This is the accepted version of the journal article: Norjmaa, Gantulga; Maréchal, Jean-Didier; Ujaque Pérez, Gregori. «Reaction rate inside the cavity of [Ga4L6]12− supramolecular metallocage is regulated by the encapsulated solvent». Chemistry, Vol. 26, issue 31 (June 2020), p. 6988-6992. 5 pàg. DOI 10.1002/chem.201905608 This version is available at https://ddd.uab.cat/record/279242 under the terms of the license COMMUNICATION Reaction Rate Inside the Cavity of [Ga4L6]12- Supramolecular Metallocage is Regulated by the Encapsulated Solvent Gantulga Norjmaa, Jean-Didier Maréchal* and Gregori Ujaque*[a] Abstract: In the present study the dependence of the reaction rate of metallocage, but not in solution. The ratio between measured carbon-carbon reductive elimination from R3PAu(MeOH)(CH3)2 Michaelis-Menten rate constants, kcat(PEt3)/ kcat(PMe3), is complexes inside [Ga4L6]12- metallocage on the nature of the calculated to be 103, whereas the ratio between observed phosphine ligand is investigated by computational means. The uncatalyzed rate constants, kuncat(PEt3)/ kuncat(PMe3), is around reductive elimination mechanism is analyzed in methanol solution and 2.7 (Scheme 1). Understanding the origin of such a different inside the metallocage. Classical molecular dynamics simulations behavior is a challenge from both chemical and computational reveal that the smaller the gold complex (which depends on the point of view but could lead to major improvement in developing phosphine ligand size) the larger the number of solvent molecules novel metallocages and/or looking for new guest reactions. encapsulated. The size of the phosphine ligands defines the space Theoretical analysis are key for understanding catalysis;[29–31] that is left available inside the cavity that can be occupied by solvent though computational studies on supramolecular catalysis are still molecules. The Gibbs energy barriers calculated at DFT level, in scarce.[32–39] In the case of highly charged hosts, as the [Ga4L6]12- excellent agreement with experiment both in solution and in the metallocage, all theoretical investigations indicate that metallocage, show that the presence/absence of explicit solvent electrostatic effects are essential for the rate acceleration.[40–43] In molecules inside the cavity significantly modifies the reaction rate. our previous study, we showed that not only encapsulation by the host, but also microsolvation is important for lowering the Gibbs energy barrier of the reductive elimination from the cationic Au(III) Supramolecular catalysis is a very rapid expanding discipline that complex, R3PAu(MeOH)(CH3)2, inside [Ga4L6]12-.[43] We here joins catalysis and supramolecular chemistry.[1–8] Several investigate computationally the origin of the different catalytic supramolecular hosts have been designed as nanoreactors and behavior observed experimentally for C-C reductive elimination applied to the host-guest catalysis, with metallocages playing a using PEt3 and PMe3 as ligands for the same gold complex prominent role.[9–12] Metallocages (MxLy) are synthesized from (Scheme 1). metal ions and organic ligands (linkers) and offer well defined cavities in size and shape to host molecules and chemical reactions.[13,14] Examples include Raymond’s Ga4L6,[15] Fujita’s Pd6L4,[16] Nitschke’s Fe4L6,[17], Lusby’s Pd2L4,[18] among others.[19,20] The tetrahedron supramolecular metallocage, K12[Ga4L6], developed by Raymond and coworkers, has been applied to many reactions as the C-C reductive elimination from Au(III) and Pt(IV) complexes,[21] the orthoformate hydrolysis,[22] Nazarov cyclization,[23] the hydroalkylation,[24] etc.[25–27] The great catalytic power of the metallocage, [Ga4L6]12-, for the C-C reductive elimination has been studied in detail by Bergman, Raymond and Toste.[21,28] One of the most interesting findings regarding the relationship between the metallocage and the hosted catalytic system is related to the dependence of the catalytic kinetics in function of the nature of the phosphine ligand. Indeed, the presence of PEt3 vs. PMe3 as gold ligand significantly influences the Gibbs energy barrier of the reductive elimination inside the Scheme 1. Schematic representation of reductive elimination from [(R3P)Au(I)(CH3)2] complex, 1. Reaction in MeOH solution (red arrow) and within [Ga4L6]12– metallocage 3, (green arrow). 1M: R=Me; 1E: R=Et. [a] G. Norjmaa, Dr. JD. Maréchal, Dr. G. Ujaque Departament de Química and Centro de Innovación en Química Avanzada (ORFEO-CINQA) Universitat Autònoma de Barcelona The C-C reductive elimination reaction is evaluated 08193 Cerdanyola del Valles, Barcelona, Catalonia, Spain computationally for [Me3PAu(I)(CH3)2] 1M as starting reactant in E-mail: jeandidier.marechal@uab.cat, gregori.ujaque@uab.cat MeOH solution (Scheme 1) including the first solvation shell explicitly (12 MeOH molecules; Figure 1 black profile).[44] Assuming the formation of the cationic species 2M-12 ([Me3PAu(MeOH)(CH3)2]+) the calculated Gibbs energy barrier is Supporting information for this article is given via a link at the end of 26.2 kcal/mol (Figure 1), in excellent agreement with the the document estimated value of 27.2 kcal/mol obtained experimentally from COMMUNICATION the measured rate constant of 6.6·10-8 s-1 at 298K.[21] In the Figure 1. Gibbs energy profiles (in kcal/mol) for the reductive elimination in MeOH solution and in metallocage. transition state, TS_2M-12, the forming C-C bond distance is 2.176 Å. For comparison, the results for complex 2E with PEt3 lead to a Gibbs energy barrier is 25.0 kcal/mol,[43] TS_2E-12, also in very good agreement with the experimental value of 26.7 Based on the molecular dynamics simulations, the reductive kcal/mol. Therefore, the difference in calculated Gibbs energy elimination process inside the metallocage was computed at DFT barriers for gold complexes with PMe3 and PEt3 ligands in solution level using the system 2M-2⊂3 (a model that includes the gold is 1.2 kcal/mol (26.2 kcal/mol vs 25.0 kcal/mol, from the starting complex, two solvent MeOH molecules with one coordinated, and gold complexes) which is also close to the experimental difference the [Ga4L6]12- metallocage 3).[44] The Gibbs energy barrier is 20.7 of 0.5 kcal/mol (Figure S4b). Interestingly, the forming C-C bond kcal/mol (Figure 1, green profile), quite close to the estimated distances in the transition states are very similar, 2.176 Å and value of 19.5 kcal/mol from the experimental rate constant of 2.177 Å for gold complexes with PMe3 and PEt3 ligands, 3.3·10-2 s-1 at 298K.[21] The forming C-C bond distance in respectively. transition state, TS_2M-2⊂3, is 2.174 Å is very similar to that in So far the study clearly indicates that electronic effects of the solution, 2.176 Å, for TS_2M-12. This shows that the geometry of phosphine ligand does not have major contribution in the the transition state is not significantly affected by encapsulation. difference observed in the rate acceleration. Following on the Importantly, the analysis for the encapsulated gold complex with previous findings on the PEt3 system, we focused on PEt3, 2E⊂3, showed that no additional solvent molecules (apart microsolvation effects. To evaluate them two additional models from the coordinated one) are present inside the cavity. The for the complex with PMe3, including one or two explicit MeOH calculated barrier is 15.5 kcal/mol is quite close to 16.7 kcal/mol molecules, 2M and 2M-2, were considered. In these cases, the value estimated from the experimental rate constant of 3.4 s-1.[21] Gibbs energy barrier diminishes to 21.0 and 23.7 kcal/mol, Both Gibbs energy barriers are in very good agreement with respectively. These results are analogous from those of our experiment and the comparison between these two processes previous study for complex 2E (Figure S4b):[43] removing explicit gives a ∆∆G‡ of 5.2 kcal/mol also in good agreement with solvent MeOH molecules around the cationic gold complex observed experimental value of ca. 3.0 kcal/mol. decreases the Gibbs energy barrier of the reductive elimination. In order to analyze microsolvation and encapsulation effects for To proceed with the study of the encapsulated reaction we 2M-2 system (containing PMe3), the reaction can be formally performed first classical molecular dynamics (MD) simulations of described in two hypothetic processes: (i) removing explicit the gold complex inside metallocage 3.[44] Calculations were microsolvation around the gold complex (until there are only two carried out within a periodic box of explicit solvent MeOH solvent molecules, 2M-2; from black to purple profiles in Figure 1) molecules. Two systems were evaluated: (i) 2M⊂3 containing the and (ii) encapsulating this system into the metallocage (from square planar gold complex, 2M, encapsulated in the metallocage purple to green profile in Figure 1). The first process diminishes 3, and (ii) 1M-I⊂3 containing a T-shaped gold complex, 1M-I, the barrier by 0.7 kcal/mol, whereas the second decreases the encapsulated in the metallocage 3. Because of the relevance of barrier by 3.0 kcal/mol for 2M-2 (Figure S6). The effect of the solvent environment identified in the first part of the study, the microsolvation and encapsulation for 2E (containing PEt3) were occupancy of methanol molecules into the cage was first analysed. found to be diminishing the barrier by 5.7 and 3.1 kcal/mol, Both systems show that there are two solvent MeOH molecules respectively.[43] The main difference comes from the in the cavity of the metallocage along with the gold complex during microsolvation process: in 2M-2, the gold complex (with PMe3) is the simulation time (over 100 ns; Figure S1). Statistical analysis surrounded by two MeOH solvent molecules (one coordinated of the cavity size of the free or loaded metallocages from the MD and one not) whereas in 2E the gold complex (with PEt3) contains simulations show that its weighted average volume is 429 ± 84.8 only one (the one coordinated). According to the calculated Å3 independently of its loaded state (see Table S1). These results barriers the presence of the second MeOH solvent molecule for point out that the relevant models should account with two solvent the complex with the smaller phosphine ligand has a decisive role MeOH molecules inside the metallocage. in hampering the reaction. So far, our study points out that the difference in microsolvation between 2M⊂3 and 2E⊂3 is likely to be the main responsible of the change in acceleration rate observed experimentally. We decided to investigate further the origin and the impact of such changes in the solvation profiles. First a series of calculations were carried out on 2M⊂3; a system where the square-planar gold complex 2M inside the metallocage has no additional solvent molecules apart from the coordinated one (Figure S3). When comparing 2M⊂3, and 2M-2⊂3, it appears that: (i) DFT optimized systems show that the Gibbs energy barrier decreases from 20.7 kcal/mol for 2M-2⊂3 (Figure S5) to 13.0 kcal/mol for 2M⊂3. The Gibbs energy barrier diminishes by removing a surrounding solvent molecule from the cavity which indicates that the presence of solvent inside the metallocage significantly influences the barrier and confirming the importance of microsolvation. COMMUNICATION (ii) Despite 2M⊂3 shows lower transition state barriers than 2M- coordinated MeOH molecule inside the cavity that causes a 2⊂3, the latter provides with the closest value to the decrease in the reaction rate. The size of the gold complex as well experiment[45]. Similar behavior was found when comparing as the size of the same cavity govern the space availability to energy barriers for the gold system with PEt3, (2E⊂3 vs. 2E- accommodate additional MeOH solvent molecules, and the 2⊂3; 15.4 kcal/mol vs. 19.7 kcal/mol, respectively). The lower presence/absence of these solvent molecules modifies the computed barriers correspond to processes where the reaction rate for the process. This evidences that size matters in reactant disposition (2M⊂3) is hardly reachable in this solvent encapsulated metallocage catalysis and that the improvement of according to MD analysis. However, a more realistic the catalytic profile of encapsulated catalysis is far from a “simple” description of the reactant inside the metallocage (2M-2⊂3) result of the incorporation of the reactive complex in the cage but gives a closer energy barrier compared to the experiment a fine balance in the interplay between host, guest and solvent (16.7 kcal/mol). This highlights that the experimental molecules. Size, shape, solvent accessibility, and modularity of behaviors observed for 2E and 2M encapsulated systems in the cage dimension are magnitudes that contribute to the rate 3 can be explained on the basis of different numbers of acceleration. Understanding and foreseeing these elements, solvent molecules in the cavity. eventually throughout computational means, could be in the (iii) C-C bond distance for TS_2M⊂3 of 2.161 Å is only slightly rational design of host-guest catalysis. shortened compared to that for TS_2M-2⊂3, 2.176 Å. This shows that there is structurally little constraints on the transition state structure in function of the number of solvent molecules (Figure S2). Acknowledgements (iv) All the DFT optimized structures of the entire study show cavities that are within 300-500 Å3 range, in agreement with The authors acknowledge the financial support of the Spanish MD simulations. For TS_2M⊂3 the volume falls down to 237 MINECO-FEDER (Grants CTQ2017-87889-P and CTQ2016- Å3; a value quite far from what appear in room temperature 81797-REDC). UAB is also acknowledged by a PIF grant to G.N., and bulk conditions. 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Himo, F. Maseras, L. Perrin, ACS Catal. 2019, 9, 6803– 6813. [32] P. Carlqvist, F. Maseras, Chem. Commun. 2007, 748–750. COMMUNICATION Entry for the Table of Contents (Please choose one layout) Layout 1: COMMUNICATION The reductive elimination process for G. Norjmaa, JD. Maréchal*, G. Ujaque* R3PAu(MeOH)(CH3)2 complexes are investigated in MeOH solution and Page No. – Page No. inside the [Ga4L6]12- metallocage. The Reaction Rate Inside the Cavity of size of the metal complex and the size [Ga4L6]12- Supramolecular of the cavity govern the space Metallocage is Regulated by the availability to accommodate additional Encapsulated Solvent MeOH solvent molecules. Reaction rate is regulated by the presence/absence of these solvent molecules. Layout 2: COMMUNICATION Author(s), Corresponding Author(s)* ((Insert TOC Graphic here)) Page No. – Page No. Title Text for Table of Contents