Nucleophilic Acyl Substitution: The Synthesis of Esters
Jose Sandino A. Bandonil Institute of Chemistry, University of the Philippines, Diliman, Quezon City 16 October 2014 30 October 2014
Abstract Esters are compounds belonging to a group known as carboxylic acid derivatives, also known as acyl compounds, due to their resemblance to carboxylic acids. Several reactions may be done in the production of esters, including a bimolecular substitution reaction between a carboxylate and an alkyl halide, and a base-catalysed reaction between an acid chloride and an alcohol. In the study, a reversible acid catalysed nucleophilic acyl substitution, known as Fischer esterification, was done. Butyric acid was reacted with ethanol in the presence of sulphuric acid and heat to produce ethyl butyrate, an ester with pineapple-like smell. 4.78 mL crude ethyl butyrate was produced. The reaction was driven forward through addition of excess alcohol and the use of absolute ethanol.
I. Introduction Esters are a group of compounds belonging to a larger grouping of functional groups known as acyl compounds, or carboxylic acid derivatives due to their resemblance to the structure of a carboxylic acid (Figure 1). They are characterised by an oxygen doubly bonded and an R and OR group singly bonded to a carbon. Known for their pleasant odour, esters have been used in the manufacture of synthetic flavours (Solomons & Fryhle, 2011).
Figure 1. A comparison between carboxylic acid structure and ester structure.
Esters can be prepared through several methods, including the bimolecular substitution reaction (S N2) between a carboxylate ion and a primary alkyl halide, or treatment of an acid chloride by an alcohol in presence of a base. Another method, the Fischer esterification (Figure 2), involves a reversible nucleophilic acyl substitution reaction between an alcohol and a carboxylic acid, catalysed by the presence of a strong acid ac id and heat (McMurry, 2004).
react ion. Figure 2. The Fischer esterification reaction. Nucleophilic acyl substitution is a slightly modified unimolecular nucleophilic substitution reaction. It involves an addition reaction performed through the attack of a nucleophile on the electron deficient carbon of an acyl derivative; this causes the formation of an unstable intermediate. The intermediate is decomposed in an elimination reaction, forming the final product: another acyl derivative (Ouellette & Rawn, 1996). II. Methodology In performing the esterification reaction, 5.00 millilitres of ethanol (CH3CH2COOH) and 6.00 millilitres of butyric acid (CH 3(CH2)2COOH) (Figure 3) was mixed in a 25 mL round bottom flask; boiling chips were added. 2-3 drops of concentrated sulphuric acid was added to the flask while swirling. The mixture was subjected to reflux distillation for 60 minutes.
Figure 3. The structures of the reagents of esterification ethanol and butyric acid.
After cooling the refluxed mixture to room temperature, it was transferred to a 30 mL separatory funnel. The reaction flask was rinsed with cold water, with the washings being added to the separatory funnel. This was repeated until the aqueous layer was twice the volume of the organic layer. The mixture was swirled and allowed to stratify, as a sodium chloride solution was added to facilitate separation. After separation, the aqueous layer was removed. Fresh cold distilled water was added to the remaining organic layer and allowed to stratify, with an NaCl solution again facilitating the separation. This was repeated thrice. Before the removal of the third washing’s aqueous layer, solid sodium bicarbonate was added to the flask until effervescence is not observed.
protonated intermediate then loses water to form a protonated form of the ester. The ester is finally formed after the deprotonation of the species through the loss of a hydrogen to the alcohol (Carey & Giuliano, 2011). The reaction is acid catalysed with concentrated sulphuric acid to attain equilibrium in a few hours, as non-acid catalysed Fischer esterification only achieves esterification of after a reflux period of several days (Furniss et. al., 1989). However, Fischer esterification is relatively difficult for the preparation of sterically hindered esters; instead, the alkylation of carboxylate salts with simple alkyl halides may be utilised, with anion exchange resins used as biphase or triphased catalysts (Moore et. al., 1979).
The organic layer of the third washing was transferred to a 25 mL Erlenmeyer flask and dried with anhydrous sodium sulphate until the drying agent stops clumping in the mixture. The volume of the resulting ester was measured. III. Results and Discussion 4.78 millilitres of the final product ethyl butyrate (CH3(CH2)2COOCH2CH3), equivalent to 65.30 mmol, was produced from the esterification of 6 mL (65.30 mmol) butyric acid with 5 mL (85.63 mmol) ethanol. A strong pineapple smell can be detected from the ester. The theoretical product of the reaction was computed to be around 8.63 mL of the ester product.
In producing the ether product, butyric acid and ethanol went through the Fisher esterification, in a six-step acid catalysed nucleophilic acyl substitution reaction (Figure 4) that occurs in two stages: the formation of a tetrahedral intermediate, followed by the production of the ester. The first step involves the protonation of the carbonyl oxygen of the carboxylic acid by a hydrogen from the protonated alcohol. The protonation increases the reactivity of the carbonyl group, allowing the alcohol to bind with the carbonyl oxygen through nucleophilic addition and form an oxonium ion in the second reaction step. A proton is lost by the oxonium ion to an alcohol, forming the tetrahedral intermediate of the first stage. For the second stage, the tetrahedral intermediate is protonated on one of the hydroxyl oxygens. The
Figure 4. The Fischer esterification process between ethanol and butyric acid, forming ethyl butyrate.
The reaction is a reversible one, with rate constant affected by the equilibrium concentrations of ethyl butyrate, water, ethanol, and butyric acid (1). Thus, the Le Chatelier principle is used in driving the reaction forward to ensure its completion.
It has been shown that the use of equimolar starting quantities for carboxylic acid and alcohol leave 0.335 mol free acid upon reaching equilibrium. Thus, to increase ester yield by Le Chatelier’s principle, unequal carboxylic acid or alcohol concentr ations are
used in the start of the reaction. Reacting either chemicals in excess give the same result. The endothermic nature of the reaction also allows for the use of heat in speeding up the process (MacKenzie, 1962). The continuous removal of water during the reaction may also be done to increase ester yield, through azeotropic distillation in a Dean and Stark water separation unit (Furniss et. al., 1989). For this study, the former method was performed, with ethanol used in excess and butyric acid acting as the limiting reagent. Another way to increase ester yield is to remove or minimise the amount of water at the start of the reaction (Moore & Dalrymple, 1976). Absolute ethanol was used as the starting reagent instead of 95% ethanol to prevent the addition of water . After completing the reaction, the excess alcohol was removed through washing with a separatory funnel, along with other aqueous contaminants. As ethanol has less than five carbons in its structure, it is soluble in water at the aqueous layer. This is due to the accepted five carbon limit for water solubility, which is caused by the principle that increased similarity in structure between the solvent and the solute causes increased solubility; the polar groups of organic compounds account for this (Shriner et. al., 1980). In the final washing of the separatory funnel, sodium bicarbonate (NaHCO3) was added in order to eliminate the sulphuric acid (H2SO4) catalyst in a neutralisation reaction (2). While sodium hydroxide (NaOH) would be a more powerful agent for neutralisation (3), sodium bicarbonate was chosen in order to more clearly indicate the presence of any remaining acid, as it produces carbon dioxide gas upon reaction.
After the final washing, sodium sulphate (Na 2SO4) was added to the organic layer as a drying agent, to remove water from the crude product. As mentioned above, 4.78 mL of pineapple-smelling ester was produced, with a percent yield of 55.39%. Another study on Fischer esterification show yields ranging from 78-95%, with tetrabutylammonium tribromide as a catalyst; long chain alcohols were reacted with acetic acid in the said study. For
esterification with acetic acid from diols, yields range form 42-87% (Naik et. al., 2006). IV. Conclusion This study shows that esters may be produced from a reversible nucleophilic acyl substitution reaction between an alcohol and a carboxylic acid, in a process known as Fischer esterification.
Ester production is ensured through the use of Le Chatelier’s principle, specifically in the addition of heat to the reaction, the addition of excess reagent, and the removal or minimisation of the amount of water in the starting reagent. V. References Carey, F.A. & Giuliano, R.M. (2011). Organic chemistry (8th ed.). New York: McGraw-Hill. Furniss, B.S., Hannaford, A.J., Smith, P.W.G., & Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (5th ed.). Harlow, Essex: Pearson Education. MacKenzie, C.A. (1962). Experimental organic chemistry (2nd ed). Eaglewood Cliffs, NJ: Prentice Hall. McMurry, J. (2004). Organic chemistry (6th ed.). Belmont, CA: Brooks/Cole. Moore, G.G., Foglia, T.A., & McGahan, T.J. (1979). Preparation of hindered esters by the alkylation of carboxylate salts with simple alkyl halides. Journal of Organic Chemistry, 44(14), 2425-2429. doi: 10.1021/jo01328a019. Moore, J.A. & Dalrymple, D.L. (1976). Experimental Methods in Organic Chemistry (2nd ed.). Philadelphia: W.B. Saunders. Naik, S., Kavala, V., Gopinath, R., & Patel, B.K. (2006). Tetrabutylammonium tribromide mediated condensation of carboxylic acids with alcohols. ARKIVOC, 1(i), 119-127. Ouellette, R.J. & Rawn, J.D. (1996). Organic chemistry (1996). London: Prentice Hall. Shriner, R.L., Fuson, R.C., Curtin, D.Y., & Morrill, T.C. (1980). The systematic identification of th organic compounds: a laboratory manual (6 ed.). New York: John Wiley & Sons. Solomons, T.W.G. & Fryhle, C.B. (2011). Organic chemistry (10th ed.). Hoboken, NJ: John Wiley & Sons.
VI. Appendix etOH = ethanol butOOH = butyric acid etbut = ethyl butyrate
Theoretical ethyl butyrate yield: Percent yield:
