Introduction Chemists often find a method to determine the level of “greenness” of a chemical reaction, or its “atom economy”. A higher atom economy is preferable because a greater amount of the reactants will be present in the product as opposed to the byproduct.1 A Suzuki reaction is classified as an organic, coupling reaction that includes boronic acid and a halide that are catalyzed by a palladium complex under basic conditions. Other palladium- catalyzed coupling mechanisms include the Heck and Stille reactions.
Palladium typically exists in the oxidation states of 0, +2, and +4. PdC12 is usually the starting compound for several other heterogeneous palladium catalysts such as Pd/C and Pd/BaSO4.1 Suzuki coupling is an efficient way to synthesize a new carbon-carbon bond because it is not very difficult to perform and does not require complex conditions.2 However, scientists are always looking to improve the atom economy of a given reaction so a new form of the Suzuki reaction was carried out using only water as the solvent.
In addition, Pd/C was used in this experiment because it has been shown to be an effective catalyst due to its easy removal from reaction mixtures. It is also inexpensive and safe to use in the presence of oxygen.2 Felbinac is an analgesic non-steroidal anti-inflammatory drug (NSAID) that is commonly used to alleviate arthritis pain and muscle inflammation. As shown in the balanced chemical reaction in figure 1, Felbinac is synthesized from 4-bromophenyl acetic acid, phenylboronic acid, and 10% Pd/C. Figure 1: The balanced chemical reaction showing the synthesis of felbinac. It functions by inhibiting cyclooxygenase-1, which releases prostaglandins that cause pain as a response to injury. In a study conducted by Moore et al., 160 patients were
subject to various topical NSAIDS to determine their effectiveness. Out of the six drugs tested, the results indicated that felbinac, ibuprofen, and piroxicam were the most useful in relieving pain due to acute and chronic conditions.3 Figure 2: The four steps involved in the catalytic cycle of a Suzuki coupling reaction. There are four key steps in the mechanism of Suzuki coupling: oxidative addition, metathetic exchange, transmetalation, and reductive elimination. In oxidative addition, the palladium catalyst is added to an organohalide between the halide and the remaining compound.
This oxidative addition initially forms a cis-palladium complex but rapidly converts to the transform.4 This changes the catalyst from a neutral species (Pd(0)) to one with a positive charge (Pd()). Next, metathetic exchange involves a base being added to the newly formed organopalladium complex. The base replaces the location of the original halide and a new palladium complex is formed. The halide is removed and forms a bond with the cation of the added base. During transmetallation, the aryl boronic acid forms a negatively charged boronic compound upon reacting with the base. This compound consists of two alcohol groups, a base, and the boron species.
The aryl group then attacks the organopalladium compound and takes the position of the base which results in a biaryl compound.4 The last step is reductive elimination in which the palladium (II) complex removes the product and regenerates the neutral palladium (0) catalyst.4 It is important to note that the organoboron compounds do not exhibit transmetallation without the presence of a base and therefore it is likely that the function of the base is to activate the organoboron compound as well as assist in the formation of R2-Pd-OtBu from R2-Pd-X.5 The purpose of this experiment was to effectively synthesize felbinac with the given starting materials. The efficacy of the “greener” method of Suzuki coupling using only water as a solvent as well as the Pd/C catalyst was also demonstrated.
TLC was used to monitor the progress of the reaction. In addition, isolation via liquid-liquid extraction and purification by recrystallization were important techniques utilized as well. The product was characterized by melting point, IR, 60 MHz 1H NMR, 400 MHz 1H NMR, and 400 MHz 13C NMR. Suzuki coupling is a versatile reaction that is important to organic chemists because it allows for the synthesis of a new carbon- carbon bond in a relatively green manner.1 Experimental Felbinac. Phenylboronic acid (215 mg, 1.76 mmol), sodium bicarbonate (197 mg, 2.35 mmol), 10% Pd/C (50 mg) and distilled water (10 ml) were stirred together.
Reaction was sealed and stirred until the mixture appeared homogenous. 4bromophenylacetic acid (121mg, 0.56 mmol) was added to the mixture which was then refluxed. The water bath was heated to 80 °C and the reaction was monitored via TLC (25% ethyl acetate/ 75% hexanes). For the starting material spot, 4bromophenylacetic acid (20 mg) was dissolved in dichloromethane (1.5ml). Two drops of reaction mixture were dissolved in methanol (1.5 ml) to be used as the reaction spot. Then, the reaction mixture was filtered off the palladium catalyst using Celite (1.5g) and ethanol (5 ml). Column chromatography sand (0.5 g) was added and the palladium catalyst was disposed of. The pH was tested and 6M HCI (2 ml) was added to the mixture.
To this acidic solution, 20 ml of ethyl acetate was added along with water (10 ml). The bottom, aqueous layer was drained while the top, organic layer was kept. The aqueous layer was reintroduced and extracted again using ethyl acetate (15 ml), and was subsequently dried over anhydrous sodium sulfate. The crude product was purified via recrystallization (50% water, 50% of ethanol). After crystals reformed in the ice bath, vacuum filtration yielded a crystalline, white solid, mp 158.7-160.1 °C; Felbinac (0.073 g,.344 mmol, 61.3% yield) 1HNMR (60 MHz, deuterated DMSO) S (ppm) 12.48 (s, 1H), 7.40-8.02 (m, 9H), 3.34(s, 2H), 11.7(s, 1H). 1HNMR (400 MHz, deuterated DMSO) 8 (ppm) 7.62 ppm (m, 4H), 7.43 (m, 4H), 7.41 (t, 1H), 3.69 (s, 1H) 13C NMR (400 MHz, deuterated DMSO) 8 (ppm) 206.28, 172.75, 141.547, 140.34, 135.06, 130.81, 129.69, 128.10, 127.67, 40.85. IR (ATR) v (cm-1) 2943.7, 2831.1, 1740.7, 1468.3, 1450.8, 1198.4
Results and Discussions This experiment used a palladium catalyst to synthesize the compound felbinac from 4-bromophenylacetic acid and phenylboronic acid. The reaction was carried out specifically with water and heterogeneous palladium (10% Pd/C) that made this reaction relatively safe and simple to isolate. First, phenylboronic acid, sodium bicarbonate, and 10% Pd/C were added to a 25 mL round bottom flask with distilled water and stirred at room temperature until it homogenized, which was about 10 minutes. Next, 4- bromophenylacetic acid was added to the flask and the mixture was refluxed for about 50 minutes at about 80°C. TLC was used to monitor the reaction progress every 15 minutes.
A relatively non-polar solvent system of 25% ethyl acetate/ 75% hexanes was used as the mobile phase. Each plate contained a starting material (4-bromophenylacetic acid), a reaction mixture spot, and a co-spot. The TLC at 15 minutes showed the starting material to have an Rf of about 0.12 and reaction mixture lane had only one spot at an Rf of 0.07, which was probably the starting material. At 30 minutes, the reaction lane showed one spot at Rf of 0.13 and another spot at Rf of 0.03. The starting material standard was seen to have an Rf of about 0.14. At 45 minutes, the reaction lane had a dark spot around 0.26 and a faint spot around 0.15 which indicates the starting material.
At 60 minutes, the reaction lane only contained one spot which had an Rf of about 0.28. This means that the reaction had completed because there was no starting material spot present in the reaction lane. The standard lane was still around 0.15 and a large co-spot was evident around Rf of 0.2. Comparing 4-bromophenylacetic acid with felbinac, it is evident that the product will have a lower polarity and higher Rf value on the TLC plate because it contains an extra aromatic ring. The starting material also contains a bromine halide which greatly increases the polarity of the compound.