Agustí Lledós

Gold-Catalyzed [4C+2C] Cycloadditions of Allenedienes, including an Enantioselective Version with New Phosphoramidite-Based Catalysts: Mechanistic Aspects of the Divergence between [4C+3C] and [4C+2C] Pathways

Gold(I) complexes featuring electron acceptor ligands such as phosphites and phosphoramidites catalyze the [4C+2C] intramolecular cycloaddition of allenedienes. The reaction is chemo- and stereoselective, and provides trans-fused bicyclic cycloadducts in good yields. Moreover, using novel chiral phosphoramidite-based gold catalysts it is possible to perform the reaction with excellent enantioselectivity. Experimental and theoretical data dismiss a cationic mechanism involving intermediate II and suggest that the formation of the [4C+2C] cycloadducts might arise from a 1,2-alkyl migration (ring contraction) in a cycloheptenyl Au-carbene intermediate (IV), itself arising from a [4C+3C] concerted cycloaddition of the allenediene. Therefore, these [4C+2C] allenediene cycloadditions and the previously reported [4C+3C] counterparts most likely share such cycloaddition step, differing in the final 1,2-migration step.

Computational Perspective on Pd-Catalyzed C–C Cross-Coupling Reaction Mechanisms

Palladium-catalyzed C-C cross-coupling reactions (Suzuki-Miyaura, Negishi, Stille, Sonogashira, etc.) are among the most useful reactions in modern organic synthesis because of their wide scope and selectivity under mild conditions. The many steps involved and the availability of competing pathways with similar energy barriers cause the mechanism to be quite complicated. In addition, the short-lived intermediates are difficult to detect, making it challenging to fully characterize the mechanism of these reactions using purely experimental techniques. Therefore, computational chemistry has proven crucial for elucidating the mechanism and shaping our current understanding of these processes. This mechanistic elucidation provides an opportunity to further expand these reactions to new substrates and to refine the selectivity of these reactions. During the past decade, we have applied computational chemistry, mostly using density functional theory (DFT), to the study of the mechanism of C-C cross-coupling reactions. This Account summarizes the results of our work, as well as significant contributions from others. Apart from a few studies on the general features of the catalytic cycles that have highlighted the existence of manifold competing pathways, most studies have focused on a specific reaction step, leading to the analysis of the oxidative addition, transmetalation, and reductive elimination steps of these processes. In oxidative addition, computational studies have clarified the connection between coordination number and selectivity. For transmetalation, computation has increased the understanding of different issues for the various named reactions: the role of the base in the Suzuki-Miyaura cross-coupling, the factors distinguishing the cyclic and open mechanisms in the Stille reaction, the identity of the active intermediates in the Negishi cross-coupling, and the different mechanistic alternatives in the Sonogashira reaction. We have also studied the closely related direct arylation process and highlighted the role of an external base as proton abstractor. Finally, we have also rationalized the effect of ligand substitution on the reductive elimination process. Computational chemistry has improved our understanding of palladium-catalyzed cross-coupling processes, allowing us to identify the mechanistic complexity of these reactions and, in a few selected cases, to fully clarify their mechanisms. Modern computational tools can deal with systems of the size and complexity involved in cross-coupling and have a continuing role in solving specific problems in this field.

Elongated dihydrogen complexes: what remains of the H–H Bond?

Of the several hundred examples of transition metal dihydrogen complexes that have been reported to date, the vast majority have H-H distances of less than 1.0 Angstrom. A small number of complexes have been reported with distances in the range of 1.1 to 1.5 Angstrom. These complexes have been termed elongated dihydrogen complexes. In this review, experimental methods for structure determination of such complexes are summarized, along with computational approaches which have proven useful in understanding the structures of these molecules.

Gold(I)-catalyzed intermolecular oxyarylation of alkynes: unexpected regiochemistry in the alkylation of arenes.

The reaction between acetylenes and sulfoxides, studied as a test case for gold-catalyzed intermolecular addition, provides the oxyarylation compounds 3 in good yields. Unpredictably, in all cases a single regioisomer arising from the electrophilic aromatic alkylation at the position adjacent to the sulfur atom is obtained instead of the expected Friedel-Crafts regioisomer. A new concerted mechanism based on DFT calculations is proposed to account for the products in this intermolecular gold(I)-catalyzed reaction.

Gold-Catalyzed [4C+3C] Intramolecular Cycloaddition of Allenedienes: Synthetic Potential and Mechanistic Implications

Efficient at room temperature: The Au complex generated in situ from [(IPr)AuCl] and AgSbF(6) promotes the [4C+3C] intramolecular cycloaddition of allenes and dienes at room temperature, and in a particularly efficient and versatile manner. A DFT study on dimethylallenyl precursors agreed with the formation and cycloaddition of a metal-allyl cation intermediate, and points to the 1,2-hydride shift as the key rate-limiting step.

Protonation of transition-metal hydrides: a not so simple process

The protonation of a transition-metal hydride is a formally simple process between a proton donor and a proton acceptor with several potential basic centres. The detailed mechanism is however quite subtle, with multistep reactions and involvement of different intermediates. The process is furthermore very sensitive to the nature of both the proton donor and the transition-metal complex, as well as to the solvent and to the presence and identity of eventual counteranions. This tutorial review summarizes the recent progress in the understanding of the reaction, obtained through the joint application of a number of computational and experimental techniques.

A computational study of the olefin epoxidation mechanism catalyzed by cyclopentadienyloxidomolybdenum(VI) complexes.

A DFT analysis of the epoxidation of C(2)H(4) by H(2)O(2) and MeOOH (as models of tert-butylhydroperoxide, TBHP) catalyzed by [Cp*MoO(2)Cl] (1) in CHCl(3) and by [Cp*MoO(2)(H(2)O)](+) in water is presented (Cp*=pentamethylcyclopentadienyl). The calculations were performed both in the gas phase and in solution with the use of the conductor-like polarizable continuum model (CPCM). A low-energy pathway has been identified, which starts with the activation of ROOH (R=H or Me) to form a hydro/alkylperoxido derivative, [Cp*MoO(OH)(OOR)Cl] or [Cp*MoO(OH)(OOR)](+) with barriers of 24.9 (26.5) and 28.7 (29.2) kcal mol(-1) for H(2)O(2) (MeOOH), respectively, in solution. The latter barrier, however, is reduced to only 1.0 (1.6) kcal mol(-1) when one additional water molecule is explicitly included in the calculations. The hydro/alkylperoxido ligand in these intermediates is eta(2)-coordinated, with a significant interaction between the Mo center and the O(beta) atom. The subsequent step is a nucleophilic attack of the ethylene molecule on the activated O(alpha) atom, requiring 13.9 (17.8) and 16.1 (17.7) kcal mol(-1) in solution, respectively. The corresponding transformation, catalyzed by the peroxido complex [Cp*MoO(O(2))Cl] in CHCl(3), requires higher barriers for both steps (ROOH activation: 34.3 (35.2) kcal mol(-1); O atom transfer: 28.5 (30.3) kcal mol(-1)), which is attributed to both greater steric crowding and to the greater electron density on the metal atom.

Palladium round trip in the Negishi coupling of trans-[PdMeCl(PMePh2)2] with ZnMeCl: an experimental and DFT study of the transmetalation step.

Compared with the detailed mechanistic knowledge of the Stille reaction, little is known about the Negishi reaction. Recently, we experimentally uncovered the complicated behavior of the transmetalation of transACHTUNGTRENNUNG[PdRfClACHTUNGTRENNUNG(PPh3)2] (Rf= 3,5-dichloro-2,4,6-trifluorophenyl) with ZnMe2 or ZnMeCl, showing that each methylating reagent afforded stereoselectively a different isomer (trans or cis, respectively) of the coupling intermediate [PdRfMe ACHTUNGTRENNUNG(PPh3)2].[4] Moreover, the study revealed the occurrence of undesired transmetalations, such as those shown in Scheme 1, which could eventually produce homocoupling products; the corresponding undesired intermediates were detected and identified by NMR spectroscopy techniques. The formation of undesired intermediates in related reactions with aryl zinc derivatives was later observed by Lei et al. Herein, we report an experimental mechanistic study of the reaction of trans-[PdClMe ACHTUNGTRENNUNG(PMePh2)2] (1) with ZnMeCl, which affords the first experimental determination of thermodynamic parameters of a Negishi transmetalation. This is complemented with a theoretical DFT study, which provides a detailed view of the reaction pathway, consistent with the experimental parameters. The reactions of 1 with ZnMeCl were carried out (with one exception) in 1:20 ratio, simulating catalytic conditions with 5 % Pd, in THF at different temperatures. At room temperature, the only product observed was cis[PdMe2ACHTUNGTRENNUNG(PMePh2)2] (2), in equilibrium with the starting material 1. In these conditions, complex 2 undergoes slow decomposition (reductive elimination) to give ethane. When the reaction was monitored by P NMR spectroscopy at 223 K (Figure 1 a), the coupling rate to give ethane became negligible and the formation of trans-[PdMe2ACHTUNGTRENNUNG(PMePh2)2] (3), as well as cis-[PdMe2ACHTUNGTRENNUNG(PMePh2)2] (2), was observed. The trans isomer 3 seemed to be formed first and then disappeared. The same reaction, carried out at 203 K in 1:1 ratio to get a slower rate of transformation, confirmed that 3 is formed noticeably faster than 2 (Figure 1 b). Thus, the observation of the cis isomer at room temperature is deceptive for the stereoselectivity of the transmetalation. Snapshots of two moments of the transmetalation reaction at 203 K, as seen by P NMR spectroscopy, are shown in Figure 1 c. The behavior of 3 is typical of a kinetic product of noticeably lower stability than the thermodynamic product (2): eventually it disappears from observation as the reaction proceeds and gets closer to the equilibrium concentrations, where the concentration of 3 is very small. In effect, during the progress of the reaction at 223 K (Figure 1 a), the concentration of 2 increases continuously; in contrast, a small accumulation of 3 is produced initially and then its concentration decreases, so that in 300 min 3 has practically disappeared. After about 10 h at 223 K, the system has reached equilibrium between the starting complex 1 and the final thermodynamic product 2 ([1]=5.8 10 3 mol l , [2]=4.4 10 3 mol l , and Keq =2.0 10 ); the concentration of 3 is below the limit of NMR observation. [a] B. Fuentes, Dr. J. A. Casares, Prof. P. Espinet IU CINQUIMA/Qu mica Inorg nica Facultad de CienciasUniversidad de Valladolid 47071 Valladolid (Spain) Fax: (+34) 983423231/ ACHTUNGTRENNUNG(+34) 983186336 E-mail : casares@qi.uva.es espinet@qi.uva.es [b] M. Garc a-Melchor, Prof. A. Lled s, Prof. F. Maseras, Dr. G. Ujaque Qu mica F sica, Edifici C.n, Universitat Aut noma de Barcelona 08193 Bellaterra, Catalonia (Spain) Fax: (+34) 935812920 E-mail : gregori@klingon.uab.es [c] Prof. F. Maseras Institute of Chemical Research of Catalonia (ICIQ) Av. Pa sos Catalans, 16, 43007 Tarragona, Catalonia (Spain) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001332. Scheme 1.

Introducing Copper as Catalyst for Oxidative Alkane Dehydrogenation

The dehydrogenation of n-hexane and cycloalkanes giving n-hexene and cycloalkenes has been observed in the reaction of such hydrocarbons with hydrogen peroxide, in the presence of copper complexes bearing trispyrazolylborate ligands. This catalytic transformation provides the typical oxidation products (alcohol and ketones) with small amounts of the alkenes, a novel feature in this kind of oxidative processes. Experimental data exclude the participation of hydroxyl radicals derived from Fenton-like reaction mechanisms. DFT studies support a copper-oxo active species, which initiates the reaction by H abstraction. Spin crossover from the triplet to the singlet state, which is required to recover the catalyst, yields the major hydroxylation and minor dehydrogenation products. Further calculations suggested that the superoxo and hydroperoxo species are less reactive than the oxo. A complete mechanistic proposal in agreement with all experimental and computational data is proposed.

Highly Efficient Redox Isomerisation of Allylic Alcohols Catalysed by Pyrazole‐Based Ruthenium(IV) Complexes in Water: Mechanisms of Bifunctional Catalysis in Water

The catalytic activity of ruthenium(IV) ([Ru(η(3):η(3)-C(10)H(16))Cl(2)L]; C(10)H(16) = 2,7-dimethylocta-2,6-diene-1,8-diyl, L = pyrazole, 3-methylpyrazole, 3,5-dimethylpyrazole, 3-methyl-5-phenylpyrazole, 2-(1H-pyrazol-3-yl)phenol or indazole) and ruthenium(II) complexes ([Ru(η(6)-arene)Cl(2)(3,5-dimethylpyrazole)]; arene = C(6)H(6), p-cymene or C(6)Me(6)) in the redox isomerisation of allylic alcohols into carbonyl compounds in water is reported. The former show much higher catalytic activity than ruthenium(II) complexes. In particular, a variety of allylic alcohols have been quantitatively isomerised by using [Ru(η(3):η(3)-C(10)H(16))Cl(2)(pyrazole)] as a catalyst; the reactions proceeded faster in water than in THF, and in the absence of base. The isomerisations of monosubstituted alcohols take place rapidly (10-60 min, turn-over frequency = 750-3000 h(-1)) and, in some cases, at 35 °C in 60 min. The nature of the aqueous species formed in water by this complex has been analysed by ESI-MS. To analyse how an aqueous medium can influence the mechanism of the bifunctional catalytic process, DFT calculations (B3LYP) including one or two explicit water molecules and using the polarisable continuum model have been carried out and provide a valuable insight into the role of water on the activity of the bifunctional catalyst. Several mechanisms have been considered and imply the formation of aqua complexes and their deprotonated species generated from [Ru(η(3):η(3)-C(10)H(16))Cl(2)(pyrazole)]. Different competitive pathways based on outer-sphere mechanisms, which imply hydrogen-transfer processes, have been analysed. The overall isomerisation implies two hydrogen-transfer steps from the substrate to the catalyst and subsequent transfer back to the substrate. In addition to the conventional Noyori outer-sphere mechanism, which involves the pyrazolide ligand, a new mechanism with a hydroxopyrazole complex as the active species can be at work in water. The possibility of formation of an enol, which isomerises easily to the keto form in water, also contributes to the efficiency in water.