Benzocaine Synthesis

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  • 1. I. Introduction Esters are important compounds in organic chemistry. They are used in numerous types ofsynthetic reactions, to create different products for a vast array of purposes, including medicinaland cosmetic. To produce an ester, one can utilize an esterification reaction. In particular, theFischer Esterification reaction was used in this lab to turn a carboxylic acid into an esterbenzocaine. Esters are used in a wide range of fields, including the medical, cosmetology and fuelsindustry. For instance, biodiesel fuel is an alternative fuel source that is composed mainly ofmonoalkyl esters from vegetable oil or animal fats (1). Green, alternative energy sources arehighly sought after in the increasingly global economy, which brings high importance toperfecting the synthesis of esters that can contribute to this. Other esters are used for their strongfruity smells in cosmetology for perfumes, while still others are used as flavor additives in foods.Benzocaine is an ester that has been used in the medical industry as a local anasethetic fordecades. Some contribute the use of benzocaine as an anesthetic to cause methemoglobinemia,which is a negative disorder that is caused by high levels of methemglobin in the blood. A casehas been documented of an 83 year old man who was diagnosed with methemoglobinemia andhad symptoms of cyanosis and cardiovascular instability after benzocaine was used as the localanesthetic for a surgery. This was considered an extreme case however, and benzocaine is stillused as a local anesthetic, and for commercial nasal and throat sprays for its numbing effect (2).Benzocaine is also used to dilute or “cut” illegal cocaine due to its similar appearance, andavailability (3). 1
  • 2. The mechanism of the Fischer Esterification that was utilized to produce benzocaine is verystraightforward carbonyl chemistry. It begins with the carbonyl oxygen of a carboxylic acidbeing protonated by the catalytic sulfuric acid. Once the double bond is broken, the lone pair ofthe ethanol oxygen backside attacks the carbonyl carbon, forming the classic tetrahedralintermediate. The oxygen of the new ethanol substituent has a positive charge; this causes thelone pairs of the sulfuric acid to attack the hydrogen of the ethanol. Next, the lone pairs on thehydroxyl group attack a hydrogen atom from sulfuric acid, forming water, a quality leavinggroup. The lone pairs on the remaining hydroxyl group swing down to form a double bond withcarbon and displace the water. The sulfuric acid then relieves the double bonded oxygen of theextra hydrogen and its unwanted positive charge. The final product is benzocaine, an ester.Figure 1: Fischer Esterification Mechanism of the Formation of Benzocaine 2
  • 3. The purpose of this lab is to synthesize benzocaine, an ester, from p-aminobenzoic acid, acarboxylic acid, by Fischer Esterification. This is a common mechanism in organic chemistry,and its mastery is important in learning how carbonyl compounds behave. P-aminobenzoic acidwill be combined with ethanol and sulfuric acid in a reflux reaction to yield the desired product.This product with then be analyzed by melting point, NMR, IR, and GC-MS to confirm itsidentity as benzocaine. A percent yield will be calculated to determine how much benzocainewas produced in lab, in comparison to how much was physically possible to synthesize. II. ExperimentalBenzocaine. P-aminobenzoic acid (119mg) and absolute ethanol (1.5mL) were added to amicroscale reaction tube and heated with a sandbath until dissolved. The mixture was thencooled with ice and concentrated sulfuric acid (0.20mg) was added dropwise. An air condenserwas used to reflux the reaction for one hour. The reaction mixture was then cooled to roomtemperature. The reaction mixture was transferred via Pasteur pipet to a 10-mL Erlenmeyerflask. Distilled water (3mL) was added. 1M sodium bicarbonate (3mL) was added dropwise;the reaction mixture was agitated after each addition. The pH was monitored until the reactionwas sufficiently neutral (pH 8). A Hirsch funnel was then used in vacuum filtration to isolate theproduct. Crystals were washed with cold distilled water (3x 1mL). White, flaky crystals(85.8%) were dried over night. Melting Point : 88-89⁰C.Chemical Shift Splitting Pattern Integral Value1.263 ppm Triplet 34.140 ppm Quartet 25.927 ppm Singlet 2 3
  • 4. 6.484 ppm Doublet 27.568 ppm Doublet 2Figure 2: 1H NMR (60 MHz, CDCl3 ) for BenzocaineFunctional Group Absorption Frequency (cm-1)N-H 3419.0C-H for C6H6 3219.4C=O for ester 1679.2Figure 3: IR (ATR) for BenzocaineComponent RT M/Z Percent CompositionBenzocaine 18.94 165.0 100.00%Figure 4: GC-MS for BenzocaineIII. Results and Discussions Fischer Esterification was used to synthesize benzocaine from p-aminobenzoic acid, orPABA. PABA was combined with excess absolute ethanol and catalytic sulfuric acid and wasallowed to reflux for over an hour. Sodium bicarbonate was then added to neutralize the excessacid. The benzocaine crystals were then vacuum filtrated and washed with cold water tomaximize yield and were allowed to dry overnight. Once dry, the crystals were analyzed bymelting point, NMR, IR, GC-MS, and a percent yield was calculated. The theoretical yield of benzocaine was 144.5mg of product. The actual yield was124.0mg, giving a percent yield of 85.8%. This is a high percent yield, indicating a successfulsynthesis. The melting point recorded in lab was 88-89⁰C; this is very close to the literaturevalue of 88-90⁰C. This accuracy in melting point indicates a pure product. Impurities in the 4
  • 5. benzocaine product would depress the melting point, and cause a wider melting point range. Theshort range and accuracy implies a successful synthesis. NMR was also used to analyze the product synthesized in lab. Five different peaksappeared in the NMR spectra of benzocaine (Figure 2, Supplemental Data), correlating to fivedifferent sets of chemically different protons. The first peak at 1.146ppm with an integral valueof three displayed the protons at the end of the ethyl group bonded to the non-carbonyl oxygen ofthe ester as a triplet. Because these hydrogen atoms are the farthest from the electronwithdrawing oxygen atoms, it makes sense that they would have the lowest chemical shift, andsuffer the most shielding of all the protons of the molecule. The next peak, a quartet, at4.140ppm corresponds to the hydrogen atoms on the carbon bonded to the non-carbonyl oxygenatom of the ester. This CH2 group has less shielding than the aforementioned CH3 group, andthus a higher chemical shift because it is closer to the oxygen atoms of the compound. The thirdpeak at 5.927ppm displays the two hydrogen atoms bonded to the amine substituent on thebenzyl functional group. These protons are deshielded by the nitrogen atom, but are not asshifted as far as the next two peaks because they are so far from the oxygen atoms of the ester.The next peak, a doublet with a chemical shift of 6.48ppm shows the symmetrical hydrogenatoms on the benzene ring closest to the ester substituent. These two protons are shifted so fardown due to the deshielding caused by the ester and the amine substituents. The final peak at7.568ppm is a doublet that shows the two symmetrical protons on the benzene ring closest to theamine group. These protons are close enough to the carbonyl ester and the amine to bedeshielded the most and to have the highest chemical shift. This NMR spectrum accounted tofor all the protons benzocaine should have, with peaks that had chemical shifts that made sense,indicating that it indeed was representing benzocaine. 5
  • 6. IR was also a useful mode of analysis for the final results of the reaction. Severalimportant peaks in the IR spectrum of benzocaine (Figure 3, Supplemental Data) were used toidentify the product as benzocaine. A short sharp spike at 3419.0cm-1 indicates the presence of anitrogen-hydrogen bond on the molecule, which corresponds to the structure of benzocaine. Apeak at 1679.2cm-1 shows the ester group of benzocaine. An alcohol spike did not appear at3500cm-1, which indicates the starting material, p-aminobenzoic acid, which has the OH groupon the carboxylic acid, was not present in the IR sample. This shows that the reactionsuccessfully went to completion. GC-MS was also used to analyze the crystals produced in lab. Only one peak waspresent in the GC-MS chromatogram (Figure 4, Supplemental Data). A peak appeared at 18.94minutes; this corresponded to the peak on mass spectrum that had a value of 165.0m/z. This isexactly the molecular weight of benzocaine, which indicates that this is what was in the crystalsproduced in lab. Other ions of benzocaine were present in the mass spectrum, including a peakat 150.12m/z, which displays the ion of benzocaine that is missing the nitrogen group off of thebenzene ring. Another peak in the mass spectrum was at 91.95m/z, which displays the ion that islacking the ester group on the benzene ring. All of these molecular weight values line up withwhat the weight of the ion would be if it was missing said functional groups. This indicates thatthe GC-MS does indeed depict benzocaine, the desired product of the Fischer Esterificationreaction.IV. Conclusion Fischer Esterification was used as a means to synthesize benzocaine, an ester, from p-aminobenzoic acid, a carboxylic acid. This is done by adding excess alcohol, in this case 6
  • 7. ethanol, and catalytic sulfuric acid. The reaction takes place as a reflux, and yields large, whiteand flaky crystals. These crystals are the benzocaine product, and their identity was confirmedby melting point, NMR, IR, and GC-MS analysis. These techniques all gave confirming resultsthat the crystals produced in lab were the desired benzocaine product. 7
  • 8. V. References(1) Wang, P.S.; Tat, M.E.; Gerpen J.V. The Production of Fatty Acid Isopropyl Esters and theirUse as a Diesel Engine Fuel. Journal of the American Oil Chemist’s Society. Springer, 2011.Volume 82, Number 11, 845-849.(2) Rodriguez, L.F.; Smolik, L.M.; Zbehlik, A.J. Benzocaine-induced Methemoglobinemia. TheAnnals of Pharmacotherapy. Harvey Whitney Books Company, 2012. Volume 28, Number 5,643-649.(3) Freye, E.; Levy, J.V. Pharmacology, and Abuse of Cocaine, Amphetamines, Ecstasy, andRelated Designer Drugs. Springer, 2009. 36. (4) Rummel, S.A. Lab Guide for Chemistry 213: Introductory Organic Chemistry Lab. Hayden, McNeil, 2011, pgs 65-82, 295-308. 8