Synthesis of new Pro-PYE ligands as co-catalysts toward Pd-catalyzed Heck–Mizoroki cross coupling reactions

The present research work describes the synthesis of five new ligands containing pyridinium amine, [H2L1][OTf]2–[H2L5][I]2 from two new precursors, [P3Et][I] and [P2Me][CF3SO3]. The structure elucidations of the compounds were confirmed by multinuclear NMR (1H, 13C), FT-IR and by single crystal XRD techniques. Theoretical DFT studies were carried out to get better insight into the electronic levels and structural features of all the molecules. These synthesized new Pro-PYE ligands [H2L1][OTf]2–[H2L5][I]2 were found to be significantly active as co-catalysts for Pd(CH3CO2)2 toward Heck–Mizoroki coupling reactions with wide substrate scope in the order of [H2L1][OTf]2 ≫ [H2L2][OTf]2 > [H2L3][OTf]2 > [H2L4][OTf]2 > [H2L5][I]2.


Introduction
Electron donor ligands are essential for those metals undergoing various oxidative addition reactions. Phosphines and Nheterocyclic carbene (NHC) ligands are prevalent in this scenario owing to their remarkable electron donor characteristics. [1][2][3] The steric hindrance of a substituted R group towards the metal in NHCs facilitates reductive elimination and product selectivity that mark this ligand as a superior choice in homogeneous catalysis, especially in cross-coupling chemistry. [4][5][6][7] In depth study reveals that the tuning of the electronic density of a ligand is desirable according to the requirement of a coordinated metal to catalyze various stages of the redox process. 8,9 Therefore the non-innocent ligands are ideally suited for this type of chemistry as they have the ability to switch and stabilize the various oxidation states of metals during chemical transformations. [10][11][12] These ligands are promising in the eld of catalysis as they are redox active spectator ligands. They not only block few coordination sites of the metal but also serve as electron reservoirs. 13,14 Anionic ligand in resonance with cationic moiety can generate this kind of ligand. For example N-(1-methylpyridin-4(1H)-ylidene) amine (PYE) is a type of neutral nitrogen donor ligand that possesses electronic density adaptable to the requirement of metal owing to its resonance structures with varying charge on nitrogen from uni-negative to neutral (Fig. 1). 15 The additional feature includes the exocyclic nitrogen atom of PYE that is pointed towards metal to control its steric environment. [16][17][18] The catalytic cycle of Heck-Mizoroki C-C cross coupling involves both oxidative addition as well as reductive elimination reaction. This coupling method is an appropriate synthetic route for synthesis of substituted olens. High electronic density around the palladium via appropriate electron rich ligand facilitates oxidative addition (the key rate determining step) of various aliphatic or aromatic halides in the coupling reaction. [19][20][21] Various palladium complexes have been used to catalyze above reaction. [22][23][24] However, the much easier way is to use a mixture of suitable ligand and palladium precursor. 25 SO 3 ]. These ligands were found to act as co-catalysts for Pd(OAc) 2 and signicantly enhanced their catalytic activity in Mizoroki-Heck coupling reactions under diverse reaction conditions. The molecular structures of all new compounds were characterized by using various spectroscopic and computational techniques.
acrylate and styrene purchased from Sigma Aldrich were used. Solvents were dried using standard procedures. N-Methyl-4chloropyridinium triate was synthesized by the reported method. 27

Apparatus and instruments used
All reactions were performed under inert environment by Schlenk line technique. Melting point analysis was performed on Shimadzu melting point apparatus. Thermo Scientic spectrometer ranges from 4000-400 cm À1 was used to record FT-IR spectras. NMR spectra were recorded by using Bruker Avance Digital 300 MHz ( 1 H) and 75 MHz ( 13 C) at 300 K in DMSO-d 6 .

Chemistry
Syntheses of seven new compounds were shown in Schemes 1-3.

Synthesis of [P 3
Et ][I] (1). 2-Iodopyridinium ethyl iodide was prepared by treating 2-chloropyridine (4.91 mL, 53 mmol, 1 eq.) with ethyl iodide (12.78 mL, 159 mmol, 3eq.) in three neck round bottom ask (250 mL). Dichloromethane was also subjected to ask. The resulted mixture was subjected to heat under water bath for 12 hours. The product was cooled and washed by subsequent addition of acetone and pure product was achieved.
Royal yellow solid, yield 56%, mp: 156 C. 1 (3). N-methylated-4-chloropyridinium triate (0.5 g, 1.8 mmol, 2 eq.) and pyridine diamine (0.1 g, 0.9 mmol, 1 eq.) was subjected into two neck ask (100 mL). An argon atmosphere was provided to reaction mixture. The reaction was heated for about 3 hours at 230 C. Aer the completion of reaction, solid was cooled to ambient temperature and scratched by spatula from ask. The off white crystals were dried in vacuo to give pure product. The crystals were grown in mixture of solvents as methanol and acetone.
Off white solid, yield 70%, mp: 165 C. 1 (4). N-methylated-4-chloropyridinium triate (1 g, 3.6 mmol, 2 eq.) along with cyclohexane diamine (0.21 mL, This journal is © The Royal Society of Chemistry 2019 1.8 mmol, 1 eq.) were added in two necked round bottom ask (50 mL). Under argon the temperature was provided to reaction mixture for about 150 minutes at 230 C. The solid was cooled and recrystallised from methanol and acetone and dried in vacuo to give pure product [H 2  [H 2 L 3 ][CF 3 SO 3 ] 2 (5). 2-Chloropyridinium methyl triate (0.5 g, 1.8 mmol, 2eq.) was added in a vacuum dried two neck round bottom ask (50 mL). Cyclohexane diamine (0.1 mL, 0.9 mmol 1 eq.) was introduced by glass syringe (100 mL) under argon into the ask. Then reaction mixture was heated for about 3 hours. Thermometer was used to monitor the temperature. Aer the completion of reaction, product was cooled to room temperature and scratched from the ask carefully via spatula. Desiccator was used to dry the solid. Good quality crystals can be grown in mixture of acetone and methanol.
Brown solid, yield 60%, mp: 232 C. 1  [H 2 L 4 ][CF 3 SO 3 ] 2 (6). Ethylene diamine (240.1 mL, 3.60 mmol) and N-methylated-2-chloropyridinium triate (2 g, 7.2 mmol) were added in a 50 mL two neck round bottom ask under inert atmosphere and ask was heated for 2 hours at 180 C. During this time, the solid reactant melts and undergoes melt reaction. Aer that time the melt was cooled to room temperature and the solid scratched from the ask. The solid was recrystallized from methanol to give pure dark brown crystalline product.

Synthesis and characterization
The N-alkylation of 2-chloropyridine was carried out with ethyl iodide and methyl triate to synthesize ligand precursors. Ethyl iodide being weak alkylating agent than methyl triate required more vigorous conditions to yield [P 3 Et ][I] as compared to [P 2 Me ] [CF 3 SO 3 ]. During the synthesis of [P 3 Et ][I], chloro attached at alpha carbon was substituted by iodo group and also appeared as counter anion, upon heating in water bath for 12 hours. 28,29 The ethylation on pyridine was suggested by a quartet and triplet peaks at 4 SO 3 ] showed aromatic stretch n(C-H) at 3069-3085, aliphatic n(C-H) at 2956, n(C]N) at 1562-1588 cm À1 , n(C]C) at 1600-1646 cm À1 , n(C-N) at 1357-1303 cm À1 , n(C-I) at 445 cm À1 , and n(C-Cl) band at 633 cm À1 respectively. All remaining peaks appeared in their respective regions.
All the ligands, were synthesised by the melt reaction between respective ligand precursor and corresponding amine. In these ligands, NH peak appeared in the range of 9-11 ppm that indicated the conversion of all primary amines to secondary amines. In aliphatic region, N-alkylated protons showed peaks for methyl and ethyl between 4.24-3.70 ppm in all ligands. Similarly carbon NMR showed these peaks between 62.3-47.8 ppm. The aromatic protons and their carbon atoms showed the respective peaks in their standard region. The peaks for cyclohexyl group appeared between 1. 17 2 . Peaks of aromatic region n(C-H) ranges 3101-3016 cm À1 while skeleton vibrations or peaks due to breathing vibrations of aromatic ring were observed around the following frequencies; 1600, 1560, 1500, 1460 cm À1 . 30 In aliphatic region, the characteristic stretching band n(C-H) appeared at 2970-2943 cm À1 and bending vibrations associated with d(C-H) present in the particular range of 1436-1459 cm À1 . Signals appeared for both secondary C]N and primary C-N stretch in the region of 1690-1590 cm À1 and 1350-1280 cm À1 respectively. Peaks between 1350-1225 cm À1 were assigned to both asymmetric and symmetric n(S]O), while signals between 828-863 cm À1 were designated to n(S-O). Sharp peak associated with n(C-F) observed in the range of 1025-1063 cm À1 .
A comparison of proton and carbon NMR spectra of [  Fig. 4 that shows successful methylation on nitrogen.   Fig. 4. Crystal structure analysis conrms the attachment of two pyridinium rings to the cyclohexyl diamine and triate is acting as counter anion. Cyclohexyl group adopts chair conformation with two substitutions at consecutive axial and equatorial positions show transoid geometry. Due to steric repulsion, the two substituted arms of cyclohexyl group shows torsion C7N1C5N2 angle of 171.8 . (Fig. 5).

Computational analysis of molecular structures
Computational studies were carried out on all the compounds using Gaussian 09 soware to gain a greater insight into the   Paper structural and electronic properties. The most signicant edge to semi-empirical calculations is the prominent increase in computational accuracy without further increase in computing time. The geometry optimization of the structures was performed using AM1 semi-empirical method and an energy calculation was carried out for each optimized structure to nd the energy minimum, (in the presence and absence of ligands). The energy of the frontier molecular orbitals (HOMO-LUMO) was also calculated (and conrmed to earlier results by Gaussian) by MOE 2016 soware 32 using semi-empirical method with a Hamiltonian force eld, MMFF94x and 0.0001 Gradient. All the computed data available in this study shows highly convergent values obtained from energy minimization of compounds using Gaussian and MOE. A number of structural parameters have been obtained from semi-empirical studies on conformers with minimum energy. The energy of the frontier molecular orbitals is also instrumental in obtaining the values of chemical hardness (h), chemical potential (c) and electrophilicity index (u) using the   Tables 1 and 2.
The reactivity of a compound can also be gauged from the HOMO and LUMO orbitals energy difference (DE HÀL ); a larger band gap indicates lower reactivity and higher chemical hardness. 35,36 The greater is the energy of HOMO, greater would be ionization potential and thus more is the ability of a molecule to donate an electron pair. While LUMO has the ability to accept electron density via back bonding from transition metal that is associated with electron affinity of molecule. 37 Table 6. [H 2 L 1 ][OTf] 2 was used for the optimization of various parameters such as amount of catalyst loading ( Table 6, entry 1-5), solvent system ( Table 6, entry 5-9), base ( Table 6, entry 10-15), temperature ( Table 6, entry [15][16][17][18][19] and molar ratio of palladium acetate to ligand ( Table 6, entry 19-20, 21, 22), with pure Pd (OAc) 2 catalyst and without any ligand reaction time 4 hours resulted in lowest 6% yield (Table  6, entry 20). Initially, bromobenzene with styrene reaction was selected for optimization of reaction conditions. A reaction with only palladium acetate or ligand yield trace amount of product ( Table 6, entry 1 or 20). The optimum reaction conditions were obtained for (entry 19,  2 presented maximum coupled product comparatively. The reason can be associated with the extensive delocalization of electrons in the in situ generated L 1 (Fig. 11) that binds with palladium acetate. This conjugation in ligand can make amido nitrogen electron rich that in turn increases the electronic density on palladium catalyst that eventually speeds up the rate of oxidative addition of bromobenzene, thus activating the catalyst towards coupling reaction.
Alkyl substituted ligands, [H 2 L 2 ][OTf] 2 -[H 2 L 5 ][I] 2 , were found less active comparatively. Nevertheless, they showed coupled product in the range of 77 to 83% owing to the inductive effect of ethyl and hexyl groups. The minor variations in product yield can be related to the steric of N-alkylated group of varying degree around the donor amido nitrogen. This catalytic activity order of co-catalysts can also be related with their E HOMO values i.e., greater is the energy of HOMO, greater would be the electron donation from ligand to Pd(II) thus more would be the stability of in situ generated active catalyst.
Substrates with a different range of electron withdrawing to electron donating substituent were coupled under optimum conditions to test the substrate scope of best catalyst system ([H 2 L 1 ][OTf] 2 /Palladium acetate). As expected, more activated aryl iodides couple more effectively than aryl bromides and aryl chloride (Table 8, entry [1][2][3][4][5][6][7][8]. The high reactivity of aryl iodides are due to small dissociation energy of C-I bond and ease of activation towards Pd(0) catalyst in oxidative addition    step. 40 Generally coupling of aryl chlorides demand high catalyst loading with low yield of coupled product. 41 Likewise, those aryl halides with electron donating substituents like methoxy, methyl or naphthyl and electron neutral group such as -H showed less reactivity than aryl halide containing electron withdrawing substituents such as nitro, aldo and keto groups ( Table 8, entry 1-13). The more electron decient quaternary carbon of aryl halide better would be the rate of oxidative addition reaction. Similar trend was shown by ethyl acrylate for the above mentioned aryl halides activated to different degrees. However the yield of all coupled products with ethyl acrylate was comparatively more than styrene (Table  8, entry [14][15][16][17][18]. The reason can be attributed to the greater polarization of the alkene with more electron-withdrawing adjacent carbonyl group in ethyl acrylate. This polarization enhances the insertion of ethyl acrylate into aryl-palladium bond during catalytic cycle. Moreover, as explained earlier, out of 3.1 eq. sodium acetate, 1.1 eq. of sodium acetate was used for catalytic reaction however remaining 2 eq. of sodium acetate was used to in situ deprotonate the ligand leading to the formation of an effective complex with ligand. Efforts to synthesize pure palladium complexes with all the ligands, [H 2 L 1 ][OTf] 2 -[H 2 L 5 ][I] 2 were proved to be futile owing to strong trans inuence by in situ generated deprotonated ligands. The resulted mixtures were attempted to be puried by various analytical techniques but was proved in vain. To full ll the urge of identifying the actual nature of catalyst, standard mercury test was performed. 150 to 300 equivalent of Hg(0) Fig. 11 Proposed structure of L 1 .   SO 3 ]. These ligands were successfully synthesized by the melt reaction between precursor and corresponding diamine. All the synthesized compounds were successfully characterized by various analytical techniques such as 1 H and 13 C NMR, FTIR, single crystal XRD and DFT studies. These ligands acted very efficiently as co-catalysts for palladium acetate in Heck-Mizoroki cross coupling reactions. These ligand systems are useful addition in the eld of electron donor ligands such as NHC and phosphines that can stabilize palladium in different oxidation states during C-C coupling reactions.

Conflicts of interest
There are no conicts of interest among authors to declare.