Erhan Selvi, CHEM 213B. Synthetic #3 FFR. aryl or vinyl halide with a boronic acid or ester with a palladium catalyst that is also run in basic

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1 Erhan Selvi, CHEM 213B Synthetic #3 FFR Introduction Suzuki coupling is a very important reaction in organic chemistry because it can be used to make carbon-carbon bonds, and is especially useful for biaryl compounds. 1 This reaction involves the use an aryl or vinyl halide with a boronic acid or ester with a palladium catalyst that is also run in basic conditions. 2 Boronic acids are used in this reaction because they are inert and stable when reacted with water and oxygen. 3 Traditionally, Pd(0) is generated in situ from PdCl 2 or Pd(OAc) 2. 2 This method of Suzuki coupling is sufficient to produce the desired product of a new carbon-carbon bond since it is easy to carry out, and works under mild conditions. 3 However, there is always room for improvement in chemistry, so a new greener version of the Suzuki coupling reaction has been developed. The new method uses water as the only solvent which is always the safest option in terms of the potential toxicity to the chemist. 2 Furthermore, Pd/C has proven to be a better alternative to generating it in situ from PdCl 2 or Pd(OAc) 2 because it can be easily removed from the reaction mixture through vacuum filtration, can be recycled well for further reactions, and is also cheap and safe to use in air or moisture. 1 The mechanism for Suzuki coupling is broken down into four main steps: oxidative addition, metathetic exchange, transmetalation, and reductive elimination. During oxidative addition, the palladium species is added to an organohalide between the halide and the rest of the molecule (transaddition) so it transitions from a neutral charged species (Pd(0)) to one with a positive two charge (Pd(II)). During the metathetic exchange phase, a base will be added to the now organopalladium species where the halide originally was located, and the halide will bond with the free halide that was just kicked off the palladium and a salt will form between the halide and the cation of the added base. Transmetalation now occurs, and during this step an aryl boronic acid will react with the added base to form a negatively charged boronic species that is bonded to the base, two alcohol groups, and the aryl 1

2 ring. This aryl group in this species acts as the nucleophile and attacks the organopalladium species which will take the place of the base such that a biaryl palladium species is now formed. The final step is the reductive elimination of the palladium from the palladium-aryl complex which occurs with the two aryl substituents bonding to each other, then eliminated from the palladium. This reduces the charge of palladium from +2 to 0, and the eliminated biaryl product with a new carbon-carbon bond is left neutral as well. 4 The mechanism for the general cycle of a Suzuki coupling reaction can be seen in scheme 1. An important part of this experiment is to carry out the reaction in a green chemistry manner. One way to measure the efficiency of a reaction is to calculate its atom economy. Atom economy is equal to the ratio of the mass of desired product divided by the total mass of substrates needed to run the reaction. 5 Therefore, a higher atom economy is more beneficial because a greater amount of the reactants will be in the product, as opposed to a byproduct, which would be a waste of atoms. Scheme 1: Suzuki coupling reaction cycle The Suzuki reaction has proven to be very useful in many reactions, and the one that will be tested in this experiment is the synthesis of felbinac. Felbinac is considered an analgesic non-steroidal 2

3 anti-inflammatory drug (NSAID), used particularly to manage arthritis pain. 4 The mechanism by which felbinac works is by inhibiting the enzyme cyclooxygenase-1. Cyclooxygenase-1 is responsible for releasing prostaglandins at the sites of injury that will generate the sensation of pain. 4 It has been tested for its efficacy as a topical drug and has proved successful in treating osteoarthritis and incisional pain in rats. 6 Furthermore, many of its derivatives are used in drugs and thus proves to be an important chemical in chemistry and biology. 4 Felbinac is synthesized from 4-bromophenyl acetic acid, phenylboronic acid, and 10% Pd/C. The balanced chemical equation can be seen in scheme 2. Scheme 2: Chemical equation for synthesis of felbinac The purpose of this experiment is to successfully synthesize felbinac using phenylboronic acid and 4-bromophenylacetic acid through palladium catalyzed Suzuki coupling. At the same time, the efficacy of the green version of Suzuki coupling, which uses distilled water as a solvent and Pd/C as the palladium source, is being tested. The product of this reaction is purified through recrystallization in a 50% water/ 50% 95% ethanol solvent and characterized by melting point, IR, 60 MHz 1 H NMR, 400 MHz 1 H NMR, and 400 MHz 13 C NMR. Experimental 4 3

4 Felbinac. Phenyboronic acid (216.5 mg, 1.78 mmol), sodium bicarbonate (198 mg, 2.36 mmol), 10% Pd/C (11 mg, mmol), and distilled water (10 ml) were added to a 25 ml round bottom flask. The reaction mixture was mixed initially for 8 minutes when it became homogenized. 4-bromophenylacetic acid (121.1mg, mmol) was then added to the reaction mixture. The mixture was then refluxed for one hour and kept below 80 C. The reaction was monitored by TLC (25% ethyl acetate / 75% hexanes) and upon completion, the reaction mixture was removed via vacuum filtration. The ph of the solution was tested using litmus paper and was slightly basic (ph~8-9) after completion of the reaction. 6M HCl (2 ml) was gently added to the reaction mixture to make it acidic (ph~2). The acidic solution, distilled water (10 ml), and ethyl acetate (15mL) were placed in a separatory funnel and the mixture was separated into an organic layer and an aqueous layer. The aqueous layer was reintroduced into the separatory funnel along with ethyl acetate (15mL) and was let to separate again. The total organic layer was dried with anhydrous sodium sulfate. After decanting off the mixture, the remaining solvent was evaporated to yield transparent oil with some visible white flakes (1.65 g). Recrystallization (50% water/ 50% 95% ethanol) afforded pure felbinac as shiny, white, statically charged crystals (12 mg, 10.04%) mp 152 C; 1 H NMR (60 MHz, deuterated acetone) δ (ppm) (m, 4H), (s, 2H); 1 H NMR (400 MHz, deuterated acetone) δ (ppm) 7.66 (d, 2H), 7.62 (d, 2H), 7.46 (d, 3H), 7.42 (2, 2H), 7.36 (t, 1H), (s, 2H); 13 C NMR (400 MHz, deuterated acetone) δ (ppm) , , , , , , , , , ; IR (ATR) ν (cm -1 ) , , , , , ; R f (15 minutes) reaction 0.05, standard 0, co-spot 0.07, (30 minutes) reaction 0.1, 0, standard 0.17, co-spot 0.1, 0, (45 minutes) reaction 0.7, standard 0.17, cospot 0.1, (60 minutes) reaction 0.16, standard 0.2, co-spot 0.2. Results and Discussion This experiment carried out a palladium catalyzed Suzuki coupling reaction to synthesize the compound felbinac from 4-bromophenylacetic acid and phenylboronic acid. The reaction was carried 4

5 out specifically with water and heterogeneous palladium in the form of 10% Pd/C that makes this reaction safe and leaves the product easy to isolate. To start the reaction, phenylboronic acid, sodium bicarbonate, and 10% Pd/C were placed in a 25 ml round bottom flask along with distilled water. This mixture was stirred at room temperature for ten minutes or until it became homogenous. At that point, 4- bromophenylacetic acid was added and the resulting mixture was refluxed for an hour at no more than 80 C. The reaction was monitored by TLC with the mobile phase of 25% ethyl acetate and 75% hexanes. A TLC was run every 15 minutes of the reaction until one hour was reached, so there were a total of four plates. Each plate consisted of a spot for the reaction mixture, a spot for the starting material (4-bromophenylacetic acid), and a co-spot of both those spots. The TLC run at 15 minutes was poorly set up because the standard sample was not spotted enough on the TLC so nothing appeared in that lane. As for the reaction mixture, there was only one spot visible which was most likely the starting material, which had an R f of This was also seen in the co-spot lane with a spot having an R f value of The TLC for the next time slot (30 minutes) revealed progress in the reaction. In the reaction mixture lane, there were two spots representing two different substances in the reaction mixture. One spot had an R f of 0.1, while the other spot had an R f of 0, not yet getting the chance to travel up the TLC plate. Both these spots were of equal intensity. The standard was correctly spotted on the TLC plate this time, and as a result, 4-bromophenylacetic acid could be observed to have an R f of The co-spot lane showed one big spot that is representative of both the product and the reactant being present. The R f values of the spots were 0.1 and 0. Moving on to the 45 minute TLC plate, the reaction lane spot appeared again at an R f of 0.7. The standard lane spot again had its spot higher up on the plate with an R f of For the co-spot lane, only one spot appeared at an R f of 0.1, but the spot was very large and due to smearing. Both the reactant and the product were present in this spot, as expected. Finally for the TLC plate run at 60 minutes, the reaction lane had a spot with an R f of The standard lane had its usual R f of 0.2, and the co-spot had a spot with the same R f of 0.2. Comparing the product (felbinac), and the starting 5

6 material (4-bromophenylacetic acid), the product would travel further up the TLC than the starting material because the aromatic halides of 4-bromophenylacetic acid would make it more polar than felbinac. Given that the mobile phase is mostly non-polar, that means polar substances being run on the TLC will travel less with the mobile phase and have a lower R f. Looking at the spots in the reaction lane mixture from 15 minutes to 45 minutes, there is first a spot around R f =0.1, and then another one that approaches R f =0.2. This signifies the progress of the reaction as the polar reactant is converted into a less polar product. After the reaction ran for an hour, it was isolated by vacuum filtration and the resulting mixture was acidified with 6 M HCl. The reaction mixture is basic due to the addition of sodium bicarbonate at the beginning of the reaction which can be verified by spotting on a litmus paper, with the reaction mixture spot showing up light green. This indicates a slightly basic solution of ph~8. After the addition of HCl, the reaction mixture spotted on the litmus paper came up red, signifying a solution of ph~2. The product was isolated via liquid/liquid extraction by adding the acidified reaction mixture, distilled water, and ethyl acetate to a separatory funnel and was separated based on solubility in the two layers. The reaction was worked up with the acid wash to remove any excess base that may have been in solution so that it would dissolve into the aqueous layer of the separatory funnel. At the same time, the organic product will dissolve into the ethyl acetate because it is an organic solvent, and water is very polar and generally immiscible with organic products. The weight of the crude product is 1.65 g. Once the product was isolated, it was purified via recrystallization. The solvent used for recrystallizing the product was 50% water/50% 95% ethanol. This solvent was prescribed because it the product is partially soluble in this solvent, meaning that it is not soluble at room temperature, but it is soluble at higher temperatures. This is the desired characteristic for a recrystallization solvent because it allows for as many of the products crystals to recrystallize as possible instead of just the ones that are present after the work-up. Furthermore, the recrystallization solution is allowed to cool to room temperature gently. This 6

7 gives the crystals of the product and the crystals of any impurities to congregate with other crystals of the same molecule (whether it s the product or impurities) and as a result, purifies the desired product from the rest of the mother liquor. After allowing the mother liquor to further cool on ice to maximize the recrystallization, the resulting crystals were isolated via vacuum filtration. The crystals were shiny, white, and very statically charged. A total of g of crystal were isolated after they were left to dry over two days. The percent recovery from the recrystallization process was 0.72%, while the percent yield was 10.04%. Both of these values are very low, considering the literature value for percent yield of felbinac is 55-80%. 6 The reason for loss of so much product is that the crystals that were produced were very statically charged and for this reason, were very difficult to remove from the filter paper that they became attached to after vacuum filtration. As for the low percent recovery, the process of recrystallization calls for the loss of some mass because the impurities are gotten rid of, but it is still too low. This again is due to the nature of the statically charged crystals, but may have also been a result of the reaction not running to completion or not exactly at its prescribed temperature of 80 C. There were several methods of characterizing the product to specify and or verify its identity. Figure 1 shows the 60 MHz 1 H NMR spectrum of the product. In the chemical shift range of ppm, there is a multiplet that has an integral value of From the chemical shift range, it is clear that these protons are aromatic hydrogen atoms, yet the integral value of about 4 does not correlate with the structure of felbinac. This will be resolved when looking at the spectrum of the 400 MHz 1 H NMR. Still looking at figure 1, the methyl protons are present at the chemical shift of ppm, with the correct integral value of 2. Finally there is also a solvent peak for deuterated acetone which occurs in the chemical shift range of ppm. There is no peak for the carboxylic acid hydrogen because a deuterated solvent was used which causes an exchange of protons between deuterium and a normal hydrogen proton. 7

8 In order to analyze the product more closely, a 400 MHz 1 H NMR was also run, and is seen in figure 2. Just as in figure 1, there is no O-H peak that should be present from the carboxylic acid of felbinac because of the use of deuterated acetone. In the aromatic region, there is the correct number of protons present. There are five chemically distinct hydrogen atoms in felbinac, and there are five distinct peaks of protons in the aromatic region. At chemical shift 7.66 ppm there is a doublet with an integral value of Next at 7.62 ppm there is another doublet with an integral value of Then there is another triplet at 7.46 ppm with an integral value of At 7.42 ppm, a fourth doublet is present that has an integral value of 1.909, which is also close to 2. Finally there is a triplet at 7.36 ppm with an integral value of In that whole range, the total integral value of those protons adds up to 8.545, which is close to the value of aromatic hydrogen atoms present in felbinac, 9. The methyl protons are present at chemical shift ppm as a singlet with an integral value of 2. Finally, there is the solvent peak at ppm. Given that the aromatic hydrogen atoms were present in both NMR spectra, especially with the correct integral value and splitting patterns in the 400 MHz 1 H NMR spectrum, it has proven that felbinac was indeed synthesized in the reaction. However, more evidenced can be provided with the 400 MHz 13 C NMR spectrum, seen in figure 3. There are a total of 10 chemically distinct carbons in felbinac due to symmetry. To begin, the carbon at ppm is the carbon on the carboxylic acid of felbinac. Carbonyl carbons are found in the ppm range. Next there are 8 peaks packed closely together in the range of ppm. These peaks are the aromatic carbons. While there are 12 aromatic carbons, 4 pairs of these carbons are chemically equivalent, so only one of each pair will count as a peak. This leaves a total of 8 peaks in the aromatic carbon region. The carbon at chemical shift is the aromatic carbon closest to the carboxylic acid group in felbinac because it is being deshielded by the electron withdrawing carboxylic acid group. The next peak at ppm represents the two chemically equivalent carbons that are the next closest to the carboxylic acid substituent of felbinac. At chemical shift ppm is the next 8

9 pair of chemically equivalent carbons that the third closest aromatic carbons to the electron withdrawing substituent. Then at chemical shift ppm is the aromatic carbon that is part of the biaryl bond in felbinac. Its commentary carbon (the carbon on the other aryl that forms the biaryl bond) logically comes next at ppm. Then at ppm there is another pair of chemically equivalent carbons that are on the aryl group not attached to the carboxylic acid substituent. The next pair of carbons follows that same pattern, with its chemical shift being ppm. Lastly of the aromatic carbons is the peak located at chemical shift ppm. This carbon is the furthest from the electron withdrawing capabilities of the carboxylic acid, therefore it will experience the least amount of deshielding and will not shift downfield as severely as all the other aromatic carbons that are closer to the carboxylic acid. Finally, there is the methyl carbon that is in between the benzene ring and the carboxylic acid that is located at ppm. The big peaks located at ppm and ppm are the solvent peaks. The solvent was deuterated acetone, so the peak at ppm is the carbonyl carbon of acetone, while the peaks at ppm are the methyl groups of acetone. There are peaks annotated at ppm and ppm, but they have not proven to represent any possible contaminants, and may just be a part of the noise of the spectrum. IR analysis also proved to be useful in characterizing the product. The IR spectrum is seen in figure 4. The characteristic peaks of felbinac can be found in this spectrum at stretches of cm -1, cm -1, cm -1, cm -1, cm -1, and cm -1. By taking a quick glance at the spectrum, it is clear that the carboxylic acid of felbinac is present because of the large, broad peak located in the ~3000 cm -1. The specific stretch value that the carboxylic acid oxygen hydrogen bond would have in this spectrum is cm -1. Next to that stretch are the stretches for the carbon-hydrogen bond of benzene ring, located at cm -1, and the generic carbon-hydrogen at cm -1. The stretch at is the carbon-oxygen double bond of the carboxylic acid in felbinac. An important stretch that is present is the aromatic carbon-carbon double bond which is at cm -1. Finally, there is the carbon- 9

10 oxygen single bond between the carbonyl carbon and the alcohol oxygen of the carboxylic acid that is present at cm -1. All of the expected stretches of felbinac are present in the IR spectrum, which helps prove the correct identity of the product. One last piece of evidence that helps prove that felbinac was correctly synthesized is measuring its melting point. The measured melting point range from this experiment turned out to be 152 C, while the literature value is C. 7 The melting point for felbinac was therefore slightly depressed indicating the possible presence of a small amount of impurity. However, the melting point was also measured very quickly due to time constraints in the lab, therefore the heating element was set to a very high rate. This can create some error because setting the Melt-Temp device to a high rate will cause the temperature to increase at a speed that is too fast to accurately record exactly when the substance first begins to melt, and when the substance is completely in liquid form. The melting point for the starting material, 4- bromophenylacetic acid, is C, so that piece of data confirms that the starting material was successfully converted into felbinac. 7 Conclusion Given the results of all the characterization data, it is clear that felbinac was successfully synthesized from 4-bromophenyl acetic acid and phenyl boronic acid through a palladium catalyzed Suzuki coupling mechanism. The Suzuki coupling method utilizes an aryl halide and a boronic acid, along with a palladium catalyst and under basic conditions, to form a new carbon-carbon bond. Older methods of Suzuki coupling involve the use of palladium through PdCl 2 or Pd(OAc) 2 that will consequently generate pure palladium in situ. However, new green methods of Suzuki coupling can accomplish the same goal while using distilled water and Pd/C instead, which are both safer alternatives. This was the method used in this experiment to generate felbinac. The reaction was run successfully, and recrystallization isolated a pure product with potentially minor impurities. The percent recovery was 0.72%, while the percent yield was 10.04% which are both very low values. Part of the reason for the 10

11 low percent recovery is the inherent concept of recrystallization which removes the mass of impurities from the crude product. However, a lot of the crystals were also lost after recrystallization because they were very statically charged. This made it very difficult to remove all of the crystals from the filter paper that they were attached to during vacuum filtration. This is the same reason for a low percent yield. But, there could have been other sources for error such as not running the reaction at the correct temperature of 80 C. The 400 MHz 1 H NMR spectrum (figure 2) showed the presence of the 9 aromatic protons of felbinac in the chemical shift range of ppm, along with the methyl protons located at ppm. In figure 3, the 400 MHz 13 C NMR proved the presence of the 10 chemically distinct carbons. The carboxylic acid carbon was located at ppm, and the methyl carbon of the acetic acid substituent was found at ppm. In the range of ppm, there were 8 chemically distinct carbons that represented the 12 carbons of the two benzene rings. There were two peaks located at ppm and ppm that were annotated as carbon peaks, but may in fact just be noise. If not, then they may represent a contaminant in product of felbinac, but it is unclear as to what it may be. The IR spectrum (figure 4) contains stretches of all the key bonds in felbinac. The stretch at cm -1 indicates the presence of a benzene carbon-hydrogen bond. There is a stretch for the carbonhydrogen bond at cm -1. Next there is a stretch at cm -1 that is indicative of an oxygenhydrogen bond from a carboxylic acid. Also from the carboxylic acid, there is the carbon-oxygen double bond stretch located at cm -1. The stretch at cm -1 represents the carbon-carbon double bond from a benzene ring. Finally the stretch at cm -1 is the carbon-oxygen single bond in a carboxylic acid. To wrap all the data together, the melting point range for the synthesized product was 152 C. This value is much closer to the literature value of felbinac ( C) than that of its reactants, 4- bromophenylacetic acid, and phenylboronic acid ( C and C, respectively). Felbinac has many uses, most of which revolve around the pharmaceutical industry. Specifically, their use in pain killers has been popular and is expanding from just being taken orally to topical 11

12 applications as well. Many of its derivatives are involved in other medicines as well. Therefore, it is important that this compound can be synthesized and isolated correctly. References (1) Hu, M.; An, Z.; Du, W.; Li, J.; Gao, A.; Chinese Journal of Chemistry, 2007, 25, (2) Aktoudianakanis, E.; Chan, E.; Edward, A. R.; Jarosz, I.; Lee, V.; Mui, L.; Thatipamala, S. S.; Dicks, A. P.; J. Chem. Educ. 2008, 85, (3) Miyaura, N.; Suzuki, A.; Chem. Commun. 1979, 95, (4) Rummel, Sheryl A; Ed. Experiment 65: Palladium Catalyzed Suzuki Coupling. Lab Guide for Chemistry 213 (Introductory Organic Chemistry Laboratory); Hayden-McNeil: Plymouth, MI, 2013 (5) Eissen, M.; Mazur, R.; Quebbemann, H.; Pennemann, K.; Helvetica Chimica Acta, 2004, 87, (6) Shinkai, N.; Korenaga, K.; Takizawa, H.; Mizu, H.; Yamauchi, H.; J. Pharm. Pharmacol.2008, 60, (7) Sigma-Aldrich, (accessed November 15, 2013) 12