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Introduction Felbinac is a common type of non-steroidal anti-inflammatory drug produced in the pharmaceutical field. It treats muscle inflammation and arthritis pain by inhibiting the cyclooxygenase-1 enzyme, which is responsible for producing prostaglandins that activate pain responses throughout the body1. Prostaglandins usually cause pain, swelling and inflammation, processes that all assist the body with repair and recovery. The production of prostaglandins from archdonic acid is catalyzed by the COX enzyme; because NSAIDs block the function of this enzyme, this class of drugs effectively suppresses pain sensations and acts as a pain killer. Felbinac can be utilized to treat significant medical injuries and provides temporary pain relief. NSAIDs can be synthesized from a variety of methods, mainly through addition and coupling reactions, such as the Suzuki reaction. The Suzuki reaction is a coupling reaction that involves a boronic acid and an aryl halide that is catalyzed by palladium2. The main application of this reaction is to efficiently create new carbon-carbon bonds, which are essential to forming commonly used styrenes and poly-olefins. Additionally, it is used on an industrial level to mass produce chemical compounds that are readily incorporated into pharmaceutical drugs, such as felbinac and caparratriene2. In this experiment, heterogeneous palladium catalyst will be utilized in addition to 4-bromophenylacetic acid and pheylboronic acid to produce felbinac1. Palladium catalyst speeds up the rate of a wide variety of organic chemistry reactions, such as hydrogenation or carbon-carbon linkage; in this specific experiment, it acts as a reducing agent for the aryl halide3. The efficiency of this reaction is determined by its atom economy, or the effectiveness of conversion of reactants into products, which is roughly 63%1. With the addition of the heterogeneous catalyst, this makes the reaction very green and desirable. The mechanism for the Suzuki coupling reaction is found below.

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The first step of the mechanism is the oxidative addition of palladium (1a) to the aryl halide (1b) to form a palladium (II) complex (1c). Then, the sodium bicarbonate (2a) attacks the palladium complex (1c) in a metathetic exchange in which the HCO3- replaces the bromide ion on the palladium complex (2b). Another molecule of the sodium bicarbonate (2a) binds to the phenylboronic acid (2c) to make the aromatic ring more reactive (2d). Then, transmetallation occurs between the activated borate (2d) and the palladium complex (2b); the aromatic ring replaces the bicarbonate ion as it is removed from the compound, forming a diaryl palladium complex (3a). The last step is reductive elimination, in which the aromatic ring linkage (4a) is formed through elimination from the palladium complex and the palladium (II) is reduced to palladium catalyst (1a) 1, 2.

The goal of this lab was to efficiently produce felbinac, a non-steroidal anti-inflammatory drug, using a palladium catalyzed Suzuki coupling reaction. Atom economy will be calculated to measure the conversion efficiency and the overall greenness of the reaction. Extraction and recrystallization will be utilized to purify the crude product and the final analysis will include melting point analysis, as well as NMR and IR analysis.

Experimental Felbinac. Phenylboronic acid (0.215g 1.76mmol), sodium bicarbonate (0.197g 2.35mmol), palladium catalyst (0.01g 0.094mmol) and distilled water (10.0g 556mmol) were combined in a flask. The mixture was stirred for 10 minutes until it became homogenous. Then, 4-bromophenylboronic acid (0.121g 0.562mmol) was added and the mixture was refluxed at 80C for 60 minutes. The reaction mixture was evaluated with thin-layer chromatography (1:3

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ethyl acetate/hexanes) to assess the progress of the reaction. At completion, the palladium catalyst was separated from the reaction mixture using vacuum filtration with ethanol (5mL) and celite fiber (1.50g). Hydrochloric acid (6M 2mL) was added to the isolated mixture to change the pH from basic to acidic. Then, the solution was mixed with water (10mL) and ethyl acetate (15mL) in a separatory funnel. The bottom aqueous layer and top organic layer were separated and the aqueous layer was combined with ethyl acetate (15mL) again. The new organic layer was combined with the previous organic layer and the aqueous layers were discarded. The organic mixture was dried with anhydrous sodium sulfate and then the ethyl acetate was evaporated and dried overnight. The crude product was recrystallized (1:1 water/95% ethanol) and separated with vacuum filtration to yield white, shimmering crystals of felbinac (0.108g 90.8%) mp 155158C (159-160C)5; 1H NMR (400 MHz, CDCl3) (ppm) 7.58 (m, 4H), 7.43 (t, 2H), 7.36 (m, 3H), 3.70(s, 2H) ; IR (AshTR) max cm-1 3027, 2927, 2744, 1683, 1485, 1411, 1247; 13C NMR (400 MHz, CDCl3) (ppm) 177.04, 140.60, 140.25, 132.20, 129.72, 128.8, 127.23,124.3, 119.8, 24.53. Results and Discussion Felbinac was synthesized from phenylboronic acid, 4-bromophenylacetic acid and a palladium catalyst using a Suzuki coupling reaction. Thin-layer chromatography was utilized to assess the progress of the reaction and determine which compounds remained after certain time intervals. The significance of this reaction is that it can be utilized to efficiently synthesize new carbon-carbon bonds; in this experiment, two aromatic rings are bonded together to yield felbinac. Because felbinac is a pain suppressant and widely utilized, the Suzuki coupling reaction can have a drastic impact on the new drugs being synthesized in the pharmaceutical field.

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A heterogeneous palladium catalyst was utilized in this synthesis because it proved to be the most efficient. It can simply be filtered off at the end of the reaction, its cheap and insensitive, and ligand-related side reactions can be minimized. Upon reaction completion, the solution was treated with concentrated hydrochloric acid to make the overall pH of the solution acidic and neutralize any residual sodium bicarbonate. A separatory funnel was utilized to wash the solution with water and ethyl acetate to form the aqueous and organic layers. The crude organic product layer was recrystallized with 1:1 water/95% ethanol to remove any unwanted impurities. The product was analyzed with melting point analysis, 400 MHz NMR, IR and 400 MHz 13C NMR. The measured melting point of felbinac was 155-158C, which is very close to the known melting point of around 159-160C. This provides evidence that the final product was relatively free of contaminants and almost entirely felbinac. The NMR analysis provided solid evidence that felbinac was indeed present, but did not allow for complete differentiation between starting material and product because of overlapping shifts in both of their respective NMR spectra. The first observed chemical shift was at 3.72 ppm, representing two hydrogens as a singlet (figure 3). This is characteristic of alkane hydrocarbons located next to a carboxylic acid, which is found in felbinac. However, because this can be found in both the reactants and product, this shift can only confirm the presence of felbinac, not allow for differentiation between the reactants and product. Similar logic was utilized for any remaining shared chemical shifts on the NMR. The remaining chemical shifts were in the aromatic region; a multiplet at 7.36ppm representing three aromatic hydrogens, a triplet at 7.43ppm representing two aromatic hydrogens and a multiplet at 7.58ppm representing four aromatic hydrogens (figure 3). It is likely that two unique hydrogens combined splitting patterns, leading to the observed complex splitting patterns. The carboxylic acid shift for felbinac

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did not show up in the NMR probably because of solvent exchange with the CDCl3, leading to significantly lower amounts of observed acid. Although both the reactants and products do have similar chemical shifts in the NMR, the number of total hydrogens is unique for each compound. The NMR data is consistent with felbinac because it shows only 11 total hydrogens (excluding the carboxylic acid), which is the exact amount felbinac is expected to have (figure 3). As with the NMR, between the two reactants and the product, there are no significantly differentiating peaks in the IR analysis. The peak at 3027 cm-1 is characteristic of aromatic carbon hydrogen bonds while the peak at 2927 cm-1 is indicative of aliphatic carbon hydrogen bonds, two types of hydrogens present in felbinac. The broad nature of the peaks from 25003500 cm-1 and the peak at 2743 cm-1 are characteristic of carboxylic acids, which are also found in felbinac (figure 1). The boron diol in the reactant would have a more distinct OH peak in IR spectra, hence why it can likely be ruled out. The last few remaining peaks on the IR spectra are 1683 cm-1, 1411-1485 cm-1, and 1247 cm-1 which are characteristic of carbon oxygen double bond in a carboxylic acid, aromatic double bonds and a scissor bend, and a carbon-oxygen bond, respectively; all of these peaks are characteristic and expected of felbinac. The 13C NMR also provided evidence for the successful synthesis of felbinac. Ten unique carbons are shown on the spectral data, which is characteristic of felbinac. There is a carbon peak at 177.04 ppm, which represents a carboxylic acid. The next series of carbon peaks, 140.60, 140.25, 132.20, 129.72, 128.8, 127.23, 124.3 and 119.8 ppm, represent 8 unique aromatic carbons, which further supports the formation of felbinac because felbinac is the only compound in this reaction with 8 aromatic carbons. The order of these carbons was determined by deciding which was the most downfield, based on proximity to the carboxylic acid group. The

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last significant carbon peak is 24.53 ppm, indicative of a carbon-carbon alkane linkage, also found in felbinac. Overall, MP, IR, and NMR analysis provided evidence for the presence of a relatively pure felbinac product, while the 90.8% yield of felbinac proved that the reaction was indeed efficient, both in terms of atom economy and greenness. In figures 1, 3 and 5, there were no significant signs of residual reactants remaining behind, which indicated that the reaction was completed successfully. Trace amounts of acetone and water were observed in figure 3, which can be explained by insufficient drying before use of NMR tube. In previously controlled experiments, the percent yield of palladium catalyzed Suzuki coupling reactions using bromine was in the mid to high 90s, so the calculated yield of 90.8% is right near that range; this effectively proves that this reaction was run effectively and produced relatively pure products1. In conclusion, Suzuki coupling reactions with a heterogeneous palladium catalyst are an effective way to construct carbon-carbon bonds. With an atom economy of roughly 63% for this reaction and the relatively high yield and pure product, this reaction was run successfully. Felbinac, a NSAID pain reliever drug, is one of many integral drugs and organic compounds that can be synthesized from this reaction. Some modifications to this lab experiment include using a wider variety of solvents, and varying levels of bases to maximize the efficiency of the catalytic cycle.

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References 1. Valente, Alex. Experiment 65: Palladium Catalyzed Suzuki Coupling, 2013. The Pennsylvania State University ANGEL course Fall 2013 Chem 213 Web Site. 2. Miyaura, Norio and Suzukint, Akira. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chemical Reviews. [Online] 1995, 95, 2457-2483. http://www. http://pubs.acs.org/doi/pdf/10.1021/cr00039a007 (accessed December 10, 2013). 3. Yang, Yang and Buchwald, Stephen L. Ligand-Controlled Palladium-Catalyzed Regiodivergent SuzukiMiyaura Cross-Coupling of Allylboronates and Aryl Halides. Journal of the American Chemical Society. [Online] 2013, 135, 10642-10645. http://www. http://pubs.acs.org/doi/pdf/10.1021/ja405950c (Accessed December 9, 2013). 4. Wang, Zhan-Yong, Ma, Qin-Na, Li, Ren-Hao and Shao, Li-Xiong. Palladium-catalyzed Suzuki-Miyaura coupling of aryl sulfamates with arylboronic acids. Organic and Biomolecular Chemistry. [Online] 2013, 11, 7899-7906. http:// http://pubs.rsc.org/en/content/articlepdf/2013/ob/c3ob41382a (Accessed December 10, 2013).

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5. Felbinac: MSDS 196487 [Online]; Sigma Aldrich: Saint Louis, MO, November 30, 2012. http://www.sigmaaldrich.com/MSDS/MSDS/196487