Synthesis of Lidocaine
2015 Sharmaine S. Robinson
East Stroudsburg University
Skills to build:
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Preparing reagents for synthesis
Doing an SN2 reaction synthesis
Using extraction to isolate the reaction product
Using recrystallization to purify the product
Obtaining a Raman spectrum
Introduction
Local anesthetics are among the most widely used drugs in the practice of
medicine and dentistry. Their ability to provide a loss of sensation in a specific body part
without loss of consciousness or impairment of central control of vital functions
revolutionized surgical procedures in medicine and dentistry. Albert Niemann isolated
cocaine and discovered its anesthetic properties in 1859-1860. The abuse potential and
frequent fatalities led to the development of procaine (Novocaine), the first injectable
local anesthetic, by Alfred Einhorn in 1905. Lidociane (Xylocaine) was developed by
Niles Lofgren in 1943 and later marketed in 1948 and serves as the current standard by
which all other local anesthetics are compared.
Synthetic local anesthetics are classified into two groups: esters and amides. Both
of these groups have the following three main parts:
a. an aromatic group – lipophilic portion
b. a terminal secondary or tertiary amino group – hydrophilic portion
c. intermediate chain – spatial link between the aromatic and amino groups
The intermediate chain serves as the basis of the anesthetic classification (Figure 1).
Procaine and lidocaine are ester and amide anesthetics, respectively.
Local anesthetics work by decreasing the permeability of the nerve
membrane to Na+ ions. A nerve fires when there is a rapid influx of sodium ions into the
interior of the nerve cell. Local anesthetics block this depolarization of the nerve
membrane, thereby, stopping the propagation of pain impulses along the nerve fibers.
Synthesis of Lidocaine
aromatic
nucleus
amino
group
linkage
O
C
Ar
O
R1
R2
N
ester
R3
H
N
Ar
C
R1
O
amide
R2
N
R3
Figure 1. Classification of local anesthetics
In solution, local anesthetics exist in both a neutral or base form and a charged or
ion form. Only the base form can diffuse across the nerve membrane, while only the
cation form produces anesthesia by binding to receptor sites inside the nerve cell. The pH
of the environment and the pKa for a particular anesthetic determine the relative
proportions of each form that is present. When pH = pKa, equal amounts of the ionized
and free base form exist. According to LeChâtelier’s principle, when the pH < pKa, more
cations than free base are present as the following equilbrium shifts to the left:
BH+ + H2O
ionized form
B + H3O+
free base
As a rule, local anesthetics with pKas closest to physiological pH (7.4) are most effective at
producing profound anesthesia. The closer an anesthetic’s pKa is to physiological pH, the
higher the percentage of free base that is available to cross the nerve membrane and
provide anesthesia. The Henderson-Hasselbalch equation can be used to predict the ratio
of free base to ion form:
pH  pK a  log
[B]
[BH  ]
Local anesthetics typically have pKas between 7.7 and 9.3. Lidocaine has a pKa of 7.8,
while procaine’s pKa is 9.1. At pH 7.4, lidocaine exists 29% in its free base form and 71%
in its ionized form.
2
Synthesis of Lidocaine
In this experiment, lidocaine will be synthesized in the free base form. While the
soluble hydrochloride salt is more widely used in medicine, it is more difficult to purify.
Starting with 2, 6-dimethylaniline, the synthesis is done in two steps:
Step 1: amine + acid chloride  amide (nucleophilic acylation substitution, NAS)
Cl
O
chloroacetyl chloride
C
Cl
O
_
Cl
+
CH2Cl
H2N
NAS
: NH2
O
NaO2CCH3
CH3
H3C
CH2Cl
HN
CH3
H3C
CH3
H3C
2,6-dimethylaniline
water-soluble
solid amide
Step 2: alkyl halide + 2 amine  3 amine (SN2)
:
Cl
lidocaine
N-(2,6-dimethylphenyl)chloroacetamide
_
diethylamine hydrochloride
Reaction summary:
CH3
O
: NH2
H3C
HN
CH3
ClCH2COCl
chloroacetyl chloride
2,6-dimethylaniline
H3C
O
CH2Cl
CH3
HN
HNEt2
H3C
CH2
N
CH3
CH2
CH3
diethylamine
chloro-2,6-dimethylacetanilide
lidocaine
3
Synthesis of Lidocaine
The product is then extracted with HCl and NaOH, filtered, and recrystallized from warm
hexane. The melting point of the purified product is used to determine identity and purity.
In addition, a Raman spectrum is obtained for comparison to a reference spectrum.
Experimental Methods and Materials
Safety considerations
Wear suitable protective clothing, gloves, and eye/face protection!
You should read the online MSDS for:
acetic acid
hexane
chloroacetyl chloride
hydrochloric acid
diethylamine
lidocaine
2,6-dimethylaniline
sodium acetate
N-(2,6-dimethylphenyl)chloroacetamide
sodium hydroxide
ethanol, denatured
toluene
4
Synthesis of Lidocaine
Preparation of N-(2,6-dimethylphenyl)chloroacetamide
In a clean, dry 125-mL Erlenmeyer flask, dispense 15.0 mL glacial acetic acid followed
by 3.00 mL (2.95 g) 2,6-dimethylaniline from the pump dispensers. Add 2.00 mL (2.85
g) chloroacetyl chloride and 25.0 mL of half-saturated aqueous sodium acetate. The
amide should precipitate at this point. Stir the product with 60 mL of cold distilled water
and use vacuum filtration to collect the product. Press dry in the Buchner funnel and use
immediately in the next step.
Preparation of lidocaine
Transfer the amide to a 100-mL round-bottom flask containing 7.50 mL (5.29 g)
diethylamine and 25 mL toluene. Place a stir bar inside the flask. Attach a condenser
and reflux for 45 minutes. Cool the reaction mixture to room temperature and transfer to a
clean, dry separatory funnel. Wash four times with 50-mL portions of water to remove
diethylamine hydrochloride and excess diethylamine. Remove the aqueous layer and
discard. Wash the organic layer with 20 mL 3 M HCl and remove the aqueous layer and
save. Wash the organic layer once with 20 mL distilled water. Remove the aqueous
layer and combine with the previous extract. Transfer the combined extracts to a 150-mL
beaker and cool to 10 C in an ice bath. Add 3 M NaOH in 5 mL increments until the cold
solution is strongly basic. Keep the temperature below 20 C at all times.
Extraction steps:
CH3
O
HN
H3C
CH3
CH2
N
CH3
lidocaine in toluene
O
CH2
HN
HCl
CH2
+
CH3
H3C
CH3
O
CH3
NH
CH2
_
CH3
Cl
lidocaine hydrochloride
HN
NaOH
H3C
CH2
N
CH3
CH2
CH3
oily layer of lidocaine
Note that the extraction procedure uses acidic and basic properties to provide a watersoluble and then water-insoluble form of lidocaine. Cool the solution in an ice bath to
crystallize the product. Weigh the top of the Buchner funnel with a piece of filter paper.
Collect the product by vacuum filtration. Wash with a small portion of cold, distilled
water. Continue to pull a vacuum for 5 minutes and then complete drying in the hood until
next week.
5
Synthesis of Lidocaine
Recrystallization
Weigh the crude crystals. Place the crude product in a 25-mL beaker and add 1
mL of hexane per gram of crude product. Warm the beaker gently on a hot plate until the
solid is dissolved. Cool in an ice bath to crystallize. Collect the crystals by vacuum
filtration. Weigh them. Determine the limiting reagent, theoretical yield, and the percent
yield of product. Perform a melting point determination on the dry crystals.
References
Department of Chemistry & Biochemistry, University of Maryland. Multi-step Synthesis
of Lidocaine. http://www.chem.umd.edu/organiclabs/Chem243/Expt08.htm (accessed
May 2006)
Fortunato, P. M. Local Anesthetics. http://www.bethesda.med.navy.mil/careers/
postgraduate_dental_school/comprehensive_dentistry/Pearls/Pearlsd6.HTM
(accessed May 2006)
Reilly, T. J. J. Chem. Educ. 1999, 76, 1557.
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