Modulating the Elementary Steps of Methanol Carbonylation by

Aug 30, 2016 - The rate of catalytic methanol carbonylation to acetic acid is typically limited by either the oxidative addition of methyl iodide or t...
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Modulating the Elementary Steps of Methanol Carbonylation by Bridging the Primary and Secondary Coordination Spheres Lauren C. Gregor,† Javier Grajeda,† Matthew R. Kita,† Peter S. White,† Andrew J. Vetter,‡ and Alexander J. M. Miller*,† †

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States Eastman Chemical Company, Kingsport, Tennessee 37660, United States

‡

S Supporting Information *

ABSTRACT: The rate of catalytic methanol carbonylation to acetic acid is typically limited by either the oxidative addition of methyl iodide or the subsequent C−C bond-forming migratory insertion step. These elementary steps have been studied independently in acetonitrile solution for iridium aminophenylphosphinite (NCOP) complexes. The modular synthesis of NCOP ligands containing a macrocyclic aza-crown ether arm enables a direct comparison of two complementary catalyst optimization strategies: synthetic modification of the phenyl backbone and noncovalent modification through cation−crown interactions with Lewis acids in the surrounding environment. The oxidative addition of methyl iodide to iridium(I) carbonyl complexes proceeds readily at room temperature to form iridium(III) methylcarbonyliodide complexes. The methyl complexes undergo migratory insertion under 1 atm CO at 70 °C to produce iridium(III) acetyl species. Synthetic tuning, by incorporation of a methoxy group into the ligand backbone, had little influence on the rate. The addition of lithium and lanthanum salts, in contrast, enhanced the rate of C−C bond formation up to 25-fold. In the case of neutral iodide complexes, mechanistic studies suggest that Lewis acidic cations act as halide abstractors. In halide-free, cationic iridium complexes, the cations bind the macrocyclic ligand arm, further activating the iridium(III) center. The macrocyclic ligand is essential to the observed reactivity: complexes supported by acyclic diethylamine-containing ligands underwent migratory insertion slowly, Lewis acid effects were negligible, and the acetyl products decomposed over time.

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INTRODUCTION Discrete group 9 transition metal complexes are the dominant industrial catalysts for methanol carbonylation processes that produce acetic acid on a global scale of ∼8 million tons per year.1−4 Early cobalt carbonylation catalysts required high temperature (250 °C) and pressure (680 bar) to achieve 90% selectivity.5 Modern processes utilize homogeneous rhodium and iridium catalysts in the presence of various promoters under milder conditions (150−200 °C, 30−60 bar) and achieve >99% selectivity.2,6 Iodide promoters generate methyl iodide (Scheme 1), facilitating oxidative addition to initiate catalysis (but producing corrosive HI in situ).2,7 Lewis acid promoters accelerate CO migratory insertion.3,8−10 In the Cativa process, Lewis acidic Ru(II) salts act as halide abstractors from iridium catalysts to generate intermediates that are more reactive toward migratory insertion.6,11 In other cases, the role of the Lewis acid is not as clear. For example, La3+ salts interact with iridium-on-carbon to form intriguing two-atom heterobimetallic active sites that promote methanol carbonylation via an unknown mechanism.10 Understanding how new ligand designs influence the elementary steps of methanol carbonylation could lead to improved catalysts, for example, avoiding the use of precious metal promoters or a large excess of corrosive iodide salts. © XXXX American Chemical Society

Iridium complexes supported by macrocyclic aminophosphinite (NCOP) pincer-crown ether ligands provide an opportunity to directly compare strategies based on synthetic ligand tuning and external promoters that interact with the ligand in the secondary coordination sphere. A range of ligand derivatives are easily accessible, such that the electronic properties and ability to interact with cations can be adjusted.12,13 The pendent crown ether could play a number of beneficial roles, based on the ability of ether donors to reversibly bind the metal as hemilabile ligands and interact with cationic Lewis acids.12,13 Usually either oxidative addition or migratory insertion is the turnover-limiting process (Scheme 1), motivating efforts to accelerate both of these elementary steps in a controlled manner. We set out to explore the ability of pincer-crown ether iridium complexes to facilitate these two key steps in methanol carbonylation. These studies provided a rare opportunity to directly compare the impact of noncovalent interactions in the secondary coordination sphere with synthetic modifications in the primary coordination sphere (Scheme 2). While synthetic modification did not prove fruitful, the macrocyclic ligand fostered noncovalent interactions with lithium and lanthanum Received: July 27, 2016

A

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Organometallics Scheme 1. Elementary Steps of Methanol Carbonylation

Scheme 3

Diastereotopic resonances for the benzylic linker and two sets of iso-propyl doublet of doublets indicate a loss of symmetry due to inequivalent ligands perpendicular to the plane of the pincer ligand. An upfield doublet (δ 0.72, 2JPH = 1.5 Hz) is attributed to the iridium methyl ligand, and a νCO stretching frequency is observed at 2021 cm−1. A sharp singlet in the 31 1 P{ H} NMR spectrum (δ 137) is found 34 ppm upfield of the Ir(I) starting material 1 (δ 171). Pale yellow crystals of 2 suitable for X-ray diffraction were obtained from a concentrated acetone solution at room temperature (Figure 1). The stereochemistry of 2, with methyl Scheme 2

salts that led to faster migratory insertion. The pincer-crown ether ligand bridges the primary and secondary coordination spheres, with cation−macrocycle interactions, in turn, disrupting iridium−ligand bonds. The mechanistic findings suggest new approaches in the design of catalysts optimized by external additives.

Figure 1. Structural representation of 2 with ellipsoids drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected distances (Å) and angles (deg): Ir1−P1 2.2472(9), Ir1−C3 2.034(3), Ir1−N1 2.347(3), Ir1−I1 2.7901(3), Ir1−C2 1.927(4), Ir1−C1 2.120(4), C2−O1 1.143(5); N1−Ir1−P1 154.02(8), N1−Ir1−I1 86.61(8).

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RESULTS AND DISCUSSION Oxidative Addition of Methyl Iodide to (15c5NCOPiPr)Ir(CO). Acetic acid synthesis typically commences with in situ conversion of methanol to methyl iodide, which more readily reacts with the catalyst to initiate a sequence of organometallic transformations (Scheme 1). Methyl iodide oxidative addition is the turnover-limiting step in Rh-catalyzed methanol carbonylation,14,15 whereas the analogous oxidative addition occurs rapidly at the electron-rich (often anionic) Ir(I) catalysts.2 Facile methyl iodide oxidative addition to pincer-crown ether Ir(I) species was, therefore, anticipated.16 The bright yellow Ir(I) carbonyl complex (15c5NCOPiPr)Ir(CO) (1) was prepared as previously described13 and treated with a slight excess of CH3I. Oxidative addition proceeded smoothly to form (15c5NCOPiPr)Ir(CH3)(CO)(I) (2) (Scheme 3) at room temperature within 1 h, accompanied by the original bright yellow color fading to a pale yellow. The 1H NMR spectrum of 2 is similar to that of previously reported octahedral Ir(III) pincer-crown ether carbonyl complexes.13

trans to iodide, and confirms a tridentate pincer binding mode in accord with solution spectroscopy. The bond distances of 2 are similar to those of the related hydride complex (15c5NCOPiPr)Ir(H)(CO)(Cl),13 except for the Ir−N and Ir−P bonds, which are longer in 2 by approximately 0.1 Å. This raises the possibility of amine dissociation to open a coordination site in the complex, as Milstein and co-workers have noted in Pt complexes and Ru catalysts.17−20 The oxidative addition of CH3I to 1 was monitored over time by UV−vis spectroscopy. Bright yellow solutions of 1 feature three strong absorbance maxima at 310, 365, and 410 nm (ε ≈ 6400, 3400, 1800 M−1 cm−1, respectively),13 whereas the pale yellow product 2 is a weak absorber. Upon addition of excess CH3I (200 equiv) to a solution of 1 in CH3CN at room B

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Organometallics temperature, the spectral features of 1 disappeared over the course of just 50 s (Figure 2A). Kinetic analysis reveals pseudo-

Scheme 4

Et2O into (Me3Si)2O. The molecular structure (Figure 3) is analogous to the previously reported (15c5NCOPiPr)Ir(CO) (1),13 with a square-planar geometry and very similar bond distances.

Figure 2. (A) UV−vis spectra tracking the reaction of CH3I (28 mM) with 1 (0.14 mM in CH3CN) with scans every 5 s at 25 °C. (B) Firstorder kinetic plot following the absorbance at 365 nm for the reaction of 1 with CH3I (red squares) and for the reaction of 5 with CH3I (blue circles).

first-order decay of the Ir(I) species (Figure 2B), with kobs = 0.046(1) s−1 (t1/2 = 15 s). The oxidative addition proceeded similarly in the presence of 1 equiv LiSO3CF3 (LiOTf), kobs = 0.047(1) s−1 (t1/2 = 15 s). Oxidative Addition of Methyl Iodide to (MeO‑15c5NCOPiPr)Ir(CO). A modular pincer-crown ether ligand synthesis facilitates primary coordination sphere tuning through variation of substituents along the pincer backbone. A methoxy group was readily installed on the arene backbone ortho to the phosphinite oxygen atom by starting from biomass-derived isovanillin. The substitution position was also chosen to prevent remetalation pathways.13 The new ligand (3, Scheme 4) was synthesized in two steps by reductive amination of iso-vanillin, followed by phosphination with NEt3 and iPr2PCl. Metalation was accomplished by refluxing (MeO‑15c5NCOPiPr)H with Ir(p-toluidine)(CO)2(Cl)21 in toluene, affording (MeO‑15c5NCOPiPr)Ir(H)(CO)(Cl) (4) in 95% yield. The spectroscopic signatures of 4 are nearly identical to those of the unsubstituted Ir(III) hydridocarbonyl chloride complex.13 Following the procedures used for the analogous unsubstituted complexes, dehydrohalogenation afforded the Ir(I) carbonyl complex (5). Bright yellow crystals of 5 suitable for X-ray diffraction were obtained from vapor diffusion of a concentrated solution of 5 in

Figure 3. Structural representation of 5 with ellipsoids drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected distances (Å) and angles (deg): Ir1−P1 2.1960(9), Ir1−C2 1.875(4), Ir1−C3 2.028(3), Ir1−N1 2.212(3), C2−O2 1.151(5); C3−Ir1−C2 177.25(15), P1−Ir1−N1 157.35(8).

Oxidative addition of CH3I to 5 produced the Ir(III) methyl complex 6 (Scheme 5). Kinetic analysis under the same pseudo-first-order conditions employed above (200:1 CH3I:5) Scheme 5

C

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(Scheme 6). The addition of [PPN][I]27 (PPN = bis(triphenylphosphine)iminium) to samples containing only the cationic acetyl complex κ4-7′ resulted in partial conversion back to the iodide complex κ3-7′. When a mixture obtained from carbonylation of 2′ was combined with 10 equiv of [PPN][I] and placed under 1 atm CO, in situ variable-temperature NMR experiments between 20 and 60 °C showed broadening of the acetyl methyl doublets of the two species, suggesting the presence of a rapid equilibrium between the cationic and neutral acetyl complexes (see the SI for spectra). No evidence for bound CH3CN in κ3-7′ or κ4-7′ was observed by 1H NMR spectroscopy in CH3CN/CD3CN or in 13 C-APT experiments.12,13 Consistent with intramolecular ether binding, addition of CH3CN to a CD2Cl2 solution of κ4-7′ resulted in no NMR spectral changes. The presence of an Iracetyl was also confirmed by the synthesis of an authentic sample by the addition of acetyl chloride to 1 (which formed in a 1:3 ratio of neutral to cationic species; see the SI for details). Having established a more complete understanding of the product distribution, the rate of migratory insertion was monitored by 1H NMR spectroscopy. For all of the migratory insertion kinetic studies described here, samples containing a standard concentration of Ir (labeled with 13CH3) were prepared in the glovebox, charged with 1 atm CO, and heated at 70 °C. 1H NMR spectra (at 25 °C) were acquired periodically (typically every 15 min). To facilitate comparisons across a wide range of conditions and complexes (without exhaustive kinetic analysis), the half-life (t1/2) of migratory insertion was obtained under standard conditions for each reaction (see the Experimental Section for details). The iridium methyl complex 2′ was consumed with t1/2 = 200 min under the standard conditions of 1 atm CO and 70 °C (Table 1). The migratory insertion is reversible, as commonly

provided an observed rate constant of oxidative addition, kobs = 0.069(1) s−1 (t1/2 = 10 s). Oxidative addition of CH3I to 5 proceeds slightly faster than oxidative addition of CH3I to 1 under the same conditions. The rate of CH3I oxidative addition to 5 is also unaffected by 1 equiv LiOTf, kobs = 0.071(2) s−1 (t1/2 = 9.8 s). Introducing Li+ salts neither promotes nor inhibits the reaction. Migratory Insertion Reactivity of (15c5NCOPiPr)Ir(CH3)(CO)(I). The migratory insertion reactivity of Ir complexes is relatively unexplored,1,22−25 and C−C bond formation is often sluggish, proceeding up to 106 times slower than Rh analogues in some cases.24 The neutral complex (15c5NCOPiPr)Ir(CH3)(CO)(I) (2) has a cis-methylcarbonyl geometry appropriate for migratory insertion. To help monitor the methyl group during the reaction, the isotopically labeled complex (15c5NCOPiPr)Ir(13CH3)(CO)(I) (2′) was prepared by addition of 13CH3I to the Ir(I) carbonyl complex 1 (isotopically labeled complexes are noted with a prime). Labeled 2′ features a doublet of doublets for the Ir−13CH3 group in the 1H NMR spectrum (δ 0.75 dd, JHP = 1.5, JHC = 132 Hz) and a doublet in the 13C{1H} NMR spectrum (δ −19.0, JCP = 7.5 Hz). Placing complex 2′ under 1 atm CO in CD3CN at ambient temperature led to no discernible change in the 1H NMR spectrum over 24 h. The reaction was then heated at 70 °C and monitored by NMR spectroscopy. After 5 h, spectra showed 40% conversion to two products with broad, overlapping 31 1 P{ H} NMR signals (δ 140) and diagnostic acetyl methyl doublets in the 1H NMR spectrum (δ 2.8, d, JHC = 128 Hz and δ 1.7, d, JHC = 128 Hz). Intense signals for two distinct Ir− C(O)13CH3 species were observed by 13C{1H} NMR, δ 51 and δ 39. IR spectroscopic analysis of the product mixture featured one CO stretch close to the starting complex (νCO = 2017 cm−1) along with another CO stretch at higher energy (νCO = 2039 cm−1) in a range similar to that of the cationic species [(15c5NCOPiPr)Ir(H)(CO)(NCCH3)]+ (νCO = 2031 cm−1),13 suggesting one cationic product and one neutral product. A broad feature in the IR spectrum at 1624 cm−1 and two downfield resonances (δ 202 and δ 207) in the 13C{1H} NMR spectrum are indicative of acetyl formation.26 The mass expected for [(15c5NCOPiPr)Ir(C(O)CH3)(CO)]+ was detected by high-resolution mass spectrometry (HRMS). On the basis of the combined characterization data, the two products are assigned as neutral (15c5NCOPiPr)Ir(C(O)13CH3)(CO)(I) (κ3-7′) and cationic [κ4-(15c5NCOPiPr)Ir(C(O)13 CH3)(CO)]+ (κ4-7′), formed in a 1:1.3 ratio (Scheme 6, where bold red C atoms are isotopically labeled). The iodide complex κ3-7′ is converted completely to the cationic complex κ4-7′ by addition of NaBArF4 (ArF = 3,5-bis(trifluoromethyl)phenyl), confirming the presence of a halide ligand in κ3-7′

Table 1. Half-Life (t1/2) of Migratory Insertion under 1 atm CO at 70°C in CD3CNa t1/2 in minutes under various conditions Ir complex 15c5

iPr

13

( NCOP )Ir( CH3)(CO)(I) (2′) [(15c5NCOPiPr)Ir(13CH3)(CO)]+ (9′)c (MeO‑15c5NCOPiPr)Ir(13CH3)(CO)(I) (6′) [(EtNCOPiPr)Ir(13CH3)(CO)]+ (13′)

no salt

LiOTf

La(OTf)3b

200 14 160 60

170 30 170 62

75 8 55 60

Reactions were heated at 70 °C and monitored by 1H NMR (25 °C), average error in measurements ±10%. Half-life (t1/2) is the time to 50% conversion based on an exponential fit of the decaying signal for the Ir methyl complex (first ∼35% conversion; see the Experimental Section for details). bThe 1H NMR integrals for each Ir-CH3 group disappearing was summed to a single integral and plotted to obtain a weighted average half-life. cRates determined in situ by 1H NMR spectroscopy with the probe heated to 70 °C. a

Scheme 6

observed28−30 in carbonylation chemistry: replacing the CO atmosphere with N2 at the conclusion of the kinetic run led to slow deinsertion. The methyldicarbonyl complex [κ3-(15c5NCOPiPr)Ir(CH3)(CO)2]+ (8) formed in ∼80% yield after 24 h at 70 °C. The identity of 8 was confirmed by independent synthesis of an authentic sample (see the Experimental Section for details). Migratory Insertion Reactivity of [κ4-(15c5NCOPiPr)Ir13 ( CH3)(CO)]+. In carbonylation catalysis, the promoting effect of Lewis acids is generally attributed to iodide abstraction to D

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Organometallics yield a cationic methyl complex,1 so we sought to compare the reactivity of the iodide complex 2 with a cationic congener. The cationic complex [(15c5NCOPiPr)Ir(CH3)(CO)][BArF4] (9) was prepared by addition of NaBArF4 to a CH2Cl2 solution of 2. Our prior studies have shown that solvent choice and salt precipitation can be important factors in the reactivity with cations;13 in this case, Na+ is acting simply as a halide abstraction reagent, driven by precipitation of NaI. In CD2Cl2, cation 9 likely adopts a tetradentate binding mode in analogy to previously characterized iridium(III) crown ether complexes.12 The CO stretching frequency (νCO = 2041 cm−1) observed by IR spectroscopy is at slightly higher energy than the neutral precursor 2, consistent with a cationic product. In CD3CN, solvent displaces the ether donor to yield a tridentate binding mode (Scheme 7), according to a 13C-APT Scheme 7

Figure 4. Two views of the molecular structure of κ4-7 with ellipsoids drawn at the 50% probability level and with H atoms and BArF4 anion omitted. Selected distances (Å) and angles (deg): Ir1−P1 2.2694(15), Ir1−O2 2.377(4), Ir1−C2 1.971(6), Ir1−N1 2.2424(5), Ir−C4 2.031(6), Ir−C3 2.010(6), C2−O3 1.22(7); N1−Ir1−P1 159.98(14), N1−Ir1−C4 89.3(2).

experiment featuring a resonance for a bound quaternary carbon at δ 119. The process is fluxional, however, as evident by broadening in the 1H NMR spectrum (see the SI for spectra). Placing complex 9 under 1 atm CO in CD3CN at ambient temperature results in partial conversion (over 15 min) to 8 (Scheme 7). Interestingly, even at room temperature, slow carbonylation is observed (60% conversion over 5 days). Heating 9 under CO at 70 °C afforded complete conversion to complex κ4-7 as the sole product after 2 h. Single crystals suitable for X-ray diffraction were obtained by vapor diffusion of cyclohexane into a concentrated solution of κ4-7 in Et2O at room temperature (Figure 4). The solid-state structure of κ4-7 reveals a cationic acetyl complex with a tetradentate binding mode of the pincer ligand, in which a crown ether oxygen occupies the site trans to the acetyl in an octahedral primary coordination sphere. Tetradentate pincercrown ether species (including the cationic methyl complex 9) typically undergo facile substitution of CH3CN for the chelating ether ligands to form tridentate analogues. In surprising contrast, the acetyl complex κ4-7 maintains a tetradentate binding mode both in the solid state and in CH3CN solution under a CO atmosphere (vide inf ra). Variable-temperature NMR spectroscopy (70 °C) was utilized to monitor the rate of migratory insertion in situ. Migratory insertion occurred with t1/2 = 14 min, an ∼11-fold rate enhancement relative to 2 under the same conditions. The cationic complex 9 undergoes migratory insertion much more readily than the neutral complex 2, and the rate enhancement

suggests that halide abstraction could be used to promote migratory insertion in iridium pincer-crown ether complexes. Migratory Insertion in the Presence of Lewis Acidic Cations. Lewis acids have long been recognized to promote migratory insertion in alkylcarbonyl complexes.31−36 McLain first showed that redox-inactive metal cations can interact with metal acyl complexes with the aid of crown ether-containing ligands.37 Recent studies by Bercaw showed that proximal Lewis acids can facilitate migratory insertion.38−41 Metal halide salts are typically required, often leading to products that feature both metal−oxygen bonds and metal−halide bonds.33,41,42 In the handful of Lewis acid accelerated migratory insertion reactions on Ir, the predominant mechanism is halide abstraction by Ru(II) (as in the Cativa process), Pt(II), or Sn(II).1,24,43 We sought to probe the effect of cations in our molecular system (Scheme 8). When the neutral methyl complex 2′ was treated with LiOTf (Scheme 8), signals in the crown ether region of the NMR spectrum broadened and shifted, as expected for a rapid, reversible cation−macrocycle interaction.13 Upon heating at 70 °C under 1 atm CO, conversion to κ3-7′ and κ4-7′ was observed (85% yield). Partial halide abstraction in the presence of Li+ was suggested by the rapid appearance of an Ir-13CH3 doublet of doublets in ∼15% yield (δ 0.55, JPH = 2.1, JHC = 126 Hz), a resonance that closely matches cationic [(15c5NCOPiPr)Ir(CH3)(CO)2]+ (8). E

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NMR spectra showed no evidence of coordinated OTf−. The new acetyl species is thus assigned as a cationic acetylcarbonylnitrile complex, [(15c5NCOPiPr)Ir(C(O)CH3)(CO)(NCCD3)][OTf] (κ3-7′-NCCD3). We hypothesize that strong La3+ binding to the crown ether moiety disrupts the tetradentate binding of the crown ether to iridium seen in κ4-7,44 facilitating nitrile association in κ3-7′-NCCD3. However, there is no evidence for strong interactions between the acetyl oxygen and the La3+ ion in the product. Migratory insertion of the halide-free cation 9′ was also monitored in the presence of 1 equiv of La(OTf)3 in CD3CN under 1 atm CO. If La3+ was simply a halide abstractor, no rate enhancement would be expected. After 22 h at 25 °C, roughly 50% conversion to κ3-7′-NCCD3 was observed, whereas 9′ alone showed less than 5% conversion under the same conditions. Utilizing variable-temperature NMR, the reaction was monitored in situ at 70 °C under 1 atm CO, collecting a 1H NMR spectrum every minute, providing t1/2 = 8 min. This experiment confirms that La3+ is more than a simple halide abstractor. To our knowledge, this is the first example of a Lewis acid promoting migratory insertion by a mechanism other than halide abstraction on iridium. Migratory Insertion of Methoxy-Substituted Complexes. When solutions of complex 6′ in CD3CN were placed under 1 atm CO and heated at 70 °C, the 1H NMR spectrum evolved over time as expected, producing a 1:1.4 mixture of iodide complex (MeO‑15c5NCOPiPr)Ir(C(O)13CH3)(CO)(I) (κ310′) and tetradentate cation [(MeO‑15c5NCOPiPr)Ir(C(O)13CH3)(CO)]+ (κ4-10′). Iodide complex 6′ undergoes C−C bond formation at about the same rate as the unsubstituted complex 2′ (Table 1). The cationic methylcarbonyl complex [(MeO‑15c5NCOPiPr)Ir(13CH3)(CO)][BArF4] (κ4-6′) was generated in situ by addition of NaBArF4 and monitored under CO. Again, the rate of migratory insertion under standard conditions (monitored by NMR spectroscopy in situ with the probe heated to 70 °C) was similar to that of the unsubstituted complex, with t1/2 = 17 min. While the rate of migratory insertion at complex 6′ was not measurably enhanced by LiOTf, the reaction proceeded 3 times faster in the presence of La(OTf)3 (Table 1). The reaction of 6′ with La(OTf)3 parallels that of 2′, with the addition of 1 equiv La(OTf)3 under N2 producing a mixture of neutral and cationic methyl species, which each undergo migratory insertion upon heating to 70 °C with slightly different half-lives (t1/2 = 12, 41, and 60 min). The cationic species was consumed the fastest. These studies illustrate the advantage of relying on external additives for rate optimization. Even with a modular ligand synthesis, at least f ive synthetic steps were required to learn that methoxy substitution had a minimal influence on the rate of migratory insertion. External Lewis acid additives work cooperatively with the macrocycle-containing complex to produce larger rate enhancements. Even without extensive optimization, cations could be used to enhance the rate of migratory insertion by a factor of ∼25. Migratory Insertion of Diethylamine-containing Complexes. The crown ether moiety can play multiple roles. The macrocycle acts as a hemilabile ligand, as seen in the shift from tridentate binding to tetradentate binding upon migratory insertion. The crown also hosts cations, as seen in the reactivity with LiOTf and La(OTf)3. To assess the importance of the macrocyclic amine donor and better understand its role in migratory insertion, we explored the reactivity of an Ir methyl

Scheme 8

Migratory insertion under 1 atm CO at 70 °C in the presence of 1 equiv LiOTf proceeded with t1/2 = 170 min, slightly faster than migratory insertion at 2′ in the absence of salts (Table 1). The slight rate enhancement is consistent with a small amount of cationic species present, with LiOTf facilitating migratory insertion by halide abstraction from 2′. Lithium also accelerates the reverse process: replacing the CO atmosphere with N2 in the presence of LiOTf generates 8 as the sole product after only 5 h at 70 °C (compared to 80% yield in 24 h at 70 °C in the absence of LiOTf). No evidence for Li+−crown interactions was evident by 1H NMR spectroscopy at the end of the reaction. A white precipitate suggests that halide abstraction and precipitation of LiI is responsible for the observed rate enhancement. Migratory insertion of isolated samples of cationic 9′ was also monitored in the presence of LiOTf. As shown in Table 1, the addition of LiOTf did not accelerate the rate of migratory insertion. The primary role of LiOTf in the case of 2′ can thus be assigned to halide abstraction and partial conversion to the more active species 9′. Lanthanum salts were examined next, inspired by a heterogeneous iridium-on-carbon catalyst that showed its best activity in the presence of a La3+ promoter.10 Whereas LiOTf simply engaged in rapid, reversible cation−macrocycle interactions, addition of La(OTf)3 to 2′ in CD3CN led to 75% conversion to two new methyliridium species at room temperature under N2 within 15 min (Scheme 8). The 1H NMR resonances in the crown ether region were also broad, indicative of a cation−crown interaction. The major species is assigned as the OTf− salt of the cationic complex 9′ (45%, 1H δ 0.79 dd and 31P{1H} δ 132), but the minor product (32%, 1H δ 1.2 dd and 31P{1H} δ 134) remains unidentified. The La3+ salt is clearly an effective halide abstractor.13 A sample of neutral iodide complex 2′ and La(OTf)3 heated at 70 °C under 1 atm CO and monitored by 1H NMR every 15−30 min revealed that the three methyl groups disappeared at similar rates (t1/2 = 64, 80, and 42 min for the Ir-CH3 groups of 1H δ 1.2, 0.79, and 0.56, respectively). After 75 min of heating, the mixture of methyl species had converted to a single major Ir acetyl product similar to, but distinct from, previously observed acetyl products. Analysis of the product by a 13C-APT NMR experiment revealed the presence of a quaternary carbon of a coordinated acetonitrile at δ 119. Additionally, 19F{1H} F

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Organometallics Scheme 9

complex supported by a diethylamine-containing NCOP pincer ligand. Treating the previously characterized Ir(I) carbonyl complex κ3-(EtNCOPiPr)Ir(CO)13 (11) with CH3I readily afforded the methylcarbonyliodide complex 12 (Scheme 9), with spectroscopic signatures nearly identical to 2. Halide abstraction in the presence of MeCN generated the cationic species 13. The rate of migratory insertion of 13′ was explored under the same conditions as previously described (1 atm CO, 70 °C, CD3CN) and monitored by 1H NMR spectroscopy. Each reaction produced a single Ir-acetyl product, [(EtNCOPiPr)Ir(C(O)13CH3)(CO)(NCCH3)][BArF4] (14′-NCCD3). The acetonitrile ligand was detected by a 13C-APT experiment. The spectroscopic signatures of the acetyl ligand were similar to those of the analogous macrocycle-containing cation κ3-7′NCCD3 (Ir-C(O)CH3: 1H δ 1.83 (JCH = 128 Hz), 13C{1H} δ 42, νC(O) = 1609 and νCO 2064 cm−1). The macrocycle-free complex 13 undergoes migratory insertion more than 3 times slower than the analogous cationic pincer-crown ether complex 9. Furthermore, as shown in Table 1, the macrocycle-free variant shows no Lewis acid acceleration with Li+ or La3+ salts. When 13 was treated with La(OTf)3 in the presence of free 12-crown-4, a slight rate enhancement was observed (t1/2 = 31 min). None of the reactions proceeded to completion, even after 24 h at 70 °C (typically ∼70% conversion), and extended heating led to multiple unidentified decomposition products. The crown ether clearly plays a critical role in accelerating the reaction and stabilizing the Ir-acetyl product. Insight into the Mechanism of Migratory Insertion. The comparative migratory insertion kinetics provide an opportunity to probe the mechanism of C−C bond formation and better understand the various roles of ligand electronics, Lewis acids, and macrocycle hemilability. The mechanism of acetyl formation was considered first in the absence of any Lewis acids, starting from carbonyl complex 8, which is the dominant species under 1 atm CO at room temperature. Three mechanisms for the production of κ4-7 were considered, as shown in Scheme 10. C−C bond formation could proceed via intramolecular insertion of CO into the Ir− CH3 bond (Path A), direct intermolecular insertion of CO into the Ir−CH3 bond (Path B), or methyl migration to CO, followed by isomerization (Path C). Isomerization of a 5coordinate acetyl complex has been observed on Fe and Ru, which avoids placing the strong phenyl and acetyl donors trans to each other.45,46 Direct insertion of a CO was recently proposed by Ison et al. for a methylrhenium(V) oxo complex.47,48 To confirm the origin of the CO fragment of the acetyl product, 9′ was placed under 1 atm 13CO and heated at 70 °C. Initial 13C{1H} NMR spectra show isotopically labeled resonances for free 13CO (δ 185) and the Ir-13CH3 group (δ −27.3). The reaction was heated for 2 h at 70 °C to ensure

Scheme 10

complete conversion to κ4-7′. Subsequent 13C{1H} NMR spectra show full 13C incorporation of the CO ligand (δ 181), consistent with either Path A or Path C. Only the methyl carbon of the acetyl contained a 13C label (from the Ir−13CH3 starting material), ruling out Path B. Further evidence against Path B is the observation of slow migratory insertion at 9′ in the absence of added CO. As illustrated in Scheme 10, migratory insertion induces a change in ligand binding mode from tridentate in the methyl complex to tetradentate in the acetyl product. Donation from the macrocycle stabilizes the final acetyl product. Ligand hemilability might also contribute to the faster rate of C−C bond formation in pincer-crown ether complexes compared to macrocycle-free diethylamino-ligated complexes, which lack an intramolecular donor to rapidly bind the high-energy fivecoordinate intermediate. The origin of this change in binding mode was probed computationally, as summarized in Figure 5. A density functional theory (DFT) study found that the tetradentate cationic acetyl κ4-7 is very close in energy to the iodide product κ3-7 (ΔG = +0.77 kcal·mol−1), consistent with the observed mixtures. On the other hand, replacement of the crown ether oxygen by an acetonitrile ligand was unfavorable by 6.9 kcal· mol−1. CO binding was similarly predicted to be unfavorable by 4.3 kcal·mol−1. The increased steric bulk of the acetyl ligand may be driving the change in ligand binding mode. When bound in a tetradentate fashion, the crown ether is pulled away from the acetyl ligand; displacement of the ether by another ligand would result in a tridentate binding mode that would have more steric interactions with the acetyl group. Consistent with this view, DFT calculations suggest that tetradentate G

DOI: 10.1021/acs.organomet.6b00607 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Scheme 11

Figure 5. DFT comparison of binding affinity of carbonyl and iodide ligands relative to tetradentate crown ether binding in Ir-hyride and acetyl complexes.

binding is less stable for the corresponding metal hydride species: the neutral tridentate iodide complex is 7 kcal·mol−1 more stable than the tetradentate cation in this case. Experimental studies corroborate that tridentate binding is preferred for hydride and methyl ligands, but tetradentate binding becomes energetically favorable once the larger acetyl ligand is formed (vide supra). The promoting effects of cations in the pincer-crown ether system could fall into three different categories, as outlined in Scheme 11. Starting from 2 or the bis-carbonyl complex 8, the following pathways were considered: (i) halide abstraction from the iridium center, leaving a more electron-deficient metal center; (ii) cation−macrocycle interactions that inductively render the amine less electron-releasing, or could even lead to amine dissociation of the hemilabile macrocyclic ligand, both leading to a more electrophilic metal center, and (iii) carbonyl oxygen binding to the cation during C−C bond formation, activating the carbonyl toward nucleophilic attack by the methyl ligand. Many examples of rate acceleration have been attributed to interactions between the Lewis acid and the carbonyl oxygen during or after C−C bond formation,8,32,33,38,39,42 whereas the halide abstraction mechanism is frequently encountered in carbonylation catalysis.2 In the few cases where macrocycles positioned a cationic Lewis acid near the carbonyl complex, carbonyl activation (or stabilization of the resulting acyl) has been invoked.37,40,41 There is good evidence for halide abstraction (path i) in the case of reactions involving the iodide complex 2. Halide-free cationic species were observed during reactions with LiOTf and La(OTf)3, and isolated samples of cationic methyl complex 3 underwent migratory insertion significantly faster than 2. Halide abstraction to access 3 would explain the observed rate enhancements. The cationic, halide-free species must be promoted via a different mechanism. Intercalation of La3+ ions into the macrocycle could pull electron density away from the Ir center (perhaps even temporarily rupturing the Ir−amine bond), providing an electrophilic species that is activated toward

migratory insertion (path ii). Alternatively, the macrocycle could be supporting carbonyl−cation interactions (path iii). Intimate cation−macrocycle interactions are indicated by the cation-independent reactivity of macrocycle-free diethylaminocontaining pincer complexes. The lack of evidence for strong acetyl−cation interactions after carbonylation might provide evidence against pathway (iii). Stable acyl products featuring metal−oxygen interactions and bridging halides are observed in most cases where carbonyl activation is invoked.32−34,40,41,49,50 The presence of La3+−macrocycle interactions does disrupt the tetradentate binding mode, leading to a product supported in a tridentate fashion, but this product exhibited no signs of significant acetyl−cation interactions. A mechanistic picture requiring access to electrophilic iridium species emerges from the mechanistic studies. This is most often achieved by iodide loss to leave a cationic species. The macrocyclic ligand arm provides access to additional pathways, however, in which the electrophilicity is tuned through the binding of electron-withdrawing cations from the surrounding medium. Ligands containing a remote site that can undergo (usually Brønsted) acid/base chemistry have been successful in tuning catalyst properties.50−54 The proximal position of the macrocycle in pincer-crown ether complexes provides stabilizing hemilability and the possibility of substrate−acid interactions in addition to electronic tuning. The lack of strong interactions of the Lewis acid salt with the carbonyl oxygen atom in the product (and the avoidance of halide salts) suggests weak and reversible Lewis acid interactions that are distinct from other macrocycle-enforced carbonyl−cation interactions and promising for catalysis. H

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Organometallics

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with an ATR module. Mass spectrometry was carried out with an LTQ FT (ICR 7T) (ThermoFisher, Bremen, Germany) mass spectrometer. Samples (in acetonitrile solution) were introduced via a microelectrospray source at a flow rate of 3 μL/min. Xcalibur (ThermoFisher, Breman, Germany) was used to analyze the data. Molecular formula assignments were determined with Molecular Formula Calculator (v 1.2.3). Single-crystal X-ray diffraction data were collected on a Bruker APEX-II CCD diffractometer at 100 K with Cu Kα radiation (λ = 1.54175 Å). Using Olex2,56 the structures were solved with the olex2.solve57 structure solution program using Charge Flipping and refined with the XL58 refinement program using leastsquares minimization. General Procedure for Migratory Insertion. A J. Young NMR tube was charged with 8−11 mg of the corresponding iridium methyl complex in approximately 600 μL of CD3CN. The NMR tube was freeze−pump−thawed twice to remove dissolved N2. When the degassed solution had returned to room temperature, 1 atm CO was admitted to the tube. The reaction was heated at 70 °C in an oil bath, and the formation of the Ir-acetyl species was monitored by NMR spectroscopy. The reactions typically followed first-order kinetics for two half-lives or more. To account for the incomplete reactions of (EtNCOPiPr)Ir complexes and to ensure that sufficient excess of CO was maintained during monitoring, the half-life was estimated based on an exponential fit of the initial decay of starting material (∼30% conversion). Computational Details. All calculations were performed using the Gaussian 09 software package.59 The PBE1PBE functional60 was used for all calculations, with the LANL2DZ basis set61 and pseudopotential used for Ir and the 6-311G(d,p) basis set62,63 used for all other atoms. After optimizing the structure, frequency optimizations were performed for each species to compute Gibbs free energy values, ensuring the absence of imaginary frequencies. A polarizable continuum model (PCM as implemented by Gaussian 09) was used to approximate the effects of acetonitrile solvent. Thermodynamic reaction parameters for interconversion of the various Ir acyl and hydride complexes are collected in Table S2. The relative free energies of the Ir acyl complexes are illustrated in Figure S130. The relative free energies of the Ir hydride complexes are illustrated in Figure S131. Geometric coordinates and the corresponding energy, enthalpy, and entropy values for each optimized structure are provided in the SI. Synthesis of ( 15c5 NCOP iPr )Ir(CH 3 )(CO)(I) (2). A 20 mL scintillation vial was charged with 12.0 mg (18.2 μmol) of (15c5NCOPiPr)Ir(CO) and CH2Cl2 (0.5 mL). To the bright yellow solution was added 2 μL (32.1 μmol) of CH3I via syringe, resulting in a decolorization of the solution to pale yellow over the course of 1 h. The solvent and any excess CH3I were removed under vacuum, yielding a yellow oil. The yellow residue was washed with pentane (2 × 1 mL) and decanted. The final solid was dried under vacuum, resulting in a yellow solid (14.4 mg, 98% yield). 1H NMR (600 MHz, CD3CN) δ 6.89 (t, J = 7.7 Hz, 1H, Ar-H), 6.83 (d, J = 7.4 Hz, 1H, ArH), 6.80 (d, J = 7.8 Hz, 1H, Ar-H), 4.79 (d, J = 13.7 Hz, 1H, ArCH2N), 4.33 (dd, J = 13.7, 3.7 Hz, 1H, ArCH2N), 4.02 (s, 2H, crown-CH), 3.94 (dq, J = 7.5, 2.7 Hz, 1H, crown-CH), 3.90−3.82 (m, 2H, crown-CH), 3.79 (tt, J = 10.2, 5.0 Hz, 2H, crown-CH), 3.66−3.51 (m, 16H, crown-CH2), 3.00 (m,, 1H, CH(CH3)2), 2.63 (m, 1H, CH(CH3)2), 1.40−1.33 (m, 6H, CH(CH3)2), 1.29−1.24 (m, 3H, CH(CH3)2), 1.19−1.12 (m, 3H, CH(CH3)2), 0.72 (d, J = 1.4 Hz, 3H, Ir-CH3). 13C{1H} NMR (151 Hz, CD2Cl2) δ 180.77 (s, Ir-CO), 160.27 (s, CAr), 152.42 (d, J = 5.50, CAr), 147.93 (s, CAr), 126.12 (s, CAr), 117.85 (s,CAr), 110.13 (d, J = 11.8 Hz, CAr), 71.25 (s, crownCH2), 71.19 (s, ArCH2N), 70.54 (s, crown-CH2), 70.46 (s, crownCH2), 70.32 (s, crown-CH2), 69.97 (s, crown-CH2), 67.05 (s, crownCH2), 60.49 (s, crown-CH2), 55.21 (s, crown-CH2), 30.09 (s, CH(CH3)2), 26.14 (d, J = 38.72 Hz, CH(CH3)2), 19.15 (s, CH(CH3)2), 18.81 (s, CH(CH3)2), 16.61 (d, J = 3.92, CH(CH3)2), 6.51 (d, J = 5.06, CH(CH3)2), −18.30 (d, JPC = 7.27 Hz, Ir-CH3). 31 1 P{ H} NMR (162 MHz, CD2Cl2) δ 136.88. IR (solid, cm−1): ν(CO) 2021 cm−1. Anal. Calcd for C25H42IIrNO6P: C, 37.41; H, 5.27; N, 1.74. Found: C, 37.21; H, 5.12; N, 1.50. HRMS (ESI+) m/z [2 − I]+ Calcd for C24H42IrNO6P 676.23789; Found 676.23841.

CONCLUSIONS Strategies to accelerate oxidative addition and migratory insertion reactions have been explored using a modular pincer-crown ether supporting ligand. Synthetic modifications to the ligand backbone were compared with noncovalent modifications based on interactions with cations present in the surrounding environment. A five-step synthetic route to install a methoxy group on the ligand backbone did not bear fruit, as the rate of migratory insertion remained essentially unchanged. On the other hand, simply adding external Lewis acids substantially enhanced the ratehalide abstraction and further acid promotion could be combined to give a 25-fold rate enhancement. La(OTf)3 provides the greatest acceleration, similar to observations of increased carbonylation activity observed for heterogeneous Ir catalysts in the presence of La3+.10 Many ligand systems that control the structure and function of the secondary coordination sphere have been explored, but few offer sufficient synthetic flexibility to carry out comparative studies of this nature. Several key observations can be made regarding the mechanism of migratory insertion in pincer iridium complexes. Two promoting pathways were observed, including the commonly encountered halide abstraction mechanism (as in the Cativa process) and an unusual mechanism promoted by noncovalent cation−macrocycle interactions. The latter mechanism was unexpected and is noteworthy for accelerating C−C bond formation without forming strong M−O and M−I bonds. In most cases, Lewis acid assisted migratory insertion leads to acyl complexes that are stabilized by strong acid binding to the carbonyl oxygen,32,33 including cases where macrocycles position a cationic Lewis acid near the metal center.37,41,55 The macrocycle-containing pincer ligand acts as a bridge between the primary and secondary coordination spheres. The crown ether group is a hemilabile primary coordination sphere ligand, improving stability of acyl products toward decomposition relative to macrocycle-free analogues. In the secondary coordination sphere, the crown ether interacts with Lewis acidic cations, which, in turn, weakens the amine bond to iridium. Macrocycle-supported noncovalent interactions with cations in the surrounding medium represents an intriguing strategy for future catalyst designs.

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EXPERIMENTAL SECTION

General Considerations. All manipulations were carried out using standard Schlenk or glovebox techniques under a N2 atmosphere. Under standard glovebox operating conditions, pentane, diethyl ether, benzene, toluene, and tetrahydrofuran were used without purging, such that traces of those solvents were present in the atmosphere and in the solvent bottles. 1H, 31P{1H}, 19F{1H}, and 13C{1H} spectra were recorded on 400, 500, or 600 MHz spectrometers at 298 K. NMR solvents were purchased from Cambridge Isotopes Laboratories, Inc. Dichloromethane-d2 (CD2Cl2), acetonitrile-d3 (CD3CN), and chlorobenzene-d5 (C6D5Cl) were freeze−pump−thaw degassed three times before drying by passage through a small column of activated alumina and stored over 3 Å molecular sieves. 1H and 13C chemical shifts are reported in ppm relative to residual protio solvent resonances. 31P chemical shifts are reported relative to 85% H3PO4 external standard (δ 0). The compounds (15c5NCOPiPr)H,12 Ir(p-toluidine)(CO)2Cl,21 (15c5NCOPiPr)Ir(CO) (1),13 and (EtNCOPiPr)Ir(CO)13 were synthesized according to literature procedures. All other reagents were commercially available and used without further purification. Elemental analyses were performed by Robertson Microlit Laboratories (Ledgewood, NJ). Infrared spectroscopy was carried out with a Thermo Scientific Nicolet iS5 FT-IR equipped with a Quest Single Reflection ATR Accessory or with a Bruker Alpha FT-IR equipped I

DOI: 10.1021/acs.organomet.6b00607 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Synthesis of 5-(Aza-15-crown-5 methyl)-2-methoxyphenol. In a glovebox, 3-hydroxy-4-methoxy benzaldehyde (0.530 g, 3.48 mmol) and aza-15-crown-5 (0.492 g, 2.24 mmol) were dissolved in 100 mL of THF in a round-bottom flask and allowed to stir for 30 min. Then, over the course of 3 h, 0.998 g (4.71 mmol) of sodium triacetoxyborohydride was added in 4 equal increments, resulting in a cloudy white slurry. The reaction was allowed to stir at room temperature for 2 days, resulting in a colorless solution with a white precipitate. The flask was removed from the glovebox, and the reaction mixture was quenched with a saturated solution of NaHCO3. The mixture was extracted with CH2Cl2 (3 × 50 mL), and the solvent was removed under vacuum to yield a yellow oil. The product was purified by column chromatography packed with a silica column. The crude product was dissolved in minimal CH2Cl2 and loaded onto the column. The column was flushed with a 60:40 mixture (v/v) of CH2Cl2:EtOAc to remove unreacted aldehyde and hydroxymethyl phenol. Then, a mixture of 85:10:5 (v/v/v) of CH2Cl2:NEt3:CH3OH was used to flush the product. The solvent was removed under vacuum, yielding a colorless oil (0.62 g, 82% yield). 1H NMR (600 MHz, CDCl3) δ 7.10 (d, J = 1.9 Hz, 1H, Ar-H), 6.77−6.68 (m, 2H, ArH), 3.83 (s, 3H, Ar-OCH3), 3.72 (td, J = 5.4, 4.3, 2.1 Hz, 1H, crownCH2), 3.67 (d, J = 8.1 Hz, 8H, crown-CH2), 3.63 (s, 1H, crown-CH), 3.62−3.59 (m, 4H, crown-CH2), 3.59−3.55 (m, 7H, crown-CH2 and ArCH2N), 2.75 (t, J = 5.7 Hz, 4H, crown-CH2). 13C{1H} NMR (151 MHz, CDCl3) δ 145.82 (CAr), 145.60 (CAr), 132.97 (Ar-OCH3), 119.71 (CAr), 115.57 (CAr), 110.53 (CAr), 70.96 (crown-CH2), 70.50 (crown-CH2), 70.11 (crown-CH2), 69.86 (crown-CH2), 59.92 (ArCH2N), 55.98 (crown-CH2), 54.70 (crown-CH2). Anal. Calcd for C18H29NO6: C, 60.85; H, 8.02; N, 3.97. Found: C 60.83; H, 8.22, N, 3.94. HRMS (ESI+) m/z: [Phenol + H]+ Calcd for C18H30NO6 356.20676; Found 356.20537. Synthesis of (MeO‑15c5NCOPiPr)H (3). In the glovebox, a 20 mL scintillation vial was charged with 0.177 g (0.497 mmol) of 5-(aza-15crown-5 methyl)-2-methoxyphenol and 10 mL of THF. To the clear and colorless solution was slowly added 77 μL of triethylamine dropwise by syringe while stirring. The mixture was allowed to stir for 15 min at room temperature, followed by the addition of 80 μL of diisopropylchlorophosphine dropwise by syringe. The solution was stirred for 4 h, during which time a white precipitate formed. The solvents were removed under vacuum, leaving a mixture of an oil and a white powder. The oil was extracted with ether (5 × 2 mL) and filtered. The ether was removed in vacuo to yield a colorless oil (0.18 g, 77% yield). 1H NMR (400 MHz, C6D6) δ 7.60 (s, 1H, Ar-H), 6.98 (d, 1H, Ar-H), 6.62 (d, J = 8.2 Hz, 1H, Ar-H), 3.66 (t, J = 6.0 Hz, 4H, crown-CH), 3.53 (s, 2H, ArCH2N), 3.52−3.48 (m, 6H, crown-CH), 3.44 (s, 3H, Ar-OCH3), 3.41 (s, 3H, crown-CH), 2.87 (t, J = 6.0 Hz, 4H, crown-CH), 1.89 (m, 2H, CH(CH3)2), 1.30 (dd, J = 10.5, 7.0 Hz, 6H, CH(CH3)2), 1.08 (dd, J = 15.4, 7.2 Hz, 6H, CH(CH3)2). 13C{1H} NMR (151 MHz, CDCl3) δ 149.53 (d, J = 2.1 Hz, CAr), 148.28 (d, J = 7.9 Hz, CAr), 132.29 (CAr), 122.46 (CAr), 120.36 (d, J = 14.3 Hz, CAr), 112.03 (CAr), 71.10 (crown-CH2), 70.66 (crown-CH2), 70.28 (d, J = 5.2 Hz, crown-CH2), 60.34 (ArCH2N), 56.02 (Ar-OCH3), 54.22 (crown-CH2), 28.63 (d, J = 18.3 Hz, CH(CH3)2), 17.87 (d, J = 20.1 Hz, CH(CH3)2), 17.27 (d, J = 8.9 Hz, CH(CH3)2). 31P{1H} NMR (162 Hz, C6D6) δ 154.1. Anal. Calcd for C24H42NO6P: C, 61.03; H, 8.98; N, 2.97. Found: C 60.62; H, 9.29, N, 3.00. HRMS (ESI+) m/z [3 + H]+ Calcd for C24H43NO6P 472.28225; Found 472.28040. Synthesis of (MeO‑15c5NCOPiPr)Ir(H)(CO)(Cl) (4). A Schlenk flask was charged with 0.140 g (0.358 mmol) of Ir(p-toluidine)(CO)2(Cl) and suspended in 10 mL of toluene. The ligand, 3 (0.157 g, 0.358 mmol), was dissolved in 10 mL of toluene and added to the Ir precursor suspension to yield a yellow solution. The mixture was refluxed under N2 for 15 h, at which point the mixture was allowed to cool and the toluene was removed under vacuum, leaving a brown residue. The residue was washed with pentane (3 × 4 mL) and extracted with benzene (5 mL). The resulting orange/brown benzene solution was evaporated under vacuum to yield a brown oil. The oil was redissolved in minimal benzene (