[IPr#–PEPPSI]: A Well-Defined, Highly Hindered and Broadly Applicable Pd(II)–NHC (NHC = N-Heterocyclic Carbene) Precatalyst for Cross-Coupling Reactions

In this Special Issue, “Featured Papers in Organometallic Chemistry”, we report on the synthesis and characterization of [IPr#–PEPPSI], a new, well-defined, highly hindered Pd(II)–NHC precatalyst for cross-coupling reactions. This catalyst was commercialized in collaboration with MilliporeSigma, Burlington, ON, Canada (no. 925489) to provide academic and industrial researchers with broad access to reaction screening and optimization. The broad activity of [IPr#–PEPPSI] in cross-coupling reactions in a range of bond activations with C–N, C–O, C–Cl, C–Br, C–S and C–H cleavage is presented. A comprehensive evaluation of the steric and electronic properties is provided. Easy access to the [IPr#–PEPPSI] class of precatalysts based on modular pyridine ligands, together with the steric impact of the IPr# peralkylation framework, will facilitate the implementation of well-defined, air- and moisture-stable Pd(II)–NHC precatalysts in chemistry research.

We recently reported on a novel class of sterically hindered NHC ligands obtained through the modular peralkylation of aniline ( Figure 1) [41,42]. These ligands combine the steric properties of sterically demanding NHCs with facile multigram-scale synthesis in a cost-effective manner utilizing feedstock aniline that is available in bulk. Furthermore, the para-substituent stabilizes the N-Ar group from rotation, enabling the improved steric control of the ortho-substituents in the catalytic pocket. Our initial studies were performed using allyl-based catalysts, such as [(IPr # )Pd(cin)Cl] (MilliporeSigma, no. 919616) [41,43]. Since it is well-established that Pd-PEPPSI complexes are complementary to Pd-allylbased catalysts and should be screened together with Pd-allyl NHC complexes [44,45], we investigated [IPr # -PEPPSI] as a readily prepared Pd(II)-NHC complex. In this Special Issue, "Featured Papers in Organometallic Chemistry", we report on the synthesis and characterization of [IPr # -PEPPSI], a highly hindered Pd(II)-NHC precatalyst for cross-coupling reactions ( Figure 1) [46]. More specifically, this complex features 3-Cl-py as an ancillary ligand, [(IPr # )Pd(3-Cl-py)Cl 2 ] (1), and belongs to the PEPPSI-type class of catalysts. This catalyst was commercialized in collaboration with MilliporeSigma (no. 925489) to provide academic and industrial researchers with broad access to reaction screening and optimization. The broad activity of [IPr # -PEPPSI] in cross-coupling reactions, as well as a comprehensive evaluation of its steric and electronic properties, is presented [17]. Easy access to [IPr # -PEPPSI] based on modular pyridine ligands, together with the steric impact of the IPr # peralkylation framework, will facilitate the implementation of well-defined Pd(II)-NHCs in chemistry research.
The complex [IPr # -PEPPSI] (1) was fully characterized via x-ray crystallography (CCDC 2262376) ( Figure 1). The single crystal was obtained through slow evaporation from dichloromethane from a dilute solution. The complex crystalized with two molecules in the unit cell. Similar to other Pd(II)-Het complexes, [IPr # -PEPPSI] (1) features a square planar geometry at the Pd center ( Figure 2, Table 1) [47,48]. The bond angles between the ligands at the metal center in complex (1)   It should be noted that the unit cell contains two molecules, and they are independent. For clarity, both of the molecules are discussed in the same manner. The atoms corresponding to the second molecule show larger ellipsoids than those of the first molecule, but the magnitude of the ellipsoids is very small. In the standard case, the anisotropic parameter for each atom is less than 0.2. There are two atoms (C198 and C174) for which the anisotropic parameter is slightly higher than 0.2. Despite our extensive attempts, the anisotropic parameter did not change.
To gain insight into the origin of the high catalytic reactivity of complex [IPr # -PEPPSI] (1), its electronic and steric properties were determined on the B3LYP 6-311++g(d,p) level. To gain further insight into the relative bond strengths, the Wiberg bond orders were determined ( Table 2)  Finally, to eliminate impacts of steric packing, the %V bur was calculated from the optimized structure of complex (1) on the B3LYP 6-311++g(d,p) level ( Figure 5) (1) features an asymmetrical distribution of the N-Ar wingtips, which is important in cross-coupling catalysis for the promotion of oxidative addition and reductive elimination steps. It should be noted that the steric map in Figure 3 is based on the crystal structure, and the steric map in Figure 5 is based on the computation. The steric distribution in Figure 3 is affected by crystal packing. The steric map in Figure 5 shows C2 symmetry in the %V bur calculation. The entire molecule is not C2-symmetric because we non-symmetric 3-Cl-py is present on the trans side.  Typically, a large steric %V bur of NHC ligands is required for effective cross-coupling reactions [25][26][27]. In general, ligands with %V bur of less than 40% are less efficient in crosscoupling due to their slower reductive elimination steps. Furthermore, it is interesting to note that ring-expanded NHCs show similar profiles to the present catalysts. For example, the six-membered analogue of IPr is characterized by a %V bur of 50.9%, and the sevenmembered ring-expanded analogue of IPr is characterized by a %V bur of 52.7% [65].

Discussion
In conclusion, we reported on the synthesis, characterization and reactivity of [IPr # -PEPPSI]. This well-defined, air-and moisture-stable catalyst is based on a sterically demanding IPr # framework obtained through the modular peralkylation of anilines. The broad activity of [IPr # -PEPPSI] in cross-coupling reactions with N-C, O-C, C-Cl, C-Br, C-S and C-H activations was demonstrated. A comprehensive evaluation of the steric and electronic properties provided further insight into the properties of [IPr # -PEPPSI]. Considering the easy accessibility of [IPr # -PEPPSI], its commercial availability (MilliporeSigma, 925489) and promising reactivity in a range of cross-coupling reactions, we expect that this class of catalysts will facilitate the broad use of Pd(II)-NHCs in catalysis research [63,64].

General Procedure for the Preparation of [IPr # -PEPPSI] (1).
An oven-dried 10 mL vial equipped with a stir bar was charged with IPr # HCl (552 mg, 0.44 mmol, 1.1 equiv), PdCl 2 (71 mg, 0.4 mmol, 1.0 equiv) and K 2 CO 3 (276 mg, 2.0 mmol, 5.0 equiv). 3-Chloropyridine (2.0 mL) was added, and the reaction was stirred at 80 • C for 24 h. After cooling to room temperature, the mixture was diluted with DCM, and we filtered out the solid. The solution was collected and concentrated through evaporation in a high vacuum to remove the 3-Chloropyridine. The pure product was obtained via recrystallization in DCM/hexane as a white solid, with a yield of 82% (494 mg), as follows: 1

Activity of [Pd # -PEPPSI] in Cross-Coupling Reactions.
All cross-coupling reactions were carried out according to previously described procedures [13]. For comparative purposes, all products were identified via 1 H NMR (500 MHz, CDCl 3 ) and GC-MS using an internal standard and comparison with authentic samples. All yields correspond to yields determined via 1  and water (0.50 mmol, 5.0 equiv) were added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature for 16 h. After the indicated time, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), filtered, and concentrated. The sample was analyzed via 1 HNMR (CDCl 3 , 500 MHz) and GC-MS to obtain its conversion, selectivity and yield using an internal standard and comparison with authentic samples.

N-C(O) Cleavage: Buchwald-Hartwig Amide Cross-Coupling (Transamidation).
An oven-dried vial equipped with a stir bar was charged with an amide substrate (29.7 mg, 0.10 mmol, 1.0 equiv), amine (24.6 mg, 0.20 mmol, 2.0 equiv), potassium carbonate (41.4 mg, 0.30 mmol, 3.0 equiv) and [IPr # -PEPPSI] (3 mol%), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under a high vacuum. DME (0.40 mL, 0.25 M) was added with vigorous stirring, and the reaction mixture was stirred at 110 • C for 16 h. After the indicated time, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), filtered, and concentrated. The sample was analyzed via 1 HNMR (CDCl 3 , 500 MHz) and GC-MS to obtain the conversion, selectivity and yield using an internal standard and comparison with authentic samples. 3.0 equiv) were added with vigorous stirring at room temperature, and the reaction was stirred at 80 • C for 16 h. After the indicated time, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), washed with water (1 × 10 mL), extracted with CH 2 Cl 2 (2 × 10 mL), dried over MgSO 4 , filtered and concentrated. The sample was analyzed via 1 HNMR (CDCl 3 , 500 MHz) and GC-MS to obtain its conversion, selectivity and yield using an internal standard and comparison with authentic samples.
C-Br Cleavage: Feringa Cross-Coupling with Alkyllithium. An oven-dried vial equipped with a stir bar was charged with an aryl bromide substrate (187 mg, 1.0 mmol, 1.0 equiv), nBuLi (2.5 M in hexanes, 2.0 mmol, 2.0 equiv) and [IPr # -PEPPSI] (2.5 mol%) at room temperature under argon and stirred for 10 min. After the indicated time, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), washed with water (1 × 10 mL), extracted with CH 2 Cl 2 (2 × 10 mL), dried over MgSO 4 , filtered and concentrated. The sample was analyzed via 1 HNMR (CDCl 3 , 500 MHz) and GC-MS to obtain its conversion, selectivity and yield using an internal standard and comparison with authentic samples. equiv) were added with vigorous stirring at room temperature, and the reaction mixture was stirred at 100 • C for 24 h. After the indicated time, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), washed with water (1 × 10 mL), extracted with CH 2 Cl 2 (2 × 10 mL), dried over MgSO 4 , filtered and concentrated. The sample was analyzed via 1 HNMR (CDCl 3 , 500 MHz) and GC-MS to obtain its conversion, selectivity and yield using an internal standard and comparison with authentic samples.
C-S Cleavage: Carbon-Sulfur Bond Metathesis. An oven-dried vial equipped with a stir bar was charged with a thioether substrate (12.4 mg, 0.10 mmol, 1.0 equiv), cyclohexanethiol (26.0 mg, 0.20 mmol, 2.0 equiv) and [IPr # -PEPPSI] (3 mol%), placed under a positive pressure flow of argon, and subjected to three evacuation/backfilling cycles under a high vacuum. Toluene (0.10 mL, 1.0 M) and LiHMDS (1.0 M in THF, 0.26 mmol, 2.6 equiv) were added with vigorous stirring at room temperature, and the reaction mixture was stirred at 110 • C for 16 h. After the indicated time, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), washed with water (1 × 10 mL), extracted with CH 2 Cl 2 (2 × 10 mL), dried over MgSO 4 , filtered and concentrated. The sample was analyzed via 1 HNMR (CDCl 3 , 500 MHz) and GC-MS to obtain its conversion, selectivity and yield using an internal standard and comparison with authentic samples.
Crystallographic Analysis. The crystal data and structure refinement summaries for [IPr#-PEPPSI] are included in Table S1 in the Supplementary Materials. The Supplementary Materials also include the large ORTEP structures of [IPr#-PEPPSI] (50% ellipsoids) in the NHC-M parallel plane and NHC-M perpendicular plane.
Computational Methods. All the calculations were performed using the Gaussian 09 suite of programs. All of the geometry optimizations were performed on the B3LYP level of theory in the gas phase with the QZVP basis set for palladium and the 6-311++G(d,p) basis set for the other atoms. For the geometry optimizations, we employed the X-ray structure of [IPr # -PEPPSI] as the starting geometry and performed full optimization. The absence of imaginary frequencies was used to characterize the structures as minima on the potential energy surface. All of the optimized geometries were verified as minima (no imaginary frequencies). NBO calculations were performed on the DFT/B3LYP level using the NBO program implemented in the Gaussian software package. The Wiberg bond indices were calculated using the NBO method. The energetic parameters were calculated under standard conditions (298.15 K and 1 atm). The structural representations were generated using CYLview software (Legault, C. Y. CYL view version 1.0 BETA, University of Sherbrooke). All other representations were generated using Gauss View (GaussView,