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Synthesis of esters has played a significant role in Organic chemistry since its infancy. The importance lies in the utility of esters both in laboratory field and industry field. In laboratory esters are important sources of corresponding amides. Also esters can be used to product ketones and aldehydes. The essential feature of esterification reaction lies in its broad utilization in industry . Esters ranging from aliphatic to aromatic are generally used as plasticizers, solvents, perfumes, and flavor chemicals and also as precursors for pharmaceuticals, agrochemicals and fine chemicals. However, Fischer Esterification is not a perfect reaction in the industry field. The use of traditional acidic catalyst such as sulfuric acid will cause side reactions and corrosion of equipment and require removal large amount of salt waste during neutralization of acid.1 Recently a new type of acid catalyst called ionic liquid was invented to overcome the problem.1 Esters generally have low melting point and low boiling point .Since esters lack hydrogen-bond donating hydrogen , the intermolecular force between the ester molecules are very week. Many esters have aroma and this property has been used in production of essence. Benzocaine is a white solid which is generally used as a external- used anesthetic. For example, it can be used to relive pain due to the oral injection.2 It can also be used to anesthetize fresh- water fish 3 . In this experiment, benzocaine will be synthesized by Fischer Esterification of p-aminobenzoic acid with ethanol in an acidic condition. The mechanism of this reaction is involved in several steps. First, the starting material p-aminobenzoic acid is activated by protonation of carbonyl oxygen. Second, the tetrahedral intermediate is formed by nucleophilic attack of ethanol on the p-aminobenzoic acid. In the third step transfer of a proton from one oxygen atom to another yields a second tetrahedral intermediate and converts the Hydroxyl group into a good leaving group. Finally, the loss of a proton from oxygen and expulsion of water regenerates the acid catalyst and gives the ester product benzocaine.
Figure 1: Formation of bezocaine from p-aminobenzoic acid
The purpose of this experiment is to synthesis benzocaine by Fischer Esterification. Refluxing method to the reaction mixture will be used in the experiment in order to proceed the esterification reaction without decreasing the amount of solvent. To precipitate the product from solution, the PH of reaction mixture is made to eight. The product will be isolated by vacuum filtration and washed by distilled water. 60 MHz analysis were applied to identify the compound. IR, GC ,GC-MS and melting point
4-aminobenzoic acid ( 0.12g ,0.8759mmol) and absolute alcohol (1.5ml) were combined and heated in a sand bath until all the solid dissolved. After it cooled to room temperature, 0.2 ml of concentrated sulfuric acid (12M) were added dropwise to the mixture. The reaction mixture was then refluxed for about 60 to 75 minutes at 50 .Upon the completion of reaction, saturated
sodium bicarbonate (1M) was added dropwise until the pH of solution was around 8 . The PH of solution was monitored by the PH paper. During the process of adding sodium bicarbonate, white precipitate of benzocaine formed. The reaction mixture was then vacuum filtrated to give benzocaine as white crystals(71 mg, 49.125% yield). Mp : 84-88 (lit:88-90 ); 60MHZ
(DMSO-d6) δ (ppm): 1.286 (t, 3H), 4.04-4.394(q, 2H) , 5.859(s,2H) 6.511-6.698(m,2H) 7.553-7.739(m, 2H). IR (ATR) ν (cm-1): 3419.2, 3338 3220.9 1679.9; GC( dichloromethane 40 to 250 at 10 at 10 per min) RT 1.53minutes, 18.63 minutes. GC-MS (dichloromethane 40
per min) : RT:18.94minutes; m/z:165.
The Fischer Esterification reaction proceeded without any notable chemical issues. The precipitation of product from the solution and the vacuum filtration were also successful. The percentage yield of the reaction is 49.1%. The yield cannot be considered poor because the Fischer Esterification is a reversible reaction under acidic condition. It’s impossible to run this reaction completely Although the refluxing process lasted about an hour, the refluxing process only extends the reaction time without proceeding the reaction. Different from the technique of distillation, the fractions of mixture are not removed in the refluxing process. Because the product benzocaine is not removed from the mixture, the concentration of product increases during the whole process of the reaction. The decreasing concentration of starting material paminobenzoic acid and increasing concentration of product benzocaine impedes the reaction from moving to the forward direction. The longer the reaction takes place, less and less products will form.
The IR Spectrum of the product shows N-H stretches in the predicted range, with two peaks at 3419.2 and 3338 , which suggest that the product contains a primary amine
group. The stretch at 3220.9 peaks around 2900 peak at 1679.9
indicates the C-H stretch of benzene ring while very weak
stand for the C-H stretches of methyl group. The intense and strong suggests the existence of C=O stretch of carbonyl group. As it is mentioned
before, the yield of this reaction is only 49%. A lot of starting material remain with the products. But it does not show up in the IR spectrum. No O-H stretch around 3550-2500 means no
carboxylic acid exists in the sample. The reason lies in the difference of solubility between two compounds in the basic environment. The starting material, p-aminobenzoic acid, is very soluble in the basic solution when it is deprotonated by the base and forms the water-soluble carboxylate anion. On the other hand, the benzocaine lacks the acidic protons and cannot be deprotonated by the base. Since final pH of the solution was made to 8, all the starting material exist as an anion rather than the solid. And when the reaction mixture was filtrated , the products can be isolated from starting material. The NMR spectrum of the product shows 4 peaks that integrate to 2 protons each and one peak that integrate to 3 protons. The two doublets, 7.553 ppm -7.739ppm and 6.511ppm – 6.698ppm indicate a para-substituted benzene ring. The peaks form 7.553 ppm to 7.739ppm should represent the the benzene protons that are near the amine group while the peaks from 6.511ppm -6.698ppm represent the aromatic protons which are close to the ester group. Because the amine group is an electron-donating activating group while the ester group is an electronwithdrawing deactivating group. The ester group is more electronegative than amine group. Any protons near electronegative groups will have higher chemical shift. The single- split peak at 5.942 ppm indicates the presence of the amine protons. The - protons next to the ester group
appear from4.04ppm to 4.394ppm expected for protons on carbon near an unsaturated center and their signal is split into quartet by coupling with the protons of neighboring methyl group. The methyl protons appear as triplet at 1.286ppm in the usual upfield region. All of these peaks mentioned above match very well with the expecting shifts and splitting pattern for benzocaine.
There are 2 impurity peaks and one solvent peak in the NMR spectrum. The peak from 2.462ppm from 2.556 ppm is due to the solvent-DMSO D6. As the NMR tube is not dried thoroughly , some acetone which is used to wash the NMR tube does not evaporate completely. The remaining acetone show up at 2.106 ppm in the spectrum . The other impurity at 3.352ppm cannot be identified. It neither came from starting material nor came from the solvent. It probably came from the residue in the NMR tube because neither IR or GC-MS supplies any information of this peak.
The melting point of the isolated product is 84-88C which matches well with the literature value 88-90
Though the measured data is a little bit lower than the literature value,
the result is acceptable as vacuum evaporation is not perfect separation method. Trace amounts of Sodium Bicarbonate may affect the melting point of product. A mixed melting point test can be performed to further confirm the identity of Benzocaine. The GC data only showed one peak at 18.63 min except the solvent peat at 1.53 min. It further suggests the purity of isolated Benzocaine. Because the identity cannot be judged from GC data, a GC-MS test was also run. It also showed one peak. And the mass spectrum for that peak showed the parent ion at a m/z ratio of 165 which matches the expected values of 165.19 which is the molecular weight of product.
IR NMR GC GC-MS and melting point test all confirmed the identity of final Benzocaine product as a pure compound, free from starting material or any by-product. The percentage yield of product was 49%. The yield is quite reasonable as the fischer esterification is a reversible reaction. Temperature , concentration of products and reactants and even pressure will affect the extent of reaction.
1. Volume 234, Issues 1–2, 14 June 2005, Pages 107–110 2. Anesth Prog. 2003; 50(4): Pages 159–163. a b c 3. Volume 53 Issue2 1991 Philip A. Gilderhus , Carol A. Lemm & L. Curry Woods III pages
105-107 4. David Woolfson and Dermot Mccafferty. Percutaneous Local Anesthesia. Page 66. Edited by Ellis Horwood Limited in 1993.
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