Comparison of two Methods for a two-Step

Synthesis of Lidocaine from 2,6-Dimethylaniline,

-Chloroacetylchloride and Diethylamine
Ristovska, Anastazija*
Chemistry Department, Rice University, Houston, Texas
77005, USA
ar24@rice.edu
Received date

2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide
also
known as lidocaine was synthesized via two different
methods, by reacting 2,6-dimethylaniline with chloroacetyl chloride and diethylamine in a two-step
process. In the first method the final product was
crystallized and vacuum filtered with 76.9% yield; via the
second method the lidocaine final product was isolated
through separatory extraction and was concentrated in a
tarred flask, with 57.1% yield.

Scheme 1. Synthesis of Lidocaine

Lidocaine is used as a local anesthetic alongside other

members of the Class 1b drugs such as Procaine, Isocaine,
and Mexiletine. Cocaine is the only naturally occurring
local anesthetic, however, due to its narcotic effects the
production of synthetic drugs such as lidocaine is
necessary. The nucleophilic substitution reactions in both
steps of the synthesis involve the displacement of a carbonbound chlorine atom by a primary or secondary-amine
nitrogen atom. In the first nucleophilic substitution reaction
the electron density of the nitrogen atom of the amine group
of 2,6-dimethylaniline attacks the carbonyl group of chloroacetylchloride whose carbon atom is more
electrophilic than the carbon atom alpha to the carbonyl

group. HCl is removed as a byproduct. In the second

nucleophilic substitution reaction the electron density of the
nitrogen atom in the secondary amine, diethylamine,
attacks the carbon atom alpha to the carbonyl group, since
in this case the -carbon is the most electronegative carbon
atom of the -chloro-2,6-dimethylacetamide, due to the
electron-withdrawing effects of the oxygen and chlorine
atoms. In my study, the first step of both synthesis methods
was carried out by heating the 2,6-dimethylaniline and chloroacetyl chloride for a relatively short period of time
followed by the addition of sodium acetate, whereas the
second step was carried out through a long refluxing
process in the presence of toluene.
The initial step of the first synthesis method resulted in the
formation of a white, cloudy, foamy precipitate, with a
91.5% yield. The yield was determined after vacuumfiltering the product that was left to dry in a desiccator for
two weeks, and has taken on crystalline form. The initial
step of the second synthesis method, on the other hand,
resulted in 85% yield. The secondary steps of the first and
second method involved refluxing for 90 min at 80C and
90C respectively; the products obtained in the refluxing
procedures were washed with hexane and pentane,
respectively, during the isolation of the product via vacuum
filtration. Beyond this step both methods required
separatory extractions and rinsings with HCl, as well as
subsequent neutralization with KOH, as well as the
extraction with pentane and water rinses. The separatory
extraction steps might have resulted in the additional loss of
product, and hence the lower yields of 76.9% and 57.1%
for the first and second procedures. The product from the
second method was obtained in an even lower yield most
likely because of the fact that, instead of isolating it via
vacuum filtration, it was concentrated in a tarred flask.
Method 1
Method 2

1st step % yield

91.5
85.0

2nd step % yield

76.9
57.1

The yield in the first step can be improved by lowering the

the temperature of the first step of the reaction or by
eliminating the vapor heat bath and heating the Erlenmeyer
flask directly on the hot stir plate; also by stirring
vigorously for longer period of time of 40-45min instead of
just 20-30min. The final product isolation should be
performed via vacuum filtration, without using the tarred
flask, and only after the product has been allowed to better
crystallize by keeping it for several days in a cold drawer or
in a fridge. Another way to increase the yield might be to
use a greater amount of toluene in the reflux reaction
proportionate
to
the
amount
of
-chloro-2,6dimethylacetanilide being refluxed.

________________________________________________
2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide. 1H
NMR (40 MHz, CDCl3), 9.09 8.63 (s, 1H), 7.25 6.74
(s, 3H), 3.43 2.94 (s, 2H), 2.98 2.33 (q, J = 7.0 Hz, 4H),
2.37 1.90 (s, 6H), 1.39 0.70 (t, J = 7.0 Hz, 6H).
________________________________________________

Figure1. 1H NMR (CDCl3, 40 MHz) Analysis of Lidocaine

________________________________________________

Method 1. 4.00g dimethylaniline, 25 mL glacial acetic

acid, and 3.73g -chloroacetyl chloride were added in a
125-mL Erlenmeyer flask. The Erlenmeyer flask was
heated on a hot stir plate for 30min at 60C. In a separate
150-mL beaker 5g sodium acetate trihydrate was dissolved
in 100 mL deionized water. The Erlenmeyer flask was
moved from the hot stir plate to the bench and was allowed
to cool. It was then placed in an ice-bath. The solution from
the 150-mL beaker was added to the Erlenmeyer flask. The
precipitate from the flask was vacuum filtered. The product
was stored in vials in the desiccator and allowed to dry for
two weeks. 1.49g of the -chloro-2,6-dimethylacetanilide
obtained in the previous step was placed in a 250-mL
round-bottom flask alongside 45 mL toluene and 1.676g
diethylamine. The solution was refluxed for 90 min at
80C. The round-bottom flask was then allowed to cool on
the bench and was then moved to an ice bath. The
crystalline solid formed was vacuum filtered and rinsed
with cold hexane. The filtrate was transferred to a 100-mL
separatory funnel and rinsed with two 25-mL portions of
3M HCl. The HCl extracts were collected in a 250-mL
Erlenmeyer flask to which 50 mL 8M KOH was added. The
Erlenmeyer flask was placed in an ice bath. The crystals
formed were vacuum filtered, washed with cold water, and
placed in vials in a desiccator. The lidocaine obtained was
then 1H NMR analyzed.
Method 2. In a 250-mL Erlenmeyer flask, 7g
dimethylaniline, 50mL glacial acetic acid, and 5.2mL -

chloroacetyl chloride were added. A hot water bath was

prepared and the solution in the Erlenmeyer flask was
warmed over the steam at 40-50C for 20min. 1g of sodium
acetate was dissolved in 100 mL deionized water in a 250mL beaker, and this solution was added to the 250-mL
Erlenmeyer flask. The flask was removed from the steam
bath and allowed to cool on the bench. The precipitated
product was isolated using vacuum filtration. The -chloro2,6-dimethylacetanilide product obtained in this step was
placed in a 100-mL round-bottom flask together with 25
mL toluene and 10.15g of diethylamine. A reflux system
was set up at 90C, and the mixture of the round-bottom
flask was refluxed for 90 min. When 90 min had passed,
the round-bottom flask was allowed to cool on the bench
and was then transferred to an ice-bath. The crystals formed
in the flask were vacuum filtered and rinsed with a small
amount of pentane. The filtrate was transferred to a 100-mL
separatory funnel and estracted with two 10-mL portions of
3M HCl solution. The aqueous layer was collected in a
100-nL Erlenmeyer flask and small amount of 30% KOH
was added until, using litmus paper, the solution was
determined to have reached the basic pH range (pH=8-9).
The content of the Erlenmeyer flask was then transferred to
another 100-mL separatory funnel and the product was
extracted with two 10-mL pentane rinses. The organic layer
was collected in a third 100-mL separatory funnel and
washed with six 10-mL portions of water. The organic layer
from the separation extraction was dried over sodium
carbonate, and the product 2-(diethylamino)-N-(2,6dimethylphenyl)acetamide was concentrated in a tarred
flask.

Supporting Information Available: For complete tables of

physical properties of the chemicals used, please visit
http://pubchem.ncbi.nlm.nih.gov
Acknowledgements. We are grateful to V. Farrukh for NMR
data.
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