Mechanistic studies of the palladium-catalyzed S,O-ligand promoted C–H olefination of aromatic compounds

Pd-catalyzed C–H functionalization reactions of non-directed substrates have recently emerged as an attractive alternative to the use of directing groups. Key to the success of these transformations has been the discovery of new ligands capable of increasing both the reactivity of the inert C–H bond and the selectivity of the process. Among them, a new type of S,O-ligand has been shown to be highly efficient in promoting a variety of Pd-catalyzed C–H olefination reactions of non-directed arenes. Despite the success of this type of S,O-ligand, its role in the C–H functionalization processes is unknown. Herein, we describe a detailed mechanistic study focused on elucidating the role of the S,O-ligand in the Pd-catalyzed C–H olefination of non-directed arenes. For this purpose, several mechanistic tools, including isolation and characterization of reactive intermediates, NMR and kinetic studies, isotope effects and DFT calculations have been employed. The data from these experiments suggest that the C–H activation is the rate-determining step in both cases with and without the S,O-ligand. Furthermore, the results indicate that the S,O-ligand triggers the formation of more reactive Pd cationic species, which explains the observed acceleration of the reaction. Together, these studies shed light on the role of the S,O-ligand in promoting Pd-catalyzed C–H functionalization reactions.

Pd(OAc)2 (5.6 mg, 25 µmol, 5 mol%), t-butyl peroxybenzoate (94 µL, 0.5 mmol, 1 equiv), ethyl acrylate (53 µL, 0.5 mmol, 1 equiv), benzene (0.5 mL, 5.6 mmol, 11.2 equiv) and AcOH (2.5 mL, 0.2 M) were added into a pressure tube. The pressure tube was sealed with a crimp cap with septa and the reaction was placed in a 100 °C pre-heated oil bath. The reaction was followed during the indicated time by sampling 50 µL. PhCl (10 µL) was added in each sample as an internal standard for quantitative GC analysis. The reaction mixture was diluted with EtOAc (1 mL). The organic layer was quenched with saturated aqueous NaHCO3 solution (1 mL). The organic layer was filtered through a plug of anh. MgSO4 and analyzed by GC.
Parallel reaction using Pd(OAc)2 and ligand L2 was performed to compare the kinetic profile. Pd(OAc)2 (5.6 mg, 25 µmol, 5 mol%), ligand L2 (4.9 mg, 25 µmol, 5 mol%), t-butyl peroxybenzoate (94 µL, 0.5 mmol, 1 equiv), ethyl acrylate (53 µL, 0.5 mmol, 1 equiv), benzene (0.5 mL, 5.6 mmol, 11.2 equiv) and AcOH (2.5 mL, 0.2 M) were added into a pressure tube. The pressure tube was sealed with a crimp cap with septa and the reaction was placed in a 100 °C pre-heated oil bath. The reaction was followed during the indicated time by sampling 50 µL. PhCl (10 µL) was added in each sample as an internal standard for quantitative GC analysis. The reaction mixture was diluted with EtOAc (1 mL). The organic layer was quenched with saturated aqueous NaHCO3 solution (1 mL). The organic layer was filtered through a plug of anh. MgSO4 and analyzed by GC.
Parallel reaction using complexes 1-cis and 1-trans was performed to compare the kinetic profile. Complexes 1-cis and 1-trans (12.4 mg, 25 µmol, 5 mol%), t-butyl peroxybenzoate (94 µL, 0.5 mmol, 1 equiv), ethyl acrylate (53 µL, 0.5 mmol, 1 equiv), benzene (0.5 mL, 5.6 mmol, 11.2 equiv) and AcOH (2.5 mL, 0.2 M) were added into a pressure tube. The pressure tube was sealed with a crimp cap with septa and the reaction was placed in a 100 °C pre-heated oil bath. The reaction was followed during the indicated time by sampling 50 µL. PhCl (10 µL) was added in each sample as an internal standard for quantitative GC analysis. The reaction mixture was diluted with EtOAc (1 mL). The organic layer was quenched with saturated aqueous NaHCO3 solution (1 mL). The organic layer was filtered through a plug of anh. MgSO4 and analyzed by GC.
Parallel reaction using complex 2 was performed to compare the kinetic profile. Complex 2 (15.6 mg, 25 µmol, 5 mol%), t-butyl peroxybenzoate (94 µL, 0.5 mmol, 1 equiv), ethyl acrylate (53 µL, 0.5 mmol, 1 equiv), benzene (0.5 mL, 5.6 mmol, 11.2 equiv) and AcOH (2.5 mL, 0.2 M) were added into a pressure tube. The pressure tube was sealed with a crimp cap with septa and the reaction was placed in a 100 °C pre-heated oil bath. The reaction was followed during the indicated time by sampling 50 µL. PhCl (10 µL) was added in each sample as an internal standard for quantitative GC analysis. The reaction mixture was diluted with EtOAc (1 mL). The organic layer was quenched with saturated aqueous NaHCO3 solution (1 mL). The organic layer was filtered through a plug of anh. MgSO4 and analyzed by GC. Procedure for the reaction of complex 2 and benzene Complex 2 (30 mg, 48.0 µmol, 1 equiv) and benzene (0.25 mL) were added into a pressure tube. The pressure tube was sealed with a screw cap and the reaction was placed in a 100 °C preheated oil bath and stirred for 10 minutes. The reaction was cooled down to room temperature. The resulting mixture was diluted with CH2Cl2, filtered through a plug of Celite and concentrated under reduced pressure. The resulting crude was measured by 1 H NMR.

Procedure for the reaction of complex 4' and ethyl acrylate
Complex 4' (32 mg, 50.0 µmol, 1 equiv) and ethyl acrylate (0.25 mL, 2.35 mmol) were added into a pressure tube. The pressure tube was sealed with a screw cap and the reaction was placed in a 100 °C pre-heated oil bath and stirred for 2 h. The reaction was cooled down to room temperature. The resulting mixture was diluted with EtOAc, filtered through a plug of Celite and concentrated under reduced pressure. The 1 H NMR yield was determined by adding CH2Br2 (6.0 µL, 85.0 µmol, 1.7 equiv) as an internal standard. The reaction provided the olefinated product in 90% 1 H NMR yield.
Procedure for the reaction of Pd(OAc)2, ligand L2, PPh3 and benzene (the reaction is performed in an NMR tube) Pd(OAc)2 (11.2 mg, 0.05 mmol, 1 equiv), ligand L2 (9.8 mg, 0.05 mmol, 1 equiv), PPh3 (13.1 mg, 0.05 mmol, 1 equiv), benzene (0.1 mL) and AcOD-d4 (0.5 mL) were added into an NMR tube. The NMR tube was sealed with a screw cap. The reaction was placed in a 100 °C pre-heated oil bath and followed during the indicated time. 1 H and 31 P NMR spectra were collected at room temperature.

Kinetic investigations
Procedure for kinetic order of the reaction Pd(OAc)2, ligand L1, tert-butyl peroxybenzoate, ethyl acrylate, benzene, NaOAc and AcOH (1.25 mL) were added into a pressure tube. The pressure tube was sealed with a crimp cap with septa and the reaction was placed in a 100 °C pre-heated oil bath. The reaction was followed during the indicated time by sampling 50 µL. PhCl (10 µL) was added in each sample as an internal standard for quantitative GC analysis. The reaction mixture was diluted with EtOAc (0.5 mL). The organic layer was quenched with saturated aqueous NaHCO3 solution (0.5 mL). The organic layer was filtered through a plug of anh. MgSO4 and analyzed by GC.

Procedure for the reaction using an excess of NaOAc with the aim to detect [L2Pd(OAc)2] -(the reaction is performed in an NMR tube)
Pd(OAc)2 (2.2 mg, 0.01 mmol, 1 equiv), L2 (2.0 mg, 0.01 mmol, 1 equiv) and AcOD-d4 (0.5 mL) were added into an NMR tube. The NMR tube was sealed with a screw cap and the reaction was placed in a 100 °C pre-heated oil bath for 20 minutes until solid was dissolved. The reaction was cooled down to room temperature and the 1 H NMR spectrum was collected. Then, NaOAc (16.4 mg, 0.2 mmol, 20 equiv) was added to the NMR tube. The NMR tube was again placed in a 100 °C pre-heated oil bath for 2 h. The reaction was cooled down to room temperature and the 1 H NMR spectrum was collected. Figure S11. 1 H NMR spectra of the mixture of Pd(OAc)2 and ligand L2 in AcOD-d4, 1) before and 2) after the addition of 20 equiv of NaOAc.
The NMR tube was placed in a 100 °C pre-heated oil bath for 6 h. The reaction was cooled down to room temperature and the 1 H NMR spectrum was collected.

Procedure for the H/D exchange experiment without ligand (the reaction is performed in an NMR tube)
Pd(OAc)2 (2.2 mg, 10.0 µmol, 10 mol%), tert-butyl peroxybenzoate (19 µL, 0.1 mmol, 1 equiv), ethyl acrylate (11 µL, 0.1 mmol, 1 equiv), mesitylene (0.14 mL, 1.0 mmol, 10 equiv) and AcOD-d4 (0.5 mL, 0.2 M) were mixed in a vial. The solution was transferred into an NMR tube, sealed with a screw cap and 1 H NMR spectrum was collected. The NMR tube was placed in a 100 °C preheated oil bath for 16 h. The reaction was cooled down to room temperature and the 1 H NMR spectrum was collected.

Procedure for the reaction of ligand L2 and oxidant
Ligand L2 (19.6 mg, 0.1 mmol, 1 equiv), tert-butyl peroxybenzoate (0.38 mL, 2.0 mmol, 20 equiv), benzene (2 mL, excess) and AcOH (10 mL) were added into a pressure tube. The pressure tube was sealed with a screw cap and the reaction was placed in a 100 °C pre-heated oil bath and stirred for 2 h. The reaction was cooled down to room temperature and concentrated under reduced pressure. The resulting crude was basified (2 M aqueous NaOH solution) until pH = 14.
The aqueous layer was washed with CH2Cl2 (3 x 10 mL). The aqueous layer was acidified (6 M aqueous HCl solution) until pH = 1 and extracted with CH2Cl2 (3 x 15 mL). The combined organic layers were dried over anh. MgSO4, filtered, concentrated under reduced pressure and analyzed by 1 H NMR.

Procedure for the reaction of complex 1 and oxidant
Complex 1 (15.5 mg, 0.03 mmol, 1 equiv) and tert-butyl peroxybenzoate (22 µL, 0.12 mmol, 4 equiv) were added into a pressure tube. The pressure tube was sealed with a screw cap and the reaction was placed in a 100 °C pre-heated oil bath and stirred for 2 h. The reaction was cooled down to room temperature, diluted with CH2Cl2, filtered through a plug of Celite, concentrated under reduced pressure and analyzed by 1 H NMR.

Mass spectrometric measurements
The mass spectra were recorded on a linear ion trap (LTQ) instrument with an electrospray ionization (ESI) source. 5 General conditions used were as follows: 4 to 5 kV spray voltage, 200 to 275 ℃ capillary temperature and 1 to 20 psi sheath gas. For positive mode, 0 to 20 V capillary voltage and 25 to 70 V tube lens while for the negative mode 0 to -20 V capillary voltage and -25 to -75 V tube lens.
Energy resolved collision induced dissociation (CID) experiments were performed on LCQ Deca mass spectrometer with an ESI source. 6 The calibration was performed using the thermometer ions using the Schroder's method to correlate the collision energy and the appearance energies of the ions. 7 In general, 1 mM fresh stock solution was prepared in the desired solvent (sonication used if turbidity observed followed by filtration, filtrate used). From these stock solutions after mixing/addition, by appropriate dilution with the desired solvent final concentration of 50 to 200 µM was injected directly into the ESI-MS inlet with the help of a silica capillary using the nitrogen overpressure in the vial.
[Pd(L2)(PPh2Ph SO3 )OAc ]Na i.e. the negatively charge tagged analog of 'complex 2' was synthesized according to the "Procedure for the synthesis of complex 2" described above with the exception that instead of triphenylphosphine, 3-(diphenylphosphino)benzenesulfonic acid sodium salt i.e. PPh2Ph SO3 Na was used and dark yellowish solid of [Pd(L2)(PPh2Ph SO3 )OAc ]Na was obtained. This was then used further for the mass spectrometry analysis.
High resolution mass spectra were recorded with a timsTOF instrument from Bruker Daltonik (Bremen, Germany) equipped with an ESI source. Calibration was performed using an Agilent ESI low concentration tune mix before the experiment. The sample and the calibration solutions were injected in the timsTOF using a glass syringe pump with 0.5 mL volume and flow rate of 0.3 µL. The timsTOF was operated in the negative ion mode in a mass range of m/z 50 to 1500 with the spray voltage of 4.5 kV. The end plate offset of -500 V with a N2 nebulizer pressure of 0.3 bar and a dry gas flow of 1.5 L min -1 at 275 ℃.

DFT calculations
All structures were optimized using density functional theory (DFT) as implemented in Gaussian 16, 8 with B3LYP 9 as functional, 6-31G(d,p) as basis set for non-metallic atoms, and SDD 10 as basis set for palladium. Final energies were obtained performing single-point calculations on the previously optimized structures at M06 11 /def2tzvpp 12 level of theory, introducing solvation factors with the IEF-PCM 13 method, and acetic acid as solvent. The stationary points were characterized by frequency calculations in order to verify that they have the right number of imaginary frequencies. Cartesian coordinates of the optimized structures are shown below, as well as their single point energy and correction to Gibbs free energy (in Hartrees).