This is the accepted version of the journal article: Sciortino, Giuseppe; Muñoz-López, Sara; Lledós, Agustí; [et al.]. «Comparative Mechanistic Study on the [Au(NHC)]+-Catalyzed Hydration of Alkynes, Alkenes, and Allenes». Organometallics, Vol. 39, Issue 19 (October 2020), p. 3469-3479. DOI 10.1021/acs.organomet.0c00292 This version is available at https://ddd.uab.cat/record/277747 under the terms of the license Comparative Mechanistic Study on [Au(NHC)]+ Catalyzed Hydration of Alkynes, Alkenes and Allenes Giuseppe Sciortino,a,b Sara Muñoz-López,a Agustí Lledós,a,* Gregori Ujaque a,* a Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Catalonia and Centro de In- novación en Química Avanzada (ORFEO-CINQA), Spain E-mail: agusti@klingon.uab.es, gregori.ujaque@uab.cat b Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy Supporting Information Placeholder ABSTRACT: The addition of water molecules to unsaturated substrates is a highly desired process. Addition to alkynes are very common, whereas addition to allenes and specially alkenes are rather scarce. One of the main aims here is to perform a comparative analysis of their reaction mechanisms for the process catalyzed by Au(I); another objective is to analyze why alkenes are much less reactive than their alkynes or allenes counterparts. With this purpose the reaction mechanism for the addition of water to terminal and internal alkynes, alkenes and allenes catalyzed by an [Au(NHC)]+complex (NHC= N-heterocyclic carbene) is analyzed by means of DFT calculations. The general catalytic cycle for the three kind of substrates can be described by three main steps: (i) reactant π-coordination to the Au(I) complex, (ii) water nucleophilic addition, and (iii) protodeauration, with subtle differences among the reactants. The comparative analysis, from the evolution of the centroids of Localized Molecular Orbitals (CLMO), of the electronic rearrangements taking place in the protodeauration step reveals different mechanisms for these three substrates, both regarding the electron pair that accepts the proton and the fate of the Au-C bond pair. Calculations show that for alkenes, despite the nucleophilic additions is relatively high but affordable, protodeauration step results in any case energetically prohibitive. The main reason is not the intrinsic barrier of the protodeauration step, just a few kcal·mol-1 higher than that of alkynes, but the high energy of the water-added intermediate. This issue is not related to the strength of the Au(I)-CC bond, but to that of the C-O bond. additions of simple reagents, as ammonia,21,22 hydrazine,23 and ▪ INTRODUCTION water10, 24 to multiple CC bonds. Carbon-carbon unsaturated bonds (alkynes, alkenes, allenes) are undoubtedly among the most important functional groups that allow the synthesis of new and more complex molecules. The addition of water molecules to these unsaturated species gives rise to the formation of alcohols or ketones. 1,2 These transformations are very desirable for their redox neutrality3 and atom economy.4 Among these unsaturated species, the hydration of alkynes is by far the most common one. 5,6,7 Hy- dration of alkenes8,9 and allenes,10,11 however, are much more scarce. The reactivity between a nonpolar reactant (unsaturat- ed C-C bond) and a highly polar molecule (water) is not fa- vorable, thus, the presence of a catalyst is required for these processes to proceed. There are several metals employed as catalysts (Rh,12 Pd,13 Pt,14 Ru,15 others16) but gold17 occupies a prominent place due to its ability to activate C-C unsaturated bonds for addition reactions.18,19 Hence, gold-catalyzed addi- tions of O-based nucleophiles have been largely explored.20 The use of the simplest O-based nucleophile, water, is com- monly found for alkynes, but is much less common for alkenes and allenes. Aimed to rationalize and guide the development of synthetic Scheme 1. Gold catalyzed hydration of alkynes (an), alkenes tools that employ simple and readily available starting materi- (bn) and allenes (cn) analyzed in the present paper. R1 and R2 als to produce higher added value chemicals, our group has may be H, Me or Ph alternatively (n0-3). A schematic repre- been involved in mechanistic analysis of gold(I)-catalyzed sentation of the [Au(NHC)]+ catalyst is also shown. 1 Despite the success in the gold-catalyzed hydration of unacti- molecules used for ΔG calculation for the deprotonation pro- vated alkynes, its application to unactivated allenes, and par- cesses was taken from ref. 32 and is depicted in Figure S2. ticularly to alkenes is much more challenging. To help on its development, this article reports a comparative DFT study on the mechanism of the gold(I)-catalyzed hydration of different ▪ RESULTS AND DISCUSSION non-activated carbon-carbon unsaturated bonds. Scheme 1 summarizes the reactions studied in the present work. For In this study we investigate the reaction mechanism for the comparative purposes our previous results on the hydration of hydration of terminal and internal alkynes (HC≡CMe, a1 allenes24 will be also summarized and included here. As a HC≡CPh, a2, MeC≡CPh, a3) and alkenes (H2C=CHMe, b1, ligand for the gold catalysts we selected the N-heterocyclic H2C=CHPh, b2, MeHC=CHPh, b3) catalyzed by a carbene ligand (NHC) [1,3-bis(2,6-dimethylphenyl)imidazole- [Au(NHC)]+ complex. They were selected as representative 2-ylidine] (Scheme 1) that was employed in our previous examples of non-activated substrates and model catalyst. For study on hydration of allenes.24 Although dual activation by the sake of completeness, the previous mechanistic analysis of diaurated species has been a subject of debate in the literature allenes is also summarized and included. For comparative of [Au(NHC)]+-catalyzed phenoxylation and hydration of purposes we have also computed the reaction with the non- alkynes,25 a recent thorough kinetic study clearly points to- substituted unsaturated hydrocarbons (HC≡CH, a0; H2C=CH2, wards a reaction mechanism involving only monoaurated b0 and H2C=C=CH2, c0). intermediates,26 and we have only considered monoaurated The general mechanism for the Au(I)-catalyzed hydration can species. In addition, to compare alkyne, allene and alkene be described by means of three fundamental steps: (i) π- functionalities, regio- and stereoselectivity issues5 have been coordination of the unsaturated substrate to the Au(I) catalyst, also analyzed with the introduction of substituents in the π (ii) nucleophilic addition of water, and (iii) proton-transfer from water to the contiguous C atom of the substrate, com- bond (Scheme 1). monly named protodeauration. The catalytic cycle of the gen- eral hydration reaction was completely explored for all the ▪ COMPUTATIONAL DETAILS substrates. The water nucleophilic attack can take place from DFT calculations were carried out using the M06 functional the gold side (inner) or from the opposite side (outer). In including an ultrafine integration grid, as implemented in coherence with previous published reports,33 the barriers for Gaussian 09;27 this functional was shown to properly describe the nucleophilic addition step are very similar for both path- this type of systems,28 and was used in our previous studies.23, ways, but the next step, proton-transfer, clearly favors the 24 Basis set BS1 was used for the optimizations and general inner addition (otherwise indicated in the text). For clarity, comparison of the different pathways. With BS1 the Au atom energy profiles are described only for the lowest energy path- was described using the scalar-relativistic Stuttgart−Dresden ways. The other pathways are gathered in the Supporting SDD pseudopotential along with its associated double-ζ basis Information, as well as a comparison of the different profiles. set; a set of f polarization functions29 were also added. For H, Regarding regioselectivity, the attack of the O-nucleophile C, O and N the 6-31G(d) basis set was employed. The reac- can, in principle, take place on each of the coordinated carbon tants, intermediates, transition states, and products were opti- atoms of the substrate (Markovnikov and anti-Markovnikov mized in solvent (THF; ε = 7.4257), by means of the SMD addition in terminal substrates). Both possibilities have been continuum model. The nucleophile (water) was modelled by also taken into account. The final product is the alcohol or including three explicit water molecules (see Figure S1); such enol, depending on the starting reactant. Results are presented a model performed properly in other hydration processes.7 in different subsections for alkynes, alkenes and as a summary Considering that the protodeauration barrier may be influ- for allenes. enced by the number and disposition of the water molecules employed, for sake of comparison the same model has been A. Hydration of alkynes. retained for each substrate and pathway.7 The NHC ligand for A.1 Internal alkynes. gold catalyst was [1,3-bis(2,6-dimethylphenyl)imidazole-2- With the substrate a3 (MeC≡CPh), inner water nucleophilic ylidine] (Scheme 1); it was employed in our previous study on hydration of allenes.24 Frequency calculations were completed attack as well as the formation of the product with Me and Ph for all the optimized geometries to confirm the nature of the substituents cis to each other, entails lower barrier and yields stationary points as either transition states or minima. Connec- the most stable product (see Supporting Information). Regard- tion between transition states and intermediates was confirmed ing regioselectivity, the addition of water may take place on by usual intrinsic reaction coordinate (IRC) calculations and the Ph or Me substituted carbon atom. In Scheme 2 these two subsequent optimization to minima. Energies of the lowest pathways for the hydration of alkyne a3 are shown reporting energy pathways were refined by single point calculations on the Gibbs energy values in kcal·mol-1 for intermediates and transition states. The computed pathways show that the for- the optimized geometries, using the extended triple- def2- mation of the 1-phenylprop-1-en-1-ol, coming from the water TZVP for main group elements and quadruple- def2-TQVP addition to Me-substituted carbon (a3_5), is favored, both in including def2 pseudopotential for Au (BS2).30 All the ener- thermodynamic and kinetic grounds (Scheme 2). The catalytic gies given in the Schemes are Gibbs energies in solution cycle starts by coordination of alkyne a3 to the gold(I) catalyst (THF) at 298K and 1 atm31 obtained adding the thermal and (a3_1). The addition of water to the Me substituted carbon, entropic corrections computed with BS1 to the electronic a3_TS12, and subsequent protodeauration, a3_TS23, step energy in THF computed with BS2. Species are named as require relative activation Gibbs energies of 27.4 and 12.5 nx_y, where n corresponds to the different unsaturated hydro- kcal·mol-1, respectively. carbon (a alkyne, b alkene and c allene), x accounts for the substituent (H, Me or Ph) and y to the position within the reaction mechanism (Scheme 1). The cluster of fourteen H2O 2 Figure 1. Protodeauration transition state for the isomerization of : a) a3_2 to a3_3, and b) a3_4 to a3_5. The relevant distances are also reported in Å. added H2O to the carbon atom, also suggesting that this mech- anism might be feasible. The protodeauration step on Au(I)- catalyzed reactions was also evaluated by Ariafard and coworkers35 assuming that the proton is already in the medi- um. On other side, Belanzoni and coworkers, 36 showed that Scheme 2. Mechanistic alternatives for the gold-catalyzed the process can be accelerated by the presence of counterions. hydration of internal alkyne a3. [Au]=[Au(NHC)]. For each A similar conclusion for a related protodeauration step in the intermediate and transition state two explicit water molecules hydroamination of dienes was proposed by some of us.37 (not shown for clarity) stabilize the nucleophilic water. Rela- tive Gibbs energies with BS2 (kcal·mol-1); transition state energies are shown in parenthesis. The Gibbs energy of the π- A.2. Terminal alkynes complex a3_1 plus a cluster of three water molecules is taken In order to study the hydration reaction of terminal alkynes as a zero energy. catalyzed by [Au(NHC)]+ we selected the HC≡CMe, a1 and HC≡CPh, a2 as representative non-activated substrates with The a3_2 intermediate and subsequent enol product aliphatic and aromatic substituents. For these two terminal coordinated to the catalyst, a3_3, have relative Gibbs energies alkynes analogous pathways to those for internal alkynes were of 15.5 and -11.8 kcal·mol-1, respectively. theoretically characterized (see Scheme 3); analogous conclu- As a general observation, the selectivity for the hydration of sions about the inner addition can be drawn (see Supporting internal alkynes is low and is highly substrate dependent, often Information). Usually, hydration of terminal alkynes proceeds resulting in multiple regioisomeric products. 5 The nucleophilic with a high level of regioselectivity to furnish predominately addition of water on the Ph substituted carbon (generating the Markovnikov products.5 We found the same regioselectivi- intermediate a3_4, at 19.7 kcal·mol-1) is more energy demand- ty in our study. The Markovnikov addition of water to the ing with an associated Gibbs energy barrier of 31.5 kcal·mol-1, alkyne in a1_1 has a Gibbs energy barrier of 20.3 kcal·mol-1, a3_TS14. The last step, protodeauration, has the transition a1_TS12, generating intermediate a1_2 at 11.6 kcal·mol-1. state at 31.3 kcal·mol-1, a3_TS45, generating the coordinated enol product, a3_5, at -11.8 kcal·mol-1. Concerning the protodeauration step from intermediate a3_2 to a3_3, or a3_4 to a3_5, respectively, we invoked a transition state in which a water molecule is mediating a proton transfer between the nucleophilic water and the acceptor carbon (Fig- ure 1 a and b.7 However, there is also the possibility of direct proton diffusion in the bulk. This process cannot be rigorously evaluated by static DFT calculations; dynamic simulations would be needed to properly model the process, but this kind of analysis is out of the scope of this work.34 Instead, we esti- mated the thermodynamics of the event computing the Gibbs energy of the reaction in which the proton is transferred from intermediates a3_2 or a3_4 to a cluster of 14 water mole- cules,32 yielding the neutral intermediates generated after the proton release to the solution: [Au(NHC)(MeCCPh(OH2))]+·(H2O)2 + (H2O)14 → [Au(NHC)(MeCCPh(OH)]·(H2O)2 + [(H(H2O)14]+ (eq. 1) Scheme 3. Mechanistic alternatives evaluated for the gold- These reactions are both markedly exergonic (with ΔG values catalyzed hydration of terminal alkynes an (n= 1, 2). R=Me of -19.2 and -22.4 kcal mol-1 for a3_2 and a3_4, respectively), (a1, blue) and R=Ph (a2, orange). [Au]=[Au(NHC)]. For each pointing out the thermodynamic feasibility of this acid-base intermediate and transition state two explicit water molecules pathway as a possible alternative to the proton-shuttle mecha- (not shown for clarity) stabilize the nucleophilic water. Rela- nism for the protodeauration step. Analogous conclusions tive Gibbs energies with BS2 (kcal·mol-1); transition state were proposed by Hashmi7a and Wu and Zhao7b groups in their energies are shown in parenthesis. The Gibbs energy of the π- theoretical analyses of the hydration using Me-C≡CH as sub- complexes an_1 plus a cluster of three water molecules is strate and [Au(PH3)]+ as catalyst. They inferred that proton taken as a zero energy. can travel to solvent instead of being involved in a cyclic The subsequent proton transfer, giving rise to intermediate mechanism through a direct and explicit motion from the a1_3 (-22.9 kcal·mol-1), requires 8.4 kcal·mol-1, a1_TS23. The 3 anti-Markovnikov nucleophilic addition to a1_1 has a Gibbs energy barrier of 32.2 kcal·mol-1, a1_TS14, giving rise to intermediate a1_4, at 14.9 kcal·mol-1. The subsequent proto- deauration generates a1_5 species (-14.7 kcal·mol-1), with transition state a1_TS45 located at 25.9 kcal·mol-1. Compar- ing the two possible nucleophilic additions on the coordinated alkyne a1_1, the one on the Me side (Markovnikov addition), as expected, is kinetically (20.3 vs 32.2 kcal·mol -1), and ther- modynamically (-22.9 vs -14.7 kcal·mol-1) favored. For the case of alkyne with a Ph substituent a2, similar conclusions are obtained. Starting from a2_1, the addition of water on the Ph-substituted carbon atom (Markovnikov addition) has a lower Gibbs energy barrier, 21.4 kcal·mol-1, a2_TS12, than the addition on the terminal carbon atom (22.0 kcal·mol-1, a2_TS14). Protodeauration by a proton-shuttle mechanism is also easier from the Markovnikov intermediate a2_2 (at 11.1 kcal·mol-1) Scheme 4. Mechanistic alternatives evaluated for the gold- than from the anti-Marovnikov intermediate a2_4 (at 16.2 catalyzed hydration of internal alkene b3. [Au]=[Au(NHC)]. kcal·mol-1). The respective Gibbs energy barriers are 8.1 and For each intermediate and transition state two explicit water 11.8 kcal mol-1 (Scheme 3). molecules (not shown for clarity) stabilize the nucleophilic Concerning the protodeauration step by means of proton diffu- water. Relative Gibbs energies with BS2 (kcal·mol-1); transi- sion into the bulk, analogue thermodynamics considerations tion state energies are shown in parenthesis. The Gibbs energy than for the internal alkyne were obtained. The ΔG values for of the π-complex b3_1 plus a cluster of three water molecules the deprotonation reactions of intermediates a1_2, a1_4, a2_2 is taken as a zero energy. and a2_4, calculated as in eq. 1,32 are -18.0, -17.3, -16.2 and - 21.3 kcal·mol-1, respectively, suggesting that the neutral spe- cies with the proton in the bulk are thermodynamically acces- The final alcohol product coordinated to the catalyst, b3_5, sible; thus, the acid-base mechanism cannot be discarded as a has a relative Gibbs energy of 1.7 kcal·mol-1. The computed feasible pathway for the proton transfer. pathways highlight that the formation of the 1-phenylprop-2-ol All terminal alkynes studied in this work share the same regi- (addition on the Me side) results kinetically favored. oselectivity giving rise to the Markovnikov water addition. The protodeauration alternative going through a proton diffu- Terminal alkynes are more reactive than internal ones by sion into the solvent was also considered, following the kinetics (lower Gibbs energy barriers) and thermodynamic scheme devised in eq. 1.32 The intermediates formed after the reasons (the relative stability of products is higher). Reaction nucleophilic attack, b3_2 and b3_4, lie very high in energy (at with internal alkynes will require rather high temperatures as 27.6 and 34.1 kcal mol-1, respectively) and, from eq. 1,32 are reported in the literature.38 greatly stabilized by deprotonation (ΔG values for the depro- tonation reactions of intermediates b3_2, b3_4 are -27.1 and - B. Hydration of alkenes. 34.7 kcal·mol-1, respectively). Thus, a priori this possibility B.1. Internal alkenes could not be discarded. Nevertheless, the fact that hydration of alkenes is hardly observed experimentally suggest that this In coherence with the case of alkynes all the possible path- process cannot take place due to kinetic reasons. ways were explored considering the nucleophilic attack to each of the coordinated carbon atoms, as well as the inner and Based on these results it can be concluded that the water nu- outer additions. cleophilic attack to internal alkenes is quite difficult but an As discussed above for the internal alkyne, the nucleophilic affordable step; moreover, the addition on the Me side is ki- addition may take place on the Ph or Me substituted carbon of netically favored over the Ph side. In comparison with internal the internal alkene, b3 (MeCH=CHPh; Scheme 4). The initial alkynes, nucleophilic additions to internal alkenes have a nucleophilic addition on the Me-substituted carbon of b3_1 slightly higher Gibbs energy barrier (27.4 vs. 31.1 kcal mol-1). has a Gibbs energy barrier of 31.1 kcal·mol-1, b3_TS12. The The relative barriers for the protodeauration step from the intermediates resulting from the water addition (a3_2 and intermediate b3_2 lies at 27.6 kcal·mol-1. The final alcohol b3_2) are similar (alkyne: 12.5 kcal mol-1; alkene: 14.4 kcal product coordinated to the catalyst, b3_3, has a relative Gibbs mol-1). The main difference is found in the relative energy of energy of 20.8 kcal·mol-1 and it is reached by overcoming the intermediates with the added water: (a3_2 lies at 15.5 kcal b3_TS23 at 42.0 kcal·mol-1 (Scheme 4). The nucleophilic mol-1, whereas b3_2 is placed at 27.6 kcal mol-1 above the addition on the Ph-substituted carbon atom over the interme- reactants. As a consequence, while the transition state for the diate b3_1 is energetically more demanding with a Gibbs protodeauration has a relative Gibbs energy of 28.0 kcal mol -1 energy barrier of 33.4 kcal·mol-1, b3_TS14. The intermediate for the internal alkyne, that for the internal alkene is 42.0 kcal lies at 34.1 kcal·mol-1, b3_4 whereas the subsequent proton mol-1, preventing the hydration reaction to take place. This is a transfer has a barrier of 9.0 kcal·mol-1 (b3_TS45 at 43.1 reason why hydration of alkenes is much more difficult than kcal·mol-1). for alkynes or allenes (vide infra). 4 Scheme 5. Mechanistic alternatives evaluated for the gold- Scheme 6. Mechanistic alternatives for the gold-catalyzed catalyzed hydration of terminal alkenes bn (n= 1, 2). R=Me hydration of internal allene c3. [Au]=[Au(NHC)]. For each (b1, blue) and R=Ph (b2, orange). [Au]=[(NHC)Au]. For each intermediate and transition state two explicit water molecules intermediate and transition state two explicit water molecules (not shown for clarity) stabilize the nucleophilic water. Rela- (not shown for clarity) stabilize the nucleophilic water. Rela- tive Gibbs energies with BS2 (kcal·mol-1); transition state tive Gibbs energies with BS2 (kcal·mol-1); transition state energies are shown in parenthesis. The Gibbs energy of the π- energies are shown in parenthesis. The Gibbs energy of the π- complex c3_1 plus a cluster of three water molecules is taken complexes bn_1 plus a cluster of three water molecules is as a zero energy. taken as a zero energy. Markovnikov addition kinetically and thermodynamically B.2. Terminal alkenes favored. As for alkynes, nucleophilic additions over internal Regarding the hydration of terminal alkenes, b1 (H2C=CMe) alkenes are slightly more demanding than for terminal ones. and b2 (H2C=CPh), Scheme 5, the Gibbs energy barrier for Nevertheless, the reaction is predicted to not proceed (at room the addition of water on the more substituted carbon atom temperature) due to the high energy of the transition states for (Markovnikov addition) are very similar, 28.1 and 28.6 the protodeauration process. kcal·mol-1, for transition states, b1_TS12 and b2_TS12, re- spectively. The formed intermediates, b1_2, and b2_2 are at C. Hydration of allenes 25.6 and 27.4 kcal·mol-1, respectively. Allenes have diverse coordination chemistry due to the pres- The subsequent protodeauration steps b1_TS23 and b2_TS23 ence of both double bonds.39 Gold-allene bond as well as the have energy barriers of 14.7 and 16.0 kcal·mol-1 respectively. reactivity has been studied in detail in the literature,40 includ- On the other side, addition on the terminal carbon atom (anti- ing many computational studies.41,42 The mechanistic study for Markovnikov addition) shows barriers of 36.5 and 32.0 the [Au(NHC)]+ catalyzed hydration of terminal kcal·mol-1 for b1_TS14 and b2_TS14, respectively, whereas (H2C=C=CHMe, c1, and H2C=C=CHPh, c2) an internal al- the intermediates are at 30.2 and 27.7 kcal·mol-1, respectively. lenes (MeCH=C=CHPh, c3) was recently published by us.24 Protodeaurations display also similar barriers that place the For the sake of completeness, a summary of those results is corresponding transition states b1_TS45 and b2_TS45 at 48.9 included here, updating Gibbs energy values with BS2 em- and 43.5 kcal·mol-1, respectively. None of the pathways eval- ployed all along this work. uated show a feasible barrier for the hydration reaction to take The pathways evaluated for the hydration of the internal allene place. In all cases the protodeauration step is high enough in MeCH=C=CHPh, c3, are shown in Scheme 6. The alternatives energy to prevent the reaction to proceed. considered were the direct addition on the coordinated allene, The alternative pathway involving a proton diffusion to bulk or the nucleophilic addition of water on the σ-allyl cation (eq. 1) was also considered.32 As found for the addition to the intermediate that can be formed, c3_3. The Gibbs energies internal alkenes, the intermediates formed after the nucleo- support a mechanism where the direct addition over the carbon philic attack (b1_2, b1_4, b2_1 and b2_4) lie very high in bearing the Ph groups was the favored one. Then there is a energy (at 25.6, 30.2, 27.4 and 27.7 kcal mol-1, respectively) protodeauration giving rise to intermediate c3_5. From this and are greatly stabilized by deprotonation (ΔG values for the intermediate there is an isomerization process that produces proton release from intermediates b1_2, b1_4, b2_2 and b2_4 the most stable product, that corresponds with the experimen- to the water cluster are -26.1, -30.5, -27.5 and -27.6 kcal·mol- tally observed one.10 The reaction mechanism for the hydra- 1 , respectively). Thus, the species formed are thermodynami- tion of terminal allenes H2C=C=CHR is shown in Scheme 7. cally accessible. Nevertheless, given the fact that these reac- For both allenes considered, R=Me, c1, and R=Ph, c2, the tions are very scarce experimentally, one may expect that the most stable product has the alcohol over the terminal carbon barrier for the overall process should be also quite high. atom. In general, water nucleophilic attack to alkenes have relatively high energy barriers but still affordable steps; being the 5 Table 1. Binding Gibbs energy of reactants to Au(I) catalyst, relative Gibbs energies of TSs and intermediate n_2 for the pre- ferred Markovnikov pathway for the hydration of non-activated alkynes, alkenes and allenes and Gibbs energy for the product by reactant substitution (kcal mol-1). Species ∆Gcoord a ∆Gn_TS12b ∆Gn_2c ∆Gn_TS23d (∆∆G) ∆Gsubst e a0 -18.7 22.8 6.5 16.4 (9.9) 3.9 a1 -17.6 20.3 11.6 20.0 (8.4) 2.2 a2 -17.1 21.4 11.1 19.2 (8.1) 1.5 a3 -16.8 27.4 15.5 28.0 (12.5) -3.5 b0 -19.8 29.8 24.8 40.4 (15.7) -24.7 b1 -20.0 28.1 25.6 40.3 (14.7) -23.2 b2 -17.9 28.6 27.4 43.4 (16.0) -24.2 b3 -17.6 31.1 27.6 42.0 (14.5) -24.5 Scheme 7. Mechanistic alternatives for the hydration of termi- c0 -17.9 23.4 16.8 29.6 (12.0) -4.3 nal allenes cn (n= 1, 2). catalyzed by Au(I) reaction. R=Me (c1, blue), R=Ph (c2, orange). [Au]=[(NHC)Au]. For each c1 -18.8 22.1 16.2 25.5 (9.2) -3.4 intermediate and transition state two explicit water molecules c2 -16.4 19.2 15.3 25.9 (10.6) -1.4 (not shown for clarity) stabilize the nucleophilic water. Rela- tive Gibbs energies with BS2 (kcal·mol-1); transition state c3 -19.9 21.7 16.6 31.3 (14.7) -3.3 energies are shown in parenthesis. The Gibbs energy of the π- a ∆G associated to: nx_y + [Au(NHC)]+ → [Au(NHC)(π–nx_y)]+. b Tran- complexes cn_1 plus a cluster of three water molecules is sition state corresponding to the Markovnikov nucleophilic attack. c Intermediate n2 coming from water addition (TS12). d Transition state of taken as a zero energy. the protodeauration step, in the case of allenes it corresponds to TS26. In parenthesis activation Gibbs energy from intermediate n2, associated to The mechanism is described by the same sequence of reaction the protodeauration step. e ∆G associated to: [Au(NHC)(Hnx_y–OH)]+ + steps: coordination, nucleophilic addition and protodeauration; nx_y → [Au(NHC)(π–nx_y)]+ + Hnx_y–OH. for R=Ph an isomerization step may be also required to give the final product. The alternative route including the formation Thus, it does not introduce any clear differentiation among the of a σ-allyl cation intermediate can be feasible for R=Ph but reactants. The overall comparison between terminal and inter- can be discarded as a general operative pathway. nal unsaturated functional groups shows that terminal ones are always more reactive; addition to internal groups are predicted D. Comparative analysis in some case hardly affordable. The non-substituted alkyne (ethyne, ao) and alkene (ethene, bo) have somewhat higher The comparison of the reaction profiles computed for the barriers for the water addition than the terminal ones, proving hydration of unsaturated C-C bonds (non-activated alkynes, the favorable impact of Me and Ph substituents in the Mar- alkenes and allenes), shows a common mechanism that can be kovnikov addition.43 Protodeauration barriers are less affected described in three main steps: (i) substrate π-coordination, (ii) by the substitution. nucleophilic addition and (iii) protodeauration; in the case of Regarding regioselectivity the three π-bonds behave in a simi- allenes an isomerization step may be required to complete the lar way: the addition on the most substituted carbon (Markov- reaction depending on the substrate. The general mechanism is nikov addition) is always favorable for all the unsaturated similar to that described for the Au(I) catalyzed hydroamina- functional groups evaluated. However, when comparing rela- tion of the analogous C-C unsaturated functional groups.23 The tive energies of transition states and intermediates for the first step, π-coordination of the unsaturated CC bond to the preferred Markovnikov pathway striking differences appear gold(I) center, shows relatively similar ∆Gcoord values for all (Table 1, ∆Gn_TS12 and ∆Gn_TS23, Table 1, columns 3 and 5, reactants (binding Gibbs energies between 16-20 kcal mol-1, respectively). Table 1, column 2). According to the results for alkynes, the Gibbs energies of the Figure 2. Optimized structures of the intermediates formed before and after the protodeauration step, for the three CC unsatura- red CC bonds considered: a) alkyne a2; b) alkene b2; c) allene c2 (R1= Ph; R2= H). In black, relative Gibbs energies with respect the corresponding π complexes, in kcal mol-1. The two additional water molecules have been omitted for clarity. 6 Figure 3. Superposition over the reactant structures of the localized orbital centroids (purple dots) along the IRC for the proto- deauration process for: a) alkyne a2, alkene b2 and allene c3 and b) the corresponding arrow-pushing schemes. transition states does not allow to clearly assign a rate deter- Table 2. Au-C and C-OH2 interaction energies in intermediates mining step. Overall, for alkynes a0-a2 the reaction takes n0_2.a place with relative low barriers (about 20 kcal mol-1), except for the case of the internal a3. For the case of allenes, they behave in a similar way than alkynes regarding barriers, although in these cases the proto- deauration can be clearly assigned as the rate determining step. The main difference is found in the stability of the inter- Species ∆EInt (Au-C) b ∆EInt (C-OH2) c ∆En0_2d ∆Gn0_2e mediates formed after the water addition (cn_2), which are about 4 kcal mol-1 less stable than the corresponding to the a0_2 -75.6 -74.8 -13.3 6.5 alkynes (an_2) (Table 1, ∆Gn_2, column 4). Overall, the hy- b0_2 -80.4 -60.3 4.8 24.8 dration reaction appears as feasible, except for the internal reactant, c3. c0_2 -79.2 -75.9 -3.6 16.8 a For the case of alkenes, the situation is quite different. Nucle- Values in kcal·mol-1 computed with BS2. b Interaction energy between ophilic addition is significantly higher in terms of Gibbs ener- the two frozen fragments obtaining breaking heterolytically the Au-C gy barrier compared with alkynes and allenes, although af- bond and assigning the electron pair to the C containing fragment. c Inter- action energy between the two frozen fragments breaking heterolytically fordable in harsher reaction conditions (∆Gn_TS12 about 30 kcal the C-OH2·(H2O)2 bond and assigning the electron pair to the O contain- mol-1, Table 1). However, the intermediates formed from the ing fragment. d Relative energy of intermediate n0_2. e Relative Gibbs water addition (bn_2) are high energy species (Table 1, ∆Gn_2, energy of intermediate n0_2. column 5), around 15 kcal mol-1 above the related alkyne intermediates. The protodeauration barriers from these inter- mediates, although not much higher than those for alkynes intermediates (i.e. for R=Ph species a2_2 and c2_2, respec- (Table 1, ∆∆G at column 5), place the protodeauration transi- tively; Figure 2, a and c). tion states at energy levels (about 40 kcal·mol-1) that make the This kind of complexes, that contain a C vinyl-Au σ-bond, have process unaffordable even at drastic reaction conditions. been characterized.44 In the case of alkene, however, the addi- To shed light on the different behavior observed, we have tion of water generates an alkyl intermediate, with a Calkyl-Au performed a deeper analysis of the species involved in the so- σ-bond, (i.e. for R=Ph intermediate b2_2, Figure 2b). Interest- called protodeauration step. That means the intermediate ingly, these intermediates are around 10-15 kcal·mol-1 higher formed after the nucleophilic addition of water, that can be in energy (Table 1), than those for alkyne and allene counter- described as a protonated enol or alcohol, the transition state parts. for the proton transfer from the protonated water to the carbon, To further analyze the origin of the energy difference among and the resulting intermediate (addition product including the these intermediates, the interaction energy between two frag- [Au(NHC]+ complex) ments involved in the Au-C bond (the one containing the The optimized structures of these two intermediates, n2_y, for Au(I) and the one containing the C-atom ligand) were calcu- the three kinds of CC multiple bonds with R 1=Ph and R2=H lated, ∆EInt (Au-C). The simplest reactants, ethyne, ethene and are depicted in Figure 2, as well as their relative energies with propa-1,2-diene (labelled as a0_2, b0_2 and c0_2, respective- respect the initial π complexes. Intermediates n2_2, formed by ly, were considered for analytical purposes (Table 2, column water addition to the CC multiple bond have a different nature 2). The same analysis has been performed for intermediates both regarding the Au-C bond and the C-OH2 moiety. Water n2_2 (Table S1 in the Supporting Information). The difference addition to alkyne and allene CC bonds yield vinyl gold(I) in interaction energies between vinyl-Au(I) and alkyl-Au(I) 7 fragments is lower than 5 kcal·mol-1 among the three species, orbitals (LMOs), and the centroids of these LMOs (CLMO) with that for alkene species, b0_2, showing the largest value. are computed for selected structures along the reaction path. Thus, the presence of a Calkyl-Au bond is stabilizing more the The movement of the localized orbital centroids along the intermediate than the Cvinyl-Au bond. These results indicate reaction path gives information about the electronic rear- that the energy differences among the intermediates in the rangements of the bond-breaking and bond-forming processes. reaction profiles cannot be mainly due to the interaction be- In this way a curly-arrow description of the process is ob- tween the vinyl- or alkyl- ligands and the Au(I) fragment. tained from the quantum mechanical calculations.46 Then, we turned our attention to the C-OH2 interaction. The Figure 3 shows the superposition over the reactant structure interaction energy between the fragments involved in the new (intermediates coming from the water addition) of the local- formed C-O bond (water and the rest of the molecule) were ized orbital centroids for the IRC configurations coming from also calculated, ∆EInt (C-OH2) (Table 2, column 3). The inter- the transition states of the protodeauration transition states. action energy between the fragments that contain the vinyl- The analysis enables a clear discrimination between the differ- Au(I) moiety (alkyne, a0_2 and allene, c0_2) and water is ent mechanisms. For the case of alkynes, the electron pair of about 15 kcal mol-1 higher than for the case of the alkene (b0- the coordinated double bond moves to form the new C-H 2). This energy difference matches the different stability of the bond, while a metal orbital is slightly moving its centroid to intermediates. Thus, the high energy of the intermediates change from a σ-Au-C bond to a π-Au-C bond (Figure 3). formed after addition of water to coordinated alkene is due to Indeed, the well-known effect of strong electron donator lig- the less stability over the formation of this C-O bond com- ands to accelerate the protodeauration36,45 is explained by this pared to the case of alkyne or allene. This reveals an intrinsic simple model: putting π-donating substituents in the C=C difficulty for the hydration of alkene by this procedure. This bond will facilitate the attack of the π-electrons to the incom- issue might be related to the fact that in the intermediates ing proton. The same effect is caused by increasing the donor coming from water addition to alkyne and allene there is a character of the gold ligand: electron-rich ligands such as C=C π-bond that allows a better accommodation of the -O PMe3 or PPh3 accelerate the reaction.35 functionality (alkyne: protonated enol; allene: the C=C π-bond For the allenes, is the electron pair of the σ-Au-C bond that and the -O functionality are separated by a C-H group). Over- moves to pick up the proton, meanwhile the π-electron pair all, the issue comes from the formation of the new C-O bond coming from the neighbor unsaturated bond forms the new η2- in the case of coordinated alkene compared to the coordinated Au-alkene coordination. In this way the coordination of alkyne or allene, not by the nature of the interaction of the [Au(NHC)]+ is preserved. Finally, the alkene protodeauration ligand (alkyl vs vinyl) with the Au(I) metal center. Indeed, this is characterized by a unique event involving the σ-Au-C bond feature is already apparent when computing the thermodynam- electron pair that moves to form the new C-H bond. The Au-C ics of the hydration reaction in the absence of the gold com- interaction is lost, entailing a considerably higher energy cost. plex (Table S2 in the Supporting Information). ΔG values of - It must be pointed out that for a related process, Au(I)- 20.5, -10.6 and -8.5 kcal mol-1 are obtained for ethyne, propa- catalyzed hydroamination of dienes,47 the computational anal- 1,2-diene and ethene hydrations, respectively, displaying a ysis displayed a favored protodeauration step that ends up with more exergonic enol than primary alcohol formation (about 12 a η2-CC complex coordinated to Au(I);37 the presence of a π- kcal mol-1). coordinating unit makes the process much more feasible. We then analyzed the protodeauration step. It has been often naively described as a simple exchange of and Au + by a pro- CONCLUSIONS ton, but recent deeper analyses of this step have disclosed a The comparative analysis of the gold(I)-catalyzed hydration of much more complex process. 35,36,45 Two kinds of intermedi- alkynes, alkenes and allenes reveals that, though these reac- ates are formed after the O- to C- proton transfer (formal pro- tions share a common general mechanism, they take place todeauration). In the alkyne and allene systems the formed with notably different reaction barriers. The nucleophilic intermediates correspond to η2-CC complexes, there is a σ/π attack step is not an issue for alkynes and allenes, whereas it is rearrangement in the nature of the electrons involved in the C- higher in energy, though affordable, for alkenes. The scarce Au bond. The [Au(NHC)]+ does not dissociate but remains π- reactivity of alkenes over the hydration reaction can be mainly coordinated to the C=C bond (Figure 2). Dissociation of C=C attributed to the high energy intermediate formed after water unit from the gold(I) takes place by ligand displacement for a addition along with the subsequent protodeauration step. The better π-ligand (the reactant). For the alkyl-gold(I) intermedi- intrinsic nature of such intermediate makes it much more ate, however, during the protodeauration the [Au(NHC)]+ unit energy demanding. The high energy of this species, compared remains connected to the organic moiety only by a much with those coming from the addition to alkynes and allenes is weaker agostic interaction. The computed values for the sub- not related to the Au(I)-CC system interaction, but to the stitution in the coordination sphere of gold(I) of the product by strength of the C-O bond in the presence of absence of a π- a new reactant molecule agree with this description. The reac- bond in the organic fragment. tion is almost thermoneutral in the case of π-bonded products Following the electronic rearrangements that take place in this enol and allyl alcohol, and highly exergonic for the weakly apparently simple protodeauration step disclose different bonded products, primary and secondary alcohols (Table 1, mechanisms for the three kind of substrates, both regarding ∆Gsubst, column 6). the origin of the electron pair that will accept the proton and The nature of the σ/π rearrangement of the protodeauration the fate of the Au-C bond electron pair. For alkynes the reac- step in vinyl Au species has been evinced by means of an tion is just the protonation of a π-bond (the electron pair in- intrinsic bond orbital analysis (IBO), based on localized mo- volved in the protonation comes from the π-bond of a gold- lecular orbitals (LMO).45 Some of us have devised a similar vinyl intermediate) and is accompanied by a σ-π- analysis from the evolution of the centroids of the localized rearrangement of the Au-C bond. In this way the reaction molecular orbitals (CLMO).46 In this approach, Kohn–Sham takes place with low barriers, always similar to those for the orbitals are transformed into maximally localized molecular 8 nucleophilic attack step. For allenes, although the electron pair S.; Raubenheimer, H., Application of (phosphine)gold(I) that pick up the proton comes from the Au-C σ-bond, it re- carboxylates, sulfonates and related compounds as highly mains another π-bond to which the gold can coordinate in a η2- efficient catalysts for the hydration of alkynes. J. Mol. Catal. CC fashion. Overall, the protodeauration barriers in allenes are A: Chem. 2004, 212, 35-42; (e) Gatto, M.; Baratta, W.; also low and relatively similar to those of alkynes. A remain- Belanzoni, P.; Belpassi, L.; Del Zotto, A.; Tarantelli, F.; ing π-bond is absent in alkenes, the use of the Au-C σ-bond Zuccaccia, D., Hydration and alkoxylation of alkynes electron pair to accept the proton completely disrupts the Au- catalyzed by NHC-Au-OTf. Green Chem. 2018, 20, 2125- C interaction, giving rise to barriers about 5 kcal mol-1 higher. 2134. However, the very low stability of the water-added intermedi- 7. (a) Krauter, C. M.; Hashmi, A. S. K.; Pernpointner, ates places the protodeauration transition states at values com- M., A New Insight into Gold(I)‐Catalyzed Hydration of pletely unaffordable. Alkynes: Proton Transfer. ChemCatChem 2010, 2, 1226-1230; (b) Jin, L.; Wu, Y.; Zhao, X., Theoretical insight into the Au(i)-catalyzed hydration of halo-substituted propargyl EXPERIMENTAL SECTION acetate: dynamic water-assisted mechanism. RSC Advances 2016, 6, 89836-89846; (c) Mazzone, G.; Russo, N.; Sicilia, E., For description of the calculation performed see Computation- Homogeneous Gold Catalysis: Hydration of 1,2- al Details section. Diphenylacetylene with Methanol in Aqueous Media. A Theoretical Viewpoint. Organometallics 2012, 31, 3074-3080; ASSOCIATED CONTENT (d) Gatto, M.; Belanzoni, P.; Belpassi, L.; Biasiolo, L.; Del Supporting Information. Water clusters used in the calcula- Zotto, A.; Tarantelli, F.; Zuccaccia, D., Solvent-, Silver-, and tions, thermodynamics of the hydration reactions in the absence Acid-Free NHC-Au-X Catalyzed Hydration of Alkynes. The of the gold complex, Au-C and C-OH2 interaction energies in Pivotal Role of the Counterion. ACS Catal. 2016, 6, 7363- intermediates n2_2 and energy profiles for all the inner and outer 7376. additions (PDF). Cartesian coordinates of all the optimized struc- 8. (a) Guo, J.; Teo, P., Anti-Markovnikov oxidation and tures (XYZ). hydration of terminal olefins. Dalton Trans. 2014, 43, 6952- 6964; (b) Hintermann, L., Anti‐Markovnikov Hydration of Notes Terminal Alkenes: A Coupled Catalytic Cycle Approach. The authors declare no competing financial interests. ChemCatChem 2012, 4, 321-322; (c) Hamasaki, A.; Yamamoto, E.; Itoh, H.; Tokunaga, M., Highly atom efficient Acknowledgments catalytic reactions utilizing water and alcohols as reagents. J. 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