Suzuki–Miyaura Reactions of (4-bromophenyl)-4,6-dichloropyrimidine through Commercially Available Palladium Catalyst: Synthesis, Optimization and Their Structural Aspects Identiﬁcation through Computational Studies

: 5-(4-bromophenyl)-4,6-dichloropyrimidine was arylated with several aryl / heteroaryl boronic acids via the Suzuki cross-coupling reaction by using Pd(0) catalyst to yield novel pyrimidine analogs ( 3a-h ). It was optimized so that good yields were obtained when 5 mol % Pd(PPh3)4 was used along with K 3 PO 4 and 1,4-Dioxane. Electron-rich boronic acids were succeeded to produce good yields of products. Density functional theory (DFT) calculations were also applied on these new compounds to analyze their reactivity descriptors and electronic and structural relationship. one. ( β compounds show them as very good non-linear optical (NLO) materials. Compound 3f β the enough a potent NLO material.


Introduction
Pyrimidines are two nitrogen containing heterocycles and, being the basic moieties in DNA and RNA, indicate their importance in a large number of biological activities [1]. It is found that pyrimidine and all the molecules containing a pyrimidine nucleus possess a wide spectrum of biological activities including anticancer [2,3], antioxidant [4], antimicrobial [5], antiviral [6], anti-inflammatory [7], analgesic [8], antimalarial [9], anti-HIV, cardiovascular [10] and anti-diabetic [11] and they also act as calcium channel blockers [12]. Such a widespread use of pyrimidine derivatives in pharmaceutical drugs and agro industries paved the way for us to synthesize various new substituted pyrimidines. During the literature survey, it was analyzed that the direct arylation of halogenated pyrimidines was the focus of many chemists, which gives excellent yield [13,14]. The production of mono-, di-and tri-substituted pyrimidines was the subject of study for many researchers by examining the halogen group to be replaced and the most reactive site of pyrimidine, and regioselectivity was also examined [13,15]. Meanwhile, the arylation of the pyrimidine-substituted bromo-phenyl ring has not been reported so far.
Many different methodologies are available for arylation [16,17], while the Suzuki coupling method is the most versatile and frequently used method [18,19], due it its tolerance for moisture by various boronic acids and also by its ability to cover a large number of functional groups [20,21]. Moreover, a number of different catalysts were reported for arylation [22,23]. From some years ago, the direct arylation of hetero-aromatics with palladium catalyst has become an efficient method for the production of arylated hetero-aromatics [24,25]. By keeping in view the importance of pyrimidines and palladium-catalyzed arylation [26], the present work focuses on synthesizing new analogs of phenyl-substituted pyrimidines through a palladium-catalyzed Suzuki cross-coupling reaction with special emphasis on the effect of halo-substituted boronic acid, solvent and base on the yield. With this context, pyrimidines substituted to phenyl are a good choice for Suzuki coupling reactions. Density functional theory (DFT) calculations have been executed on the newly arylated products to know about their electronic and structural properties. An analysis of frontier orbitals and other reactivity descriptors including A, I, µ, η and ω was performed. Hyperpolarizability (β) values of the compounds have been calculated to check the compounds for their electron push and pull mechanism through the intramolecular charge transfer which can predict them to be good non-linear optical (NLO) materials.

Chemicals Used for Coupling of 5-(4-bromophenyl)-4,6-dichloropyrimidine with Boronic Acid
Analytical-grade reagents were used in all experiments and purchased from Sigma Aldrich Alfa and Aesar Chemical Company. All reactions were performed in inert atmosphere by using a Schlenk flask. The reactions were checked with TLC by using silica gel plates. Visualization was accomplished by 254 nm UV light.

Procedure for Synthesis of 5-([17]-4-yl)-4,6-dichloropyrimidine
Pd (PPh 3 ) 4 (5 mol %) catalyst and 5-(4-bromophenyl)-4,6-dichloropyrimidine (0.986 mmoL) were added in the Schlenk flask containing 6 mL of solvent, and the mixture was stirred under an inert atmosphere for 30 min at room temperature. After half an hour, aryl/het-aryl boronic acids (1.08 mmoL), base (1.972 mmoL) and distilled. H 2 O (1.5 mL) were added in the reaction mixture and the mixture continued to reflux at 70-80 • C for 18-22 h. After completion, the reaction mixture was allowed to cool to room temperature and then ethyl acetate was added in the reaction mixture. The organic fraction was separated, dried with magnesium sulphate (MgSO 4 ) and solvent was removed by a rotary evaporator. The crude product was refined by a flash column using n-hexane and ethyl acetate. Final products were confirmed via 1H-NMR, 13C-NMR, mass spectrometry and elemental analysis [27,28].

Computational Methods
For the prediction of different electronic characteristics of compounds, computational study has been proved a powerful tool and Gaussian 09 software was used to compute these properties [29]. A hybrid density functional (PBE0) [30] with 25% Hartree Fock exchange was used [31]. Triple ζ basis set Def2-TZVP [32] was used with empirical dispersion correction (D3) by Grimme [33][34][35]. The solvent effect was also induced through the polarizable continuum model (PCM) [36][37][38][39][40][41][42] with the Solvent Model Density (SMD) parameter set by Truhlar [43]. In all computations, water was used as solvent. To verify the structures as true minima, frequency calculations were measured on optimized geometries. No imaginary frequencies confirmed the structures to be true minima. Structural visualizations were done through CYLview and GaussView 5.0.9 [44] software.

Computational Methods
For the prediction of different electronic characteristics of compounds, computational study has been proved a powerful tool and Gaussian 09 software was used to compute these properties [29]. A hybrid density functional (PBE0) [30] with 25% Hartree Fock exchange was used [31]. Triple ζ basis set Def2-TZVP [32] was used with empirical dispersion correction (D3) by Grimme [33][34][35]. The solvent effect was also induced through the polarizable continuum model (PCM) [36][37][38][39][40][41][42] with the Solvent Model Density (SMD) parameter set by Truhlar [43]. In all computations, water was used as solvent. To verify the structures as true minima, frequency calculations were measured on optimized geometries. No imaginary frequencies confirmed the structures to be true minima. Structural visualizations were done through CYLview and GaussView 5.0.9 [44] software.

Chemistry
The general pathway for the preparation of a series of 5-([1,1′-biphenyl]-4-yl)-4,6dichloropyrimidine is shown in Scheme 1, Figure 1.  Table 1). The influence of different bases and solvents was examined for these couplings ( Table 1). All the reactions were done by using Pd(PPh3)4 at 70-80 °C and under inert atmosphere. However, during this research work, 3a was synthesized by taking the K3PO4 as the base but three different solvents, dry toluene, acetonitrile and 1,4-dioxane, were examined. A moderate to good (40%, 36%, 60%) yield was gained (Table 1). Similarly, 3d was synthesized by keeping the base the same but two different solvents, 1,4-dioxane and DMF, were tested for getting a better yield. A 15% yield was produced in 1,4-dioxane, while 20% yield was gained when DMF was used (Table 1). It was noticed that 3d was gained in better yield in DMF than 1,4-dioxane but DMF was not selected for further reactions due to its difficulty in removal at the end of the reaction. However, 3b was synthesized by taking dry toluene as solvent, whereas two different bases (K3PO4 and Cs2CO3) were examined. A good (70%, 80%) yield was gained (Table 1). Moreover, we tried to synthesize 3c by using two different solvents (dry toluene and 1,4-dioxane) and two different bases (K3PO4 and Cs2CO3). It was noted that the required product was not produced when electron-withdrawing aryl boronic acids were used with different bases and solvents due to the large number of side products obtained in both cases (Table 1).  13    Pyrimidine derivatives (3a-3h) obtained by Suzuki cross-coupling using 5-(4-bromophenyl)-4,6-dichloropyrimidine as the coupling component.

Scheme 1. Arylation of pyrimidine derivatives by the Suzuki cross-coupling reaction.
The Suzuki-Miyaura reaction of 5-(4-bromophenyl)-4,6-dichloropyrimidine (1) with various aryl-boronic acids (1.1 equivalents) afforded 5-([1,1 -biphenyl]-4-yl)-4,6-dichloropyrimidines (Scheme 1, Table 1). The influence of different bases and solvents was examined for these couplings (Table 1). All the reactions were done by using Pd(PPh 3 ) 4 at 70-80 • C and under inert atmosphere. However, during this research work, 3a was synthesized by taking the K 3 PO 4 as the base but three different solvents, dry toluene, acetonitrile and 1,4-dioxane, were examined. A moderate to good (40%, 36%, 60%) yield was gained (Table 1). Similarly, 3d was synthesized by keeping the base the same but two different solvents, 1,4-dioxane and DMF, were tested for getting a better yield. A 15% yield was produced in 1,4-dioxane, while 20% yield was gained when DMF was used (Table 1). It was noticed that 3d was gained in better yield in DMF than 1,4-dioxane but DMF was not selected for further reactions due to its difficulty in removal at the end of the reaction. However, 3b was synthesized by taking dry toluene as solvent, whereas two different bases (K 3 PO 4 and Cs 2 CO 3 ) were examined. A good (70%, 80%) yield was gained (Table 1). Moreover, we tried to synthesize 3c by using two different solvents (dry toluene and 1,4-dioxane) and two different bases (K 3 PO 4 and Cs 2 CO 3 ). It was noted that the required product was not produced when electron-withdrawing aryl boronic acids were used with different bases and solvents due to the large number of side products obtained in both cases (Table 1).
In the present research work, after examining the different bases, solvents and the results of 3a-3d, it was found that 5 mol% Pd(PPh 3 ) 4 produced the best yield along with K 3 PO 4 and 1,4-Dioxane (Table 1). So, 1,4-dioxane and K3PO4 were selected for all the later reactions. It was also noted that electron-rich boronic acids produced good yields as compared to others. It was noteworthy that 3e and 3f were gained in good yield (60% and 55%, respectively) ( Table 1). Compounds 3g and 3h gave a low yield (25% and 30%, respectively) ( Table 1). During the literature survey, it was noted that a low yield might be attributed to the coordination of the transition metal of catalyst (Pd) with a nitrogen center [45,46] which results in its lower activity. Itoh and Mase had reported the coordination of two nitrogen atoms of pyrimidine with palladium catalyst [47]. The phenomenon of chelation had also been reported for a Schiff base containing nitrogen of pyridine and sulfur of thiophene which are involved in binding with the electrophilic Pd of Pd(PPh 3 ) 4 [48] Therefore pyrimidines, having two nitrogen centers, are more liable to such a sort of ligation effect [49]. On the other side, poor yields were obtained with electron-withdrawing substituents, namely boronic acids. Due to the deficiency of electrons on aryl boronic acids, the transmetalation step is slowed [50]. Moreover, the most probable side reaction which lowers the yield is protodeboronation which was reported by Kuivila for the first time in both acidic and basic media and also in the presence of metal ions which leads to the formation of Ar-H linking of aryl boronic acid instead of Ar-Ar/R bond formation with substrates [51][52][53].
Cox and his coworkers also reported that aryl boronic acids with electron-withdrawing groups like halo groups were very much susceptible to protodeboronation especially at higher levels of pH [54]. Moreover, it was observed that such substrates which contain an electron-deficient center like nitrogen as pyrimidine have also been shown to exhibit poor yield and slower reaction rates as compared to homo-aryl substrates. So, it was concluded that nitrogen atoms of pyrimidine and electron-withdrawing boronic acids might be affecting the yields of final products (3c, 3d, 3g-3h), while use of electron-rich boronic acid and 5-(4-bromophenyl)-4,6-dichloropyrimidine (1) with a suitable solvent and catalyst is an ideal condition for the formation of final products (3a-b, 3e-f), as shown in Table 1.

Computational Studies
All the dichloropyrimidine derivatives (3a-3h, Figure 2) with different substituents have been modeled in 3D and optimized at the PBE0-D3BJ/def2-TZVP/SMD water level of theory. The geometries of the optimized structures were then subjected to the measurement of their vibrational frequencies. This proved them to be true minima on the PES.

Frontier Molecular Orbital (FMO) Analysis and Hyperpolarizability
DFT makes it very easy to calculate the energies of FMOs and this is a necessary part of DFT computation. We can investigate the reactivity of a molecule and other different properties with the help of its FMOs energies [55]. The HOMO-LUMO energy difference of a molecule gives us information about the general reactivity of the molecule. As the gap increases, the reactivity of the compound decreases and vice versa. Optimization calculations have been used to derive FMOs energies and their plots are shown in Figure 3.

Computational Studies
All the dichloropyrimidine derivatives (3a-3h, Figure 2) with different substituents have been modeled in 3D and optimized at the PBE0-D3BJ/def2-TZVP/SMD water level of theory. The geometries of the optimized structures were then subjected to the measurement of their vibrational frequencies. This proved them to be true minima on the PES. Figure 2. Optimized structures of derivatives (3a-3h) at the PBE0-D3BJ/def2-TZVP/SMD water level of theory. In 3D models, gray color denotes carbon, white signifies hydrogen, red symbolizes oxygen, green represents chlorine, blue displays nitrogen and brown is for bromine atoms.

Frontier Molecular Orbital (FMO) Analysis and Hyperpolarizability
DFT makes it very easy to calculate the energies of FMOs and this is a necessary part of DFT computation. We can investigate the reactivity of a molecule and other different properties with the help of its FMOs energies [55]. The HOMO-LUMO energy difference of a molecule gives us information about the general reactivity of the molecule. As the gap increases, the reactivity of the compound decreases and vice versa. Optimization calculations have been used to derive FMOs energies and their plots are shown in Figure 3.

Figure 2.
Optimized structures of derivatives (3a-3h) at the PBE0-D3BJ/def2-TZVP/SMD water level of theory. In 3D models, gray color denotes carbon, white signifies hydrogen, red symbolizes oxygen, green represents chlorine, blue displays nitrogen and brown is for bromine atoms.   compounds (3a-3h). The ΔE values of the studied molecules lie in a relatively narrow range from 4.29 to 5.09 eV, representing that their reactivity is generally similar. The lowest ΔE value belongs to that of compound 3f, i.e., 4.29 eV, suggesting it is the most reactive compound in the series. The -SCH3 group in the molecule can be considered to have an activating nature. Similarly, 3g has the highest ΔE value (5.09 eV) which makes it the most stable compared to other compounds in the series. 3c is   (3a-3h). The ∆E values of the studied molecules lie in a relatively narrow range from 4.29 to 5.09 eV, representing that their reactivity is generally similar. The lowest ∆E value belongs to that of compound 3f, i.e., 4.29 eV, suggesting it is the most reactive compound in the series. The -SCH3 group in the molecule can be considered to have an activating nature. Similarly, 3g has the highest ∆E value (5.09 eV) which makes it the most stable compared to other compounds in the series. 3c is the other most stable compound which has deactivating groups (Cl and F) on the aromatic rings. The iso-density dispersion is looking very similar in these compounds. In the series of 5-([1,1 -biphenyl]-4-yl)-4,6-dichloropyrimidine, it is mostly present over all aromatic portions except for 4,6-dichloropyrimidine in the case of HOMO. In LUMO, it is generally found on the 4,6-dichloropyrimidine ring in all the compounds except 3e and 3h. In compounds 3e and 3h, it is distributed on the whole molecule.
The hyperpolarizability (β) values of these compounds do not show them as very good non-linear optical (NLO) materials. Compound 3f has the highest β value among all the compounds under study and the second highest value is shown by 3a which is due to -SCH 3 and methoxy groups on the compounds, respectively. These groups are activating and electron-donating due to which they govern the electrons' push and pull mechanism in these molecules. These values are still not high enough to render these compounds as great NLO response materials.

Molecular Electrostatic Potential
Molecular electrostatic potential (MESP) maps are important 3D plots that help us to visualize the shape, size and charge distribution of compounds under study. These maps represent the density of electrons in different colors. As seen in the scale in Figure 4, the red color shows electron-rich sites of the molecule, while the blue side shows the low-electron density positions. Figure 4 represents MESP plots of compounds. With the help of these plots, the size of the molecule and its electron-rich and electron-deficient sites can be easily visualized that may be helpful in designing reactions of the molecules under study. the shape, size and charge distribution of compounds under study. These maps represent the density of electrons in different colors. As seen in the scale in Figure 4, the red color shows electron-rich sites of the molecule, while the blue side shows the low-electron density positions. Figure 4 represents MESP plots of compounds. With the help of these plots, the size of the molecule and its electron-rich and electron-deficient sites can be easily visualized that may be helpful in designing reactions of the molecules under study.

Conceptual DFT Reactivity Descriptors
Chemical reactivity descriptors [56] like electron affinity (A), electronic chemical potential (μ), ionization potential (I) and chemical hardness (ƞ) are also derived from the FMO calculations. Reactivity descriptors' values of observed compounds are mentioned in Table 3. The value measurement of I and A has been calculated by Koopman's theorem and according to it, the negative

Conceptual DFT Reactivity Descriptors
Chemical reactivity descriptors [56] like electron affinity (A), electronic chemical potential (µ), ionization potential (I) and chemical hardness (η) are also derived from the FMO calculations. Reactivity descriptors' values of observed compounds are mentioned in Table 3. The value measurement of I and A has been calculated by Koopman's theorem and according to it, the negative of E HOMO -E LUMO relates to the electron affinity (A) and ionization potential (I) of compounds [57,58]. Electrophilicity index (ω), chemical hardness (η) and electronic chemical potential (µ) are then calculated from it as follows: The lowest values of electron affinity and ionization energy of compound 3f suggest its reactivity is also estimated by FMO analysis and thus can be co-linked. This supports the greater predicted reactivity of 3f in the series. It is clearly related to the fact that a higher energy of HOMO is related to a greater reactivity of the molecules in electrophilic reactions and vi. Compound 3f has the highest HOMO energy as evident from Table 2. Similarly, the chemical hardness (η) of the molecule is directly related to the HOMO-LUMO energy gap. A larger gap would mean a harder molecule and vice versa. This also supports the findings of the FMO analysis, thus predicting compounds 3g and 3c to be the most stable molecules in the chemical reaction as compared to the others under study.

Conclusions
The ability of 5-([1,1 -biphenyl]-4-yl)-4,6-dichloropyrimidine for Suzuki coupling was described. The examples reported in the literature indicate pyrimidine is an excellent substrate for the coupling reaction, while the above-mentioned phenyl-substituted pyrimidine proved to deviate from this trend. It was concluded that yields of newly synthesized compounds might be affected by nitrogen atoms of pyrimidine and electron-withdrawing boronic acids, whereas good to better yields were obtained with the use of electron-rich boronic acid and 5-(4-bromophenyl)-4,6-dichloropyrimidine (1) with a suitable solvent, base and Pd(PPh 3 ) 4 . DFT calculations have been calculated on newly prepared products to know about their electronic and structural properties. Exploration of frontier orbitals and reactivity descriptors, i.e., electron affinity, ionization potential, electrophilicity index, electronic chemical potential and chemical hardness, exposed that the compound 3g is the most stable, while 3f is the most reactive in the whole series.