Nucleophilic Acyl Substitution: The Synthesis of Ethyl Butanoate

Ruther Harvey Idiong-Cabral Institute of Biology, University of the Philippines, Diliman, Quezon City 1101 Philippines Date Performed: 15 August 2013; Date Submitted: 3 September 2013 Esters are a class of compounds that are abundant in nature, most of which have very fragrant odors. To synthesize such substances, a carboxylic acid and an alcohol must react, in the presence of an acid catalyst, in a type of nucleophilic acyl substitution called a Fischer esterification reaction. In this experiment, 7.2 mL of ethyl butanoate was synthesized from ethanol and butyric acid with a 60.54% yield. To improve the yield of the experiment, more accurate materials and better techniques were recommended. Introduction When a nucleophile is added to a carboxylic acid and its derivatives, the initially formed alkoxide ion intermediate will eliminate one of the previous substituents of the carbon, leading to a net substitution reaction (Figure 1). This reaction is more known as nucleophilic acyl substitution1.
O Nu R
2 -

nucleophilic acyl substitution. This is called a Fischer esterification, or simply esterification3. In this experiment, ethyl butanoate was synthesized via esterification of ethanol and butyric acid (Figure 2).
O H3C OH O

+ H3C

OH H3C O CH3

Figure 2. The overall reaction between butyric acid and ethanol

O Nu

R R

Experimental Details
R Nu

Figure 1. General mechanism of nucleophilic acyl substitution Direct nucleophilic acyl substitution of carboxylic acids is hard to do in the laboratory since OH is not a good leaving group. It is usually necessary to enhance the reactivity of the acid, but under right circumstances, carboxylic acid derivatives can be prepared from nucleophilic acyl substitutions1. One of the more useful applications of nucleophilic acyl substitutions in carboxylic acids is preparing esters1. Simple esters can be observed to have very fragrant odors. Many, but not all, characteristic odors of flowers and fruits are due to the presence of an ester group2. Esters can be prepared with a carboxylic acid and an alcohol, via

To synthesize ethyl butanoate, 8.28 mL of butyric acid and 5.28 mL of ethanol was used and poured into a 25-mL round bottom flask. A few drops of concentrated sulfuric acid were also added into the mixture. The solution was then heated using a reflux set-up (Figure 3). After refluxing, the mixture was cooled to room temperature, and placed into a 30-mL separatory funnel. The reaction flask from earlier was washed with cold water and the washings were added into the separatory funnel. This was done until the aqueous layer was twice the volume of the organic layer. The funnel was shaken, and the layers were then allowed to stratify. Saturated NaCl was added to hasten the separation, and solid NaHCO3 was added to remove excess acid. The organic layer was collected and dried using anhydrous

Na2SO4. The crude ester was transferred to a vial and submitted to the instructor.

OH C
+

OH

OH OH R OH

+R

OH

R OH R' OH R' O Figure 5. Addition of ROH and loss of H+ from the ROH

The next step of the mechanism protonates an OH group and yields a second tetrahedral intermediate (Figure 6)1.
OH R R' O OH

H+
R R'

OH OH2 O
+

Figure 3. A reflux set-up Results and Discussion In the first part of the experiment, ethanol and butyric acid react will each other via Fischer esterification reaction, which was named after the German chemist, Emil Fischer4. The mechanism of an esterification reaction presents a series of protonations and deprotonations, along with an addition, then an elimination step3. The first step of the mechanism includes protonating the carbonyl group of the carboxylic acid. This resulting intermediate is pretty stable due to the presence of resonance structures (Figure 4)3.
O OH
+

Figure 6. Protonation of an OH group The previous protonation makes the OH group a better leaving group. In the final step, the OH group leaves as water and another deprotonation takes place. The final product of the reaction will be the ester (Figure 7).
OH R R' O
+ OH2

-H2O
R

O C
+

-H+
R

R' O

OR'

Figure 7. Removal of water and deprotonation The mechanism of esterification illustrates the general pattern of other substitution reactions of carboxylic acids. As illustrated above, substitutions in the carbonyl carbon, or nucleophilic acyl substitutions, involves an addition to the carbonyl group followed by an elimination4. It is also important to note that this reaction is reversible1. Esterification, however, is a very slow process. An acid catalyst is used to increase the rate of the reaction. The acid also supplies the necessary proton to start the reaction, as seen in Figure 4. Because of this, the reaction is also often called as an acid-catalyzed esterification5. In the experiment, concentrated sulfuric acid (H2SO4) was used as the catalyst.

H+
OH R

OH C
+

OH

OH

OH

H3C

OH

Figure 4. Protonation of the carbonyl group, with resonance structures After the protonation, the alcohol attacks the carbonyl carbon, since it is weakly nucleophilic, deprotonating the alcohol in the process3. This forms a tetrahedral intermediate (Figure 5)1.

Esterification also needs heat to make the reaction faster, thus in the experiment, the mixture was heated5. As mentioned earlier, the reaction is reversible, and thus, the reaction must occur in equilibrium. The equilibrium constant (K) of the reaction can be expressed by the concentration of the reactants and products3. [ ][ ] [ ][ ] Figure 8. The equilibrium equation of a Fischer esterification reaction Because of this equilibrium, if the molar ratio of alcohol to carboxylic acid is 1:1, the highest possible yield of the ester is 67%. If the objective of the experiment is to produce esters, then it would seem impractical to synthesize it and expecting a relatively smaller yield3. This problem can easily be solved by shifting the equilibrium, as explained in Le Chateliers principle. It is said that if we add more reactants, the equilibrium will shift to produce more products and vice versa5. To increase the yield of the ester, it is possible to use one of the reactants (typically the cheaper one) in excess. This will lead to production of more of the product. It is also important that the reactants, including ethanol, used should be pure and void of water, since the presence of more water will shift the equilibrium to produce more reactants3. Another technique that can be used to improve the yield of ester includes removing water as it is formed by azeotropic distillation. This technique also includes recycling the solvent, making it more efficient. However, a Dean-Stark trap is needed by the technique6. In this experiment, an excess of 0.3 mL of alcohol was used, making the butyric acid the limiting reagent. This excess will now favor the production of more products. As noted above, esterification needs heat, but most of its reactants are highly volatile and will likely escape in a typical water bath. This will definitely shift the

equilibrium of the reaction. To avoid this, a reflux setup (Figure 3) was used. The cooling water in the condenser will condense any escaping vapors, and thus keep the equilibrium of the reaction 2. After refluxing, the mixture will most likely contain ethyl butanoate, unreacted butyric acid, unreacted ethanol, sulfuric acid and some unwanted by-products. To remove the excess reactants and catalyst, the mixture was poured in a separatory funnel and washed with water. The ethanol will most likely dissolve in water, due to H-bonding. Solid NaHCO3 was added to react with the unreacted acids, which will produce salts. The salts will then dissolve in water. Addition of NaHCO3 is also efficient in signalling the presence of acids in the mixture, since its reaction (Figure 9) with acids produces carbon dioxide, a gas. Thus, if bubbles can still be seen in the mixture, unreacted acids are still present5.

Figure 9. Reaction of sodium bicarbonate with sulfuric acid After separation, the organic layer was then dried using anhydrous Na2SO4. This reagent removes any substance with an unhindered O-atom, including water. This is another way to purify the product5. After drying, the amount of crude ethyl butanoate was measured using a graduated cylinder. The experiment yielded 7.2 mL of crude ethyl butanoate. After calculations, this would lead to a 60.54% yield. This, however, is not the actual yield, since the product is still crude. As with all experiments, errors may have been present, which may have affected the yield of the experiment. Water may have been present in the reagents, which could have shifted the equilibrium leading to a smaller yield. There may have been unnecessary water present in the instruments used in the experiment, which also could have shifted the

equilibrium. The water used in the condenser may not be cold enough to effectively condense all vapor, which can also upset the equilibrium of the reaction. It was also observed that after drying the crude product, the solution became light orange, which could indicate the presence of dyes in the mixture. Also, the instruments used in measuring the reagents may not be as accurate as intended, which also could lead in errors. The conditions in which the experiment was done, including temperature and humidity, may have affected the outcome of the experiment. Conclusion To conclude, the objectives of the experiment were achieved. An ester, ethyl butanoate was synthesized using ethanol and butyric acid as the reactants. The principles behind the experiment were also discussed. Even though only 7.2 mL and 60.54% yield of ethyl butanoate was produced, the experiment can still be considered a success, since the objectives were attained. For future experiments, it is recommended to use more accurate and precise instruments. Other techniques can also be explored, including the azeotropic distillation, for use in the experiment. Other reagents which can yield other esters may also be used for the experiment. References [1] McMurry, J. Organic Chemistry, 8th ed. ; Brooks/Cole: Belmont, CA, 2012; pp. 818-819; 824-825. Pavia, D.L. Introduction to Organic Laboratory Techniques: A Contemporary Approach; Saunders College: Philadelphia, PA, 1982; pp. 83-85; 469-470. Fessenden, R.J., and Fessenden, J.S. Techniques and Experiments for Organic Chemistry; Willard Grant Press: Boston, MA, 1983; pp. 294295. Loudon, G.M. Organic Chemistry, 3rd ed.; The Benjamin/Cummings

[5]

[6]

Publishing Company, Inc.: Redwood City, CA, 1995; pp. 946-949. Lehman, J.W. Operational Organic Chemistry: A Laboratory Course, 2nd ed.; Allyn and Bacon, Inc.: Needham Heights, MA., 1988; pp. 348-354. Puterbaugh, W.H., Vanselow, C.H., Nelson, K., Shrawder, E.J. Esterification for the Introductory Organic Laboratory Course: A Modified Dean-Stark Trap. Journal of Chemical Education 40(7); 1963; pp. 349-350.

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