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 (SN2)
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 and heat (McMurry, 2004).

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 (CH3(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 washings 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 Chateliers principle,
unequal carboxylic acid or alcohol concentrations 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 (Na2SO4)

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
Chateliers 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
organic compounds: a laboratory manual (6th
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: