes (and both cis and trans isomers). off-cycle resting state (Figure 1). Based on these experimental The reductive elimination from the cis-[(Me3P)2PtI(CH3)3], evidences we decided to perform the comparative analysis for cis1P, complex was first evaluated because this process can be the reductive elimination in solution and inside the metallocage directly compared with experiment (Figure 2). The measured on the trans-Pt(IV) isomer. rate constant of 9.2 × 10 7 s 1 at 40 °C in MeOH solution, Considering the experimental data exposed previously our corresponds to a Gibbs energy barrier of 27.0 kcal/mol. The working methodology consists in: 1) studying the reaction in calculated Gibbs energy barrier for the reductive elimination solution, 2) studying the reaction in the metallocage, 3) inves- step for the cis1P complex in solution is 28.7 kcal/mol (the stigating the origin of the rate acceleration within the metallo- iodide ligand is non-coordinated at the transition state, with a cage compared to that in solution, and finally 4) comparative Pt···I distance of 4.5 Å). Nevertheless, the reaction is supposed analysis on the origin of the catalysis between the Pt(IV) and to go through the formation a cationic species by losing the the Au(III)-counterparts. iodide ligand. Two complexes may be formed, a penta- coordinated complex cis-[(Me3P)2Pt(CH3)3] +, cis1P-I, or the solvento complex cis-[(Me3P)2Pt(MeOH)(CH3)3] +, cis2P. The rela- Chem. Eur. J. 2021, 27, 15973 – 15980 www.chemeurj.org 15974 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202102250 Figure 2. Gibbs energy profiles of reductive eliminations from cis- and trans-Pt(IV) species in solution. tive Gibbs energy value for the formation of cis1P-I complex is converge once the solvento complex is considered. Thus, 9.7 kcal/mol. Nevertheless, such a penta-coordinated complex is including the coordinated solvent molecule along with the not stable. The inclusion of explicit solvent molecules in the continuum model nicely reproduces the experimental value for calculation, a MeOH molecule, shows a spontaneous binding to the reductive elimination barrier; no additional solvent mole- the metal species forming the solvento complex cis2P, with a cules need to be considered. Indeed, calculated barriers range relative energy of 0.3 kcal/mol. The reductive elimination from from 25.4 to 27.4 kcal/mol, in excellent agreement with this intermediate has a relative Gibbs energy barrier of experimental value of 27.0 kcal/mol. 27.4 kcal/mol. The reductive elimination from complex trans-[(Me3P)2PtI To evaluate microsolvation for this process, we calculated (CH3)3], 1P, was also analysed (Figure 2). 1P has a relative Gibbs the Gibbs energy barrier for the reductive elimination process energy of 3.9 kcal/mol compared to cis1P, with an energy including additional solvent molecules explicitly. For the case of barrier for the direct reductive elimination of 22.5 kcal/mol. This the solvento complex with an additional MeOH hydrogen- complex loses the iodide ligand and can potentially form two bonding the coordinated one, complex cis2P-2, the Gibbs intermediates: a penta-coordinated complex trans-[(Me3P)2Pt- energy barrier slightly decreases to 26.9 kcal/mol. The Gibbs (CH3)3] +, 1P-I, or the solvento complex trans-[(Me3P)2Pt- energy barrier was also calculated for the systems including (MeOH)(CH3)3] +, 2P. Their relative energies are 14.5 and 1.3 kcal/ three, cis2P-3, four, cis2P-4 and five, cis2P-5 explicit solvent mol, respectively, compared to the most stable complex, cis1P. molecules. The values obtained are 26.3, 25.4 and 26.9 kcal/mol, Once again, the penta-coordinated complex, 1P-I, is not stable: for transition states TS_cis2P-3, TS_cis2P-4 and TS_cis2P-5, a MeOH molecule spontaneously binds the metal species respectively (Table 1). These barriers are quite similar and they forming 2P. The relative Gibbs energy of 2P and cis2P complexes are 1.3 and 0.3 kcal/mol, respectively. The reductive elimination was calculated from intermediate 2P with a relative Table 1. Gibbs energy barrier for the reductive elimination as a function of Gibbs energy barrier of 23.8 kcal/mol, TS_2P. Inclusion of solvent molecules included in the model (in kcal/mol). another explicit solvent MeOH, forming species 2P-2, it gives Explicit solvent molecules Cis-isomer of Pt(IV) Trans-isomer of Pt(IV) rise to a Gibbs energy barrier of 26.3 kcal/mol, TS_2P-2. The 0 (penta coordinated) 18.3 11.7 values obtained for the Gibbs energy barriers including addi- 1 27.4 23.8 tional solvent molecules are 24.4, 24.4 and 24.3 kcal/mol, for 2 26.9 26.3 3 26.3 24.4 TS_2P-3, four, TS_2P-4 and five, TS_2P-5, respectively (Table 1). 4 25.4 24.4 In agreement with the cis isomers, these results illustrate that 5 26.9 24.3 microsolvation effects are not significantly contributing to the Chem. Eur. J. 2021, 27, 15973 – 15980 www.chemeurj.org 15975 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202102250 reduction of Gibbs energy barrier once the solvento complex is Reaction inside the metallocage considered. As far as the cis- and trans- complexes are affecting the reductive elimination itself, all the barriers for the cis As previously commented, for the reaction taking place inside complex are ~ 5 kcal/mol systematically higher than their the [Ga4L6]12 metallocage 3 it is assumed that the trans isomer analogous trans complexes (i. e. TS_cis2P vs. TS_2P corresponds is the one involved in the catalytic cycle. Thus, we performed to 27.4 vs. 23.8 kcal/mol, or TS_cis1P vs. TS_1P corresponds to the computational analysis on the encapsulated trans isomer of 28.7 vs. 22.5 kcal/mol, respectively). Therefore, the trans isomer the Pt complex, 2P. is always favoured for the reductive elimination over the cis First, we performed classical molecular dynamic (MD) isomer. This is in line with the fact that the trans isomer is the simulation of 2P complex inside metallocage, 3, (2P�3).[50] one involved in the catalytic reaction inside the metallocage Classical MD simulations were carried out within a periodic box (see below). of explicit solvent MeOH molecules. The simulation of the host- The optimized geometries of the transition states for cis and guest complex, 2P�3, shows that there are no solvent MeOH trans species are shown in Figure 3. In the transition states, molecules inside the metallocage along with 2P complex during TS2P-2, and TScis2P-2, the forming C C bond distances are 2.03 Å the simulation time (over 100 ns; Figure S1). This suggests that and 2.06 Å, showing that the forming C C bond distances are 2P fills in the cavity of the metallocage without availability for quite similar for both trans- and cis-isomers of the Pt(IV) accommodating additional solvent molecules. In fact, the complex. Regarding the effect of microsolvation in the geo- packing coefficient of 59 % is calculated for the optimized metries, for transition state, TS_2P, the forming C C bond structure of the 2P�3 complex, which is consistent with the distance is 2.04 Å compared to that of 2.03 Å for the TS_2P-2. Rebek’s 55 % rule. This indicates that microsolvation does not significantly modify The reductive elimination process inside the metallocage the C C forming bond distance at the transition state. Similar was computed at DFT-D3 level using the host-guest complex, behaviour is found when comparing TS_cis2P-2 and TS_cis2P-5 2P�3. This system was selected based on the MD simulations: geometries with 2 and 5 solvent molecules explicitly included. they indicate that no additional solvent molecules are encapsu- Overall, microsolvation effects are not playing a significant role lated. The calculated Gibbs energy barrier is 17.3 kcal/mol in the geometry of the reductive elimination transition states (Figure 4, green profile), in very good agreement with the for cis and trans isomers, once the solvento complex is estimated value of 19.8 kcal/mol from the experimental rate considered. constant of 2.0 · 10 2 s 1 at 25 °C.[29] These results contrast with what was found for Au(III) A comparison of the Gibbs energy barrier of the reductive complexes. The reductive elimination of the Au(III) complex elimination in solution (24.3 kcal/mol for TS2P-5) and inside the analysed in our previous work,[30] showed that microsolvation is metallocage (17.3 kcal/mol for TS2P�3), shows that the overall crucial. In fact, it was found that by removing explicit solvent reduction is 7.0 kcal/mol. The effect of performing the reductive molecules around the complex the barrier can diminish by up elimination within the metallocage is huge. To gain under- to 5.7 kcal/mol. As far as for geometries is concerned, for the standing on the process, the microsolvation and encapsulation case of Au(III) complex, microsolvation does not modifies the effects on the barrier decrease were analysed in detail (Figure 4; geometries significantly. All these results show that micro- Table S2). As described in the previous section microsolvation solvation is playing a very different role depending on the effects are rather low. They are obtained by computing the process considered. Thus, its effect on the octahedral Pt(IV) Gibbs energy difference between the process in solution, by complex is nearly irrelevant, whereas the effect on the square considering explicit solvent molecules surrounding the metal planar Au(III) complex is decisive. complex, and the analogous process by removing explicit solvent molecules (always accounting for solvent effects by a continuum method). Their Gibbs energy barriers are 24.3 kcal/ Figure 3. Optimized geometries of the transition states of reductive eliminations from 2P, 2P-2, cis2P-2 and cis2P-5. Bond distances are in Å. Color code: Pt in brown, P in pink, C in gray, O is in red, and H in white. Chem. Eur. J. 2021, 27, 15973 – 15980 www.chemeurj.org 15976 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202102250 Figure 4. Gibbs energy profiles (in kcal/mol) for the reductive elimination in solution and inside metallocage. mol, TS_2P-5, and 23.8 kcal/mol, TS_2P, respectively (both significantly affected by encapsulation. The other metal ligand shown in Figure 4). Therefore, microsolvation effects account distances are not significantly modified either. for a decrease of the Gibbs energy barrier of only 0.5 kcal/mol. The Gibbs energy barrier is computed by adding thermal The encapsulation effect can be obtained by comparing the corrections (roughly related to the entropic term) to the Gibbs energy barrier for the reductive elimination of the potential energy (closely related to the enthalpic term). The “naked” solvento complex in solution, TS_2P, and inside the thermal correction for the process in solution is 2.2 kcal/mol, metallocage, TS_2P�3. The barrier decreases by as much as whereas it is 1.0 kcal/mol for the encapsulated process. 6.5 kcal/mol. These results illustrate that microsolvation effects Therefore, thermal effects are rather similar in both environ- are small whereas encapsulation effects are the major contrib- ments, although the reduction of the barrier is slightly lower utors to the overall Gibbs energy decrease. inside the cavity by 1.2 kcal/mol. Overall, these results suggest As far as for the geometrical parameters is concerned, the that thermal effects are not playing a significant role upon geometry of the transition state encapsulated in the metallo- encapsulation. cage is illustrated in Figure 4. The forming C C bond distance As far as the potential energy is concerned, the calculated in the transition state, TS2P�3, is 2.06 Å; this value is very similar barrier is highly affected by encapsulation by as much as to that for the transition state in solution, TS2P, of 2.04 Å 7.7 kcal/mol. This magnitude can be analysed in terms of strain (Figure 3). This evidences that the forming bond distance is not and interaction energies. In solution, the potential energy barrier is 26.0 kcal/mol (2P!TS_2P; black line in Figure 5). The Figure 5. Decomposition analysis of Gibbs energy and potential energy barriers for the process in solution and inside the metallocage. Energies in kcal/mol. Chem. Eur. J. 2021, 27, 15973 – 15980 www.chemeurj.org 15977 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202102250 barrier for the process calculated in solution taking frozen effect of the metallocage is larger for Pt(IV) than for Au(III) by geometries of the encapsulated reactant (2P*) and the encapsu- 3.4 kcal/mol. Overall, microsolvation effects are much larger in lated transition state (TS2P*), and considering solvent effects by the case of Au(III), whereas encapsulation effects are larger for continuum model (2P*!TS_2P*), is 26.2 kcal/mol (blue line in the case of Pt(IV) complex. Figure 5). This barrier is very similar to the one obtained in We performed a comparative analysis in terms of potential solution 26.0 kcal/mol. This is because the reactant and energy and thermal correction magnitudes. Comparison of the transition state are both similarly strained upon encapsulation: thermal correction term in solution and encapsulated processes reactant is strained by 3.2 kcal/mol (2P!2P*), whereas the shows different trends for both metal complexes. In solution, transition state is strained by 3.4 kcal/mol, (TS_2P!TS_2P*), thermal corrections are rather similar for both the Pt(IV) respectively. Therefore, the overall strain effect is negligible. complex ( 2.2 kcal/mol; Figure 5) and the Au(III) complex This means that the effect of the metallocage on the geometry ( 3.0 kcal/mol).[30] Inside the metallocage they are calculated to modification along the reaction is practically insignificant be 1.0 kcal/mol for the Pt(IV) complex (Figure 5), favouring the (ΔΔE�strain = 0.2 kcal/mol). reaction, whereas they are 1.7 kcal/mol for the Au(III) complex, The potential energy barrier calculated for the encapsulated disfavouring the reaction. Anticipating the sign of the thermal process, 2P�3! TS_2P�3, is 18.3 kcal/mol (green line in contributions is therefore quite difficult even for similar Figure 5). These results indicate that the reductive elimination processes. from the Pt(IV) complex 2P is reduced by 7.9 kcal/mol upon Further energy decomposition analysis of the potential encapsulation. Therefore, encapsulation accounts for the largest energy allows identifying the strain and interaction energies influence in reducing the barrier. When considering strain associated. Contributions from the strain term to the reduction (0.2 kcal/mol) and interaction (-7.9 kcal/mol) energies together, of energy barrier for both complexes are 0.2 kcal/mol for Pt(IV) the potential energy barrier for the process is reduced by (Figure 5) and 1.2 kcal/mol for Au(III) complexes, respectively. 7.7 kcal/mol (from 26.0 to 18.3, Figure 5). A summary of the The strain term is nearly negligible for both complexes. The decomposition analysis of the reduction of the Gibbs energy interaction term is calculated to be 7.9 kcal/mol for Pt(IV) barrier over encapsulation is presented in Table S2. complex (Figure 5), and 9.0 kcal/mol for the Au(III) complex, A non-covalent interaction (NCI)[51,52] analysis of the encap- respectively. It is the most important term and similar to both sulated reactant, 2P�3, and transition state, TS 2P�3, shows complexes. Interestingly, Pt(IV) and Au(III) complexes have a that the greatest differences between both structures come very different geometry (octahedral and square planar, respec- from the interaction with the coordinated MeOH solvent tively), but the interaction energy is similar for both cases. This molecule. In the TS such a molecule is not bonded to the metal reveals that the shape of the complex may not be so relevant thus becoming available to attractively interact with the metal- for the encapsulated process. Overall, the effect of the metallo- locage through one of the oxygens of the metallocage (H···O cage environment on the potential energy is crucial for acceptor distance of 1.84 Å; Figure S2). Such an interaction is diminishing the barrier for both processes. missing in the reactant. Moreover, the Me ligands involved in In summary, the contribution of microsolvation and encap- the forming C C bond interact slightly strongerly with one of sulation terms to diminishing the Gibbs energy barrier are not the naphthalene rings of the metallocage than when they are similar for both complexes. Whereas microsolvation is the most pure Me ligands in the reactant state. important contribution for Au(III) complex, for Pt(IV) it is by far We also performed a comparative analysis among the the encapsulation term. Regarding the energy decomposition results for Pt(IV) complex (here studied) and Au(III) complex analysis, it shows that the strain term is negligible for both (studied in a previous work).[30] The Gibbs energy barrier complexes, whereas the interaction term is clearly the most reduction for the encapsulated process in the case of Au(III) important one. This agrees with previous works on related complex, [(Et3P)Au(MeOH)(CH3)2] + , is 8.8 kcal/mol, whereas that processes.[32,33,49] for Pt(IV) complex, trans-[(Me3P)2Pt(MeOH)(CH3)3] +, is 7.0 kcal/ mol. Both complexes are equally positively charged, + 1, and the barrier decrease is relatively similar, though slightly larger Conclusions for the Au(III) complex. We explored if the origin of the reduction on the barrier is analogous for both complexes. The observed rate acceleration of the alkyl-alkyl reductive The MD simulations of the encapsulated complexes show elimination from the Pt(IV) complex encapsulated in the that there are no additional solvent molecules inside the cavity [Ga4L6]12 supramolecular metallocage is examined by means of for any of them. Therefore, in both cases the solvento complex computational calculations. The reaction is analysed in MeOH becomes “naked” inside the metallocage. The microsolvation solution and inside [Ga4L6]12 metallocage 3. The reaction in for the Au(III) complex was computed to be 5.7 kcal/mol, solution is investigated for cis- and trans-[(Me3P)2Pt- whereas that for Pt(IV) is 0.5 kcal/mol. Hence, microsolvation is (MeOH)(CH3)3] +, cis2P and 2P, complexes, respectively. For both very different for both metallic complexes. Note that this is a complexes, the formation of the pentacoordinated structure (by feature that depends on the reaction itself, not on the nature of losing the iodide ligand) was found to be not stable, instead, the metallocage. As far as encapsulation is concerned, the Gibbs the solvento complex was spontaneously formed. The Gibbs energy barrier decrease for the case of Au(III) was calculated to energy barriers from the trans and cis isomers of the solvento be 3.1 kcal/mol, whereas for Pt(IV) is 6.5 kcal/mol. Thus, the complex (2P and cis2P) are very similar whose values are 24.3 Chem. Eur. J. 2021, 27, 15973 – 15980 www.chemeurj.org 15978 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202102250 and 26.9 kcal/mol, respectively. They are in very good agree- parameters were taken from a general AMBER force field.[67] The ment with the experimental value of 27.0 kcal/mol for the cis simulations were performed under isothermal-isobaric (NPT) con- complex. ditions (P = 1 bar, T = 298.15 K) with a periodic box of 68 Å × 68 Å × 68 Å (MEOHBOX) including 11 K + counter ions; this corresponds to The reaction inside the metallocage was evaluated for the approximately experimental concentration of the metallocage in trans complex, 2P�3. The MD simulations show that there are solution (5 mM). To determine solvent MeOH molecules in the no additional solvent molecules inside the cage (apart from cavity, the last 100 ns were considered from a production phase of that coordinated to the metal complex). The Gibbs energy 160 ns after an equilibration period of 60 ns. barrier for the reductive elimination was found to be 17.3 kcal/ mol, in very good agreement with experimental value of 19.8 kcal/mol. The analysis of microsolvation and encapsulation Acknowledgements effects show that whereas the first is very low (0.5 kcal/mol), the latter is crucial (6.5 kcal/mol). Energy decomposition analysis, in The authors acknowledge the financial support of the Spanish turn, show that the interaction energy (between the metallo- MINECO-FEDER (Grants CTQ2017-87889-P and PID2020- cage and the solvento complex) is by far the most important 116861GB-I00). UAB is also acknowledged by a PIF grant to contribution, in agreement with other proposals.[32,33,49] The G. N. contribution of strain energies, in turn, are nearly negligible. The comparative analysis between octahedral Pt(IV) com- plex and the square planar Au(III) complex show that the Conflict of Interest decrease of the Gibbs energy barrier for the encapsulated reaction is similar, by 7.0 and 8.8 kcal/mol, respectively. The The authors declare no conflict of interest. contribution of microsolvation and encapsulation terms, how- ever, are not analogous: whereas microsolvation is the most Keywords: density functional theory · metallocage · molecular important contribution for Au(III) complex (with a relevant dynamics · platinum · reductive elimination · supramolecular contribution of encapsulation too), for Pt(IV) it is the encapsula- catalysis tion the most important term (with a slight contribution of the microsolvation term). The comparative energy decomposition analysis show that strain is negligible whereas interaction with [1] Y. Fang, J. A. Powell, E. Li, Q. Wang, Z. Perry, A. Kirchon, X. Yang, Z. Xiao, the metallocage is very similar for both metal complexes, C. Zhu, L. Zhang, F. Huang, H.-C. Zhou, Chem. Soc. Rev. 2019, 48, 4707– 4730. despite having different geometries (octahedral and square- [2] L. Zhao, X. Jing, X. Li, X. Guo, L. Zeng, C. He, C. Duan, Coord. Chem. 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