Understanding Precatalyst Activation in Cross-Coupling Reactions: Alcohol Facilitated Reduction from Pd(II) to Pd(0) in Precatalysts of the Type (η³‑allyl)Pd(L)(Cl) and (η³‑indenyl)Pd(L)(Cl)

Complexes of the type (η³-allyl)­Pd­(L)­(Cl) (L = PR₃ or NHC), have been used extensively as precatalysts for cross-coupling and related reactions, with systems containing substituents in the 1-position of the η³-allyl ligand, such as (η³-cinnamyl)­Pd­(L)­(Cl), giving the highest activity. Recently, we reported a new precatalyst scaffold based on an η³-indenyl ligand, (η³-indenyl)­Pd­(L)­(Cl), which typically provides higher activity than even η³-cinnamyl supported systems. In particular, precatalysts of the type (η³-1-^tBu-indenyl)­Pd­(L)­(Cl) give the highest activity. In cross-coupling reactions using this type of Pd­(II) precatalyst, it is proposed that the active species is monoligated Pd(0), and the rate of reduction to Pd(0) is crucial. Here, we describe detailed experimental and computational studies which explore the pathway by which the Pd­(II) complexes (η³-allyl)­Pd­(IPr)­(Cl) (IPr = 1,3-bis­(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene), (η³-cinnamyl)­Pd­(IPr)­(Cl), (η³-indenyl)­Pd­(IPr)­(Cl) and (η³-1-^tBu-indenyl)­Pd­(IPr)­(Cl) are reduced to Pd(0) in alcoholic solvents, which are commonly used in Suzuki–Miyaura and α-arylation reactions. The rates of reduction for the different precatalysts are compared and we observe significant variability based on the exact reaction conditions. However, in general, η³-indenyl systems are reduced faster than η³-allyl systems, and DFT calculations show that this is in part due to the ability of the indenyl ligand to undergo facile ring slippage. Our results are consistent with the η³-indenyl systems giving increased catalytic activity and provide fundamental information about how to design systems that will rapidly generate monoligated Pd(0) in the presence of alcohols

How Solvent Dynamics Controls the Schlenk Equilibrium of Grignard Reagents: A Computational Study of CH₃MgCl in Tetrahydrofuran

The Schlenk equilibrium is a complex reaction governing the presence of multiple chemical species in solution of Grignard reagents. The full characterization at the molecular level of the transformation of CH₃MgCl into MgCl₂ and Mg­(CH₃)₂ in tetrahydrofuran (THF) by means of ab initio molecular dynamics simulations with enhanced-sampling metadynamics is presented. The reaction occurs via formation of dinuclear species bridged by chlorine atoms. At room temperature, the different chemical species involved in the reaction accept multiple solvation structures, with two to four THF molecules that can coordinate the Mg atoms. The energy difference between all dinuclear solvated structures is lower than 5 kcal mol^–1. The solvent is shown to be a direct key player driving the Schlenk mechanism. In particular, this study illustrates how the most stable symmetrically solvated dinuclear species, (THF)­CH₃Mg­(μ-Cl)₂MgCH₃(THF) and (THF)­CH₃Mg­(μ-Cl)­(μ-CH₃)­MgCl­(THF), need to evolve to <i>less</i> stable asymmetrically solvated species, (THF)­CH₃Mg­(μ-Cl)₂MgCH₃(THF)₂ and (THF)­CH₃Mg­(μ-Cl)­(μ-CH₃)­MgCl­(THF)₂, in order to yield ligand exchange or product dissociation. In addition, the transferred ligands are always departing from an axial position of a pentacoordinated Mg atom. Thus, solvent dynamics is key to successive Mg–Cl and Mg–CH₃ bond cleavages because bond breaking occurs at the most solvated Mg atom and the formation of bonds takes place at the least solvated one. The dynamics of the solvent also contributes to keep relatively flat the free energy profile of the Schlenk equilibrium. These results shed light on one of the most used organometallic reagents whose structure in solvent remains experimentally unresolved. These results may also help to develop a more efficient catalyst for reactions involving these species

Synthesis and Reactions of a Cyclopentadienyl-Amidinate Titanium <i>tert-</i>Butoxyimido Compound

We report the first detailed reactivity study of a group 4 alkoxyimido complex, namely Cp*Ti­{PhC­(NⁱPr)₂}­(NO^tBu) (<b>19</b>), with heterocumulenes, aldehydes, ketones, organic nitriles, Ar^F₅CCH, and B­(Ar^F₅)₃ (Ar^F₅ = C₆F₅). Compound <b>19</b> was synthesized via imide/alkoxyamine exchange from Cp*Ti­{PhC­(NⁱPr)₂}­(N^tBu) and ^tBuONH₂. Reaction of <b>19</b> with CS₂ and Ar′NCO (Ar′ = 2,6-C₆H₃ⁱPr₂) gave the [2 + 2] cycloaddition products Cp*Ti­{PhC­(NⁱPr)₂}­{SC­(S)­N­(O^tBu)} and Cp*Ti­{PhC­(NⁱPr)₂}­{N­(O^tBu)­C­(NAr′)­O}, respectively, whereas reaction with 2 equiv of TolNCO afforded Cp*Ti­{PhC­(NⁱPr)₂}­{OC­(NTol)­N­(Tol)­C­(NO^tBu)­O} following a sequence of cycloaddition–extrusion and cycloaddition–insertion steps. Net NO^tBu group transfer was observed with both ^tBuNCO and PhC­(O)­R, yielding the oxo-bridged dimer [Cp*Ti­{PhC­(NⁱPr)₂}­(μ-O)]₂ and either the alkoxycarbodiimide ^tBuNCNO^tBu or the oxime ethers PhC­(NO^tBu)­R (R = H (<b>25a</b>), Me (<b>25b</b>), Ph (<b>25c</b>)). DFT studies showed that in the reaction with PhC­(O)­R (R = H, Me) the product distribution between the <i>syn</i> and <i>anti</i> isomers of PhC­(NO^tBu)­R was under kinetic control. Reaction of <b>19</b> with ArCN gave the TiN_α insertion products Cp*Ti­{PhC­(NⁱPr)₂}­{NC­(Ar)­NO^tBu} (Ar = Ph (<b>28</b>), 2,6-C₆H₃F₂ (<b>27</b>), Ar^F₅ (<b>26</b>)) containing <i>tert</i>-butoxybenzimidamide ligands. Reaction of <b>19</b> or <b>26</b> with an excess of Ar^F₅CN gave Cp*Ti­{PhC­(NⁱPr)₂}­{NC­(Ar^F₅)­NC­(Ar^F₅)­N­(C­{Ar^F₅}­NO^tBu)} (<b>29</b>) following net head-to-tail coupling of 2 equiv of Ar^F₅CN across the TiN_α bond of <b>26</b>. Reductive N_α–O_β bond cleavage was observed with Ar^F₅CCH, forming Cp*Ti­(O^tBu)­{NC­(Ar^F₅)­C­(H)­N­(ⁱPr)­C­(Ph)­N­(ⁱPr)} (<b>30</b>). Addition of 2 equiv of [Et₃NH]­[BPh₄] to <b>19</b> in THF-<i>d</i>₈ resulted in protonolysis of the amidinate ligand, forming [PhC­(NHⁱPr)₂]­[BPh₄] and the cationic alkoxyimido complex [Cp*Ti­(NO^tBu)­(THF-<i>d</i>₈)₂]⁺. In contrast, reaction with B­(Ar^F₅)₃ resulted in elimination of isobutene and formation of Cp*Ti­{PhC­(NⁱPr)₂}­{η²-ON­(H)­B­(Ar^F₅)₃}

DFT Investigation of Suzuki–Miyaura Reactions with Aryl Sulfamates Using a Dialkylbiarylphosphine-Ligated Palladium Catalyst

Aryl sulfamates are valuable electrophiles for cross-coupling reactions because they can easily be synthesized from phenols and can act as directing groups for C–H bond functionalization prior to cross-coupling. Recently, it was demonstrated that (1-^tBu-Indenyl)­Pd­(XPhos)­Cl (XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) is a highly active precatalyst for room-temperature Suzuki–Miyaura couplings of a variety of aryl sulfamates. Herein, we report an in-depth computational investigation into the mechanism of Suzuki–Miyaura reactions with aryl sulfamates using an XPhos-ligated palladium catalyst. Particular emphasis is placed on the turnover-limiting oxidative addition of the aryl sulfamate C–O bond, which has not been studied in detail previously. We show that bidentate coordination of the XPhos ligand via an additional interaction between the biaryl ring and palladium plays a key role in lowering the barrier to oxidative addition. This result is supported by NBO and NCI-Plot analysis on the transition states for oxidative addition. After oxidative addition, the catalytic cycle is completed by transmetalation and reductive elimination, which are both calculated to be facile processes. Our computational findings explain a number of experimental results, including why elevated temperatures are required for the coupling of phenyl sulfamates without electron-withdrawing groups and why aryl carbamate electrophiles are not reactive with this catalyst

Synthesis and Reactions of a Cyclopentadienyl-Amidinate Titanium <i>tert-</i>Butoxyimido Compound

We report the first detailed reactivity study of a group 4 alkoxyimido complex, namely Cp*Ti­{PhC­(NⁱPr)₂}­(NO^tBu) (<b>19</b>), with heterocumulenes, aldehydes, ketones, organic nitriles, Ar^F₅CCH, and B­(Ar^F₅)₃ (Ar^F₅ = C₆F₅). Compound <b>19</b> was synthesized via imide/alkoxyamine exchange from Cp*Ti­{PhC­(NⁱPr)₂}­(N^tBu) and ^tBuONH₂. Reaction of <b>19</b> with CS₂ and Ar′NCO (Ar′ = 2,6-C₆H₃ⁱPr₂) gave the [2 + 2] cycloaddition products Cp*Ti­{PhC­(NⁱPr)₂}­{SC­(S)­N­(O^tBu)} and Cp*Ti­{PhC­(NⁱPr)₂}­{N­(O^tBu)­C­(NAr′)­O}, respectively, whereas reaction with 2 equiv of TolNCO afforded Cp*Ti­{PhC­(NⁱPr)₂}­{OC­(NTol)­N­(Tol)­C­(NO^tBu)­O} following a sequence of cycloaddition–extrusion and cycloaddition–insertion steps. Net NO^tBu group transfer was observed with both ^tBuNCO and PhC­(O)­R, yielding the oxo-bridged dimer [Cp*Ti­{PhC­(NⁱPr)₂}­(μ-O)]₂ and either the alkoxycarbodiimide ^tBuNCNO^tBu or the oxime ethers PhC­(NO^tBu)­R (R = H (<b>25a</b>), Me (<b>25b</b>), Ph (<b>25c</b>)). DFT studies showed that in the reaction with PhC­(O)­R (R = H, Me) the product distribution between the <i>syn</i> and <i>anti</i> isomers of PhC­(NO^tBu)­R was under kinetic control. Reaction of <b>19</b> with ArCN gave the TiN_α insertion products Cp*Ti­{PhC­(NⁱPr)₂}­{NC­(Ar)­NO^tBu} (Ar = Ph (<b>28</b>), 2,6-C₆H₃F₂ (<b>27</b>), Ar^F₅ (<b>26</b>)) containing <i>tert</i>-butoxybenzimidamide ligands. Reaction of <b>19</b> or <b>26</b> with an excess of Ar^F₅CN gave Cp*Ti­{PhC­(NⁱPr)₂}­{NC­(Ar^F₅)­NC­(Ar^F₅)­N­(C­{Ar^F₅}­NO^tBu)} (<b>29</b>) following net head-to-tail coupling of 2 equiv of Ar^F₅CN across the TiN_α bond of <b>26</b>. Reductive N_α–O_β bond cleavage was observed with Ar^F₅CCH, forming Cp*Ti­(O^tBu)­{NC­(Ar^F₅)­C­(H)­N­(ⁱPr)­C­(Ph)­N­(ⁱPr)} (<b>30</b>). Addition of 2 equiv of [Et₃NH]­[BPh₄] to <b>19</b> in THF-<i>d</i>₈ resulted in protonolysis of the amidinate ligand, forming [PhC­(NHⁱPr)₂]­[BPh₄] and the cationic alkoxyimido complex [Cp*Ti­(NO^tBu)­(THF-<i>d</i>₈)₂]⁺. In contrast, reaction with B­(Ar^F₅)₃ resulted in elimination of isobutene and formation of Cp*Ti­{PhC­(NⁱPr)₂}­{η²-ON­(H)­B­(Ar^F₅)₃}

Directed Palladium-Catalyzed γ‑C(sp³)–H Alkenylation of (Aza and Oxa) Cyclohexanamines with Bromoalkenes: Bromide Precipitation as an Alternative to Silver Scavenging

Directed palladium-catalyzed coupling of remote C(sp3)–H bonds of aliphatic amines with organohalides is a powerful synthetic tool. However, these reactions still possess limitations with respect to cost and resource efficiency, requiring more reactive iodinated reactants and superstoichiometric silver salt reagents. In this work, an efficient regio- and stereospecific silver-free Pd-catalyzed γ-C(sp3)–H alkenylation of cyclohexanamines and heterocyclic analogues with bromoalkenes is reported, which can also be applied on five- and seven-membered rings. DFT methods revealed that the oxidative addition of the organobromide to Pd(II) is not the rate-limiting step but rather γ-C(sp3)–H bond activation in the substrate. The lowest energy complex in the catalytic cycle is a Pd(II)-Br complex coordinated with the reaction product (η2-alkene and a bidentate directing group). The stability of this complex defines the overall energy span of the reaction. Co-catalyst KOPiv plays a pivotal role by exchanging bromide for pivalate in the complex, via precipitation of the KBr coproduct. This removal of bromide from the reaction media decreases the energy span, avoiding the use of superstoichiometric silver salt reagents and allowing decoordination of the reaction product. In addition, pivalate facilitates the C(sp3)–H bond activation in the substrate once another substrate molecule is coordinated. The reaction conditions could be directly applied for (hetero)arylation given the weaker coordination of the reaction product, featuring a (hetero)aryl versus alkenyl and change in resting state. The picolinoyl directing group can be removed via amide esterification

A Gold Exchange: A Mechanistic Study of a Reversible, Formal Ethylene Insertion into a Gold(III)–Oxygen Bond

The Au­(III) complex Au­(OAc^F)₂(tpy) (<b>1</b>, OAc^F = OCOCF₃; tpy = 2-<i>p</i>-tolylpyridine) undergoes reversible dissociation of the OAc^F ligand <i>trans</i> to C, as seen by ¹⁹F NMR. In dichloromethane or trifluoroacetic acid (TFA), the reaction between <b>1</b> and ethylene produces Au­(OAc^F)­(CH₂CH₂OAc^F)­(tpy) (<b>2</b>). The reaction is a formal insertion of the olefin into the Au–O bond <i>trans</i> to N. In TFA this reaction occurs in less than 5 min at ambient temperature, while 1 day is required in dichloromethane. In trifluoroethanol (TFE), Au­(OAc^F)­(CH₂CH₂OCH₂CF₃)­(tpy) (<b>3</b>) is formed as the major product. Both <b>2</b> and <b>3</b> have been characterized by X-ray crystallography. In TFA/TFE mixtures, <b>2</b> and <b>3</b> are in equilibrium with a slight thermodynamic preference for <b>2</b> over <b>3</b>. Exposure of <b>2</b> to ethylene-<i>d</i>₄ in TFA caused exchange of ethylene-<i>d</i>₄ for ethylene at room temperature. The reaction of <b>1</b> with <i>cis</i>-1,2-dideuterioethylene furnished Au­(OAc^F)­(<i>threo</i>-CHDCHDOAc^F)­(tpy), consistent with an overall <i>anti</i> addition to ethylene. DFT­(PBE0-D3) calculations indicate that the first step of the formal insertion is an associative substitution of the OAc^F <i>trans</i> to N by ethylene. Addition of free ^–OAc^F to coordinated ethylene furnishes <b>2</b>. While substitution of OAc^F by ethylene <i>trans</i> to C has a lower barrier, the kinetic and thermodynamic preference of <b>2</b> over the isomer with CH₂CH₂OAc^F <i>trans</i> to C accounts for the selective formation of <b>2</b>. The DFT calculations suggest that the higher reaction rates observed in TFA and TFE compared with CH₂Cl₂ arise from stabilization of the ^–OAc^F anion lost during the first reaction step

Computational Studies Explain the Importance of Two Different Substituents on the Chelating Bis(amido) Ligand for Transfer Hydrogenation by Bifunctional Cp*Rh(III) Catalysts

A computational approach (DFT-B3PW91) is used to address previous experimental studies (<i>Chem. Commun.</i> <b>2009</b>, 6801) that showed that transfer hydrogenation of a cyclic imine by Et₃N·HCO₂H in dichloromethane catalyzed by 16-electron bifunctional Cp*Rh^III­(XNC₆H₄NX′) is faster when XNC₆H₄NX′ = TsNC₆H₄NH than when XNC₆H₄NX′ = HNC₆H₄NH or TsNC₆H₄NTs (Cp* = η⁵-C₅Me₅, Ts = toluenesulfonyl). The computational study also considers the role of the formate complex observed experimentally at low temperature. Using a model of the experimental complex in which Cp* is replaced by Cp and Ts by benzenesulfonyl (Bs), the calculations for the systems in gas phase reveal that dehydrogenation of formic acid generates CpRh^IIIH­(XNC₆H₄NX′H) via an outer-sphere mechanism. The 16-electron Rh complex + formic acid are shown to be at equilibrium with the formate complex, but the latter lies outside the pathway for dehydrogenation. The calculations reproduce the experimental observation that the transfer hydrogenation reaction is fastest for the nonsymmetrically substituted complex CpRh^III­(XNC₆H₄NX′) (X = Bs and X′ = H). The effect of the linker between the two N atoms on the pathway is also considered. The Gibbs energy barrier for dehydrogenation of formic acid is calculated to be much lower for CpRh^III­(XNCHPhCHPhNX′) than for CpRh^III­(XNC₆H₄NX′) for all combinations of X and X′. The energy barrier for hydrogenation of the imine by the rhodium hydride complex is much higher than the barrier for hydride transfer to the corresponding iminium ion, in agreement with mechanisms proposed for related systems on the basis of experimental data. Interpretation of the results by MO and NBO analyses shows that the most reactive catalyst for dehydrogenation of formic acid contains a localized Rh–NH π-bond that is associated with the shortest Rh–N distance in the corresponding 16-electron complex. The asymmetric complex CpRh^III(BsNC₆H₄NH) is shown to generate a good bifunctional catalyst for transfer hydrogenation because it combines an electrophilic metal center and a nucleophilic NH group

Computational Studies Explain the Importance of Two Different Substituents on the Chelating Bis(amido) Ligand for Transfer Hydrogenation by Bifunctional Cp*Rh(III) Catalysts

A computational approach (DFT-B3PW91) is used to address previous experimental studies (<i>Chem. Commun.</i> <b>2009</b>, 6801) that showed that transfer hydrogenation of a cyclic imine by Et₃N·HCO₂H in dichloromethane catalyzed by 16-electron bifunctional Cp*Rh^III­(XNC₆H₄NX′) is faster when XNC₆H₄NX′ = TsNC₆H₄NH than when XNC₆H₄NX′ = HNC₆H₄NH or TsNC₆H₄NTs (Cp* = η⁵-C₅Me₅, Ts = toluenesulfonyl). The computational study also considers the role of the formate complex observed experimentally at low temperature. Using a model of the experimental complex in which Cp* is replaced by Cp and Ts by benzenesulfonyl (Bs), the calculations for the systems in gas phase reveal that dehydrogenation of formic acid generates CpRh^IIIH­(XNC₆H₄NX′H) via an outer-sphere mechanism. The 16-electron Rh complex + formic acid are shown to be at equilibrium with the formate complex, but the latter lies outside the pathway for dehydrogenation. The calculations reproduce the experimental observation that the transfer hydrogenation reaction is fastest for the nonsymmetrically substituted complex CpRh^III­(XNC₆H₄NX′) (X = Bs and X′ = H). The effect of the linker between the two N atoms on the pathway is also considered. The Gibbs energy barrier for dehydrogenation of formic acid is calculated to be much lower for CpRh^III­(XNCHPhCHPhNX′) than for CpRh^III­(XNC₆H₄NX′) for all combinations of X and X′. The energy barrier for hydrogenation of the imine by the rhodium hydride complex is much higher than the barrier for hydride transfer to the corresponding iminium ion, in agreement with mechanisms proposed for related systems on the basis of experimental data. Interpretation of the results by MO and NBO analyses shows that the most reactive catalyst for dehydrogenation of formic acid contains a localized Rh–NH π-bond that is associated with the shortest Rh–N distance in the corresponding 16-electron complex. The asymmetric complex CpRh^III(BsNC₆H₄NH) is shown to generate a good bifunctional catalyst for transfer hydrogenation because it combines an electrophilic metal center and a nucleophilic NH group

Design of a Versatile and Improved Precatalyst Scaffold for Palladium-Catalyzed Cross-Coupling: (η³‑1‑^tBu-indenyl)₂(μ-Cl)₂Pd₂

We describe the development of (η³-1-^tBu-indenyl)₂(μ-Cl)₂Pd₂, a versatile precatalyst scaffold for Pd-catalyzed cross-coupling. Our new system is more active than commercially available (η³-cinnamyl)₂(μ-Cl)₂Pd₂ and is compatible with a range of NHC and phosphine ligands. Precatalysts of the type (η³-1-^tBu-indenyl)­Pd­(Cl)­(L) can either be isolated through the reaction of (η³-1-^tBu-indenyl)₂(μ-Cl)₂Pd₂ with the appropriate ligand or generated in situ, which offers advantages for ligand screening. We show that the (η³-1-^tBu-indenyl)₂(μ-Cl)₂Pd₂ scaffold generates highly active systems for a number of challenging cross-coupling reactions. The reason for the improved catalytic activity of systems generated from the (η³-1-^tBu-indenyl)₂(μ-Cl)₂Pd₂ scaffold compared to (η³-cinnamyl)₂(μ-Cl)₂Pd₂ is that inactive Pd^I dimers are not formed during catalysis