Synthesis of Lidocaine: Chemistry 212 Laboratory
Synthesis of Lidocaine: Chemistry 212 Laboratory
Synthesis of Lidocaine: Chemistry 212 Laboratory
Synthesis of Lidocaine
INTRODUCTION:
Local anesthetics (pain killers) are an important and well-studied class of synthetic drugs.
Some common local anesthetics are shown below. Of these, only cocaine is a naturally
occurring compound, and the synthetic drugs are used to avoid the narcotic effects of the
former.
In most of the hundreds of local anesthetics that have been synthesized, two features are
prominent: The compounds are benzoate esters or anilides and contain a dialkylamino
group separated by one or four atoms from the carbonyl center, as indicated in the structure
of cocaine. The dialkylamino group is a characteristic unit in the structures of many diverse
medicinal agents such as antihistamines, antimalarial compounds, and tranquilizers.
In this experiment the local anesthetic lidocaine will be synthesized and isolated in the
form of its bisulfate salt. (The hydrochloride is the salt generally used in medicine, but it is
considerably more difficult to purify.) Lidocaine (the generic name) is sold under various
trade names, the most common of which is Xylocaine. It is noted for its relatively high
anesthetic activity when applied to the skin or injected into nerves, it also has a low toxicity
and incidence of side effects. Another important use of lidocaine is treatment of
arrhythmia.
The synthetic sequence shown below illustrates several important reactions. The reduction
of an aromatic nitro compound is most commonly accomplished with metals such as iron,
zinc, or tin. Stannous chloride is more rapid and convenient because the reaction is
homogeneous; however it is a rather expensive reagent. It is possible to begin the sequence
with 2,6-dimethylaniline, since this compound is commercially available and actually costs
less per gram than the nitro compound. The second and third steps in the synthesis are
Chemistry 212 Laboratory
acylation of the aniline by the highly reactive chloroacetyl chloride and alkylation of
dimethylamine by the chloroamide. This last step is an SN2 displacement, which is
facilitated by the adjacent carbonyl group.
Check in lab,
is it NaOH or
KOH?
Procedure:
(1st week)
A: Synthesis of 2,6-Dimethylaniline via Reduction of 2,6-Dimethylnitrobenzene
1. Dissolve1.0 g of 2,6-dimethylnitrobenzene in 10 mL of glacial acetic acid in a 50
mL Erlenmeyer flask.
2. In a 25 mL flask, dissolve 4.6 grams of SnCl2 · 2H2O in 8 mL of concentrated HCl,
inside the fume hood.
3. Add the SnCl2 solution in one portion to the nitroxylene solution, magnetically
swirl and mix, and let the mixture stand for 15 minutes.
4. Cool the mixture and collect the crystalline salt (dimethylaniline in the salt form:
C6H5NH3+Cl-) in a Buchner funnel.
5. Transfer the moist crystals to an Erlenmeyer flask, add 5-10 mL of water, and make
the solution strongly basic (to remove the acid and change C6H5NH3+Cl- back into
Chemistry 212 Laboratory
(2nd week)
C: Synthesis of α-diethylamino-2,6-dimethylacetanilide
1. In a 50 mL round-bottom flask, place the chloroacetoxylidide obtained from the
preceding step and 25mL of toluene; then add three moles of diethylamine per mole
of xylidide.
2. Save out a few milligrams of the starting material for later TLC analysis. In order
to observe the progress of the reaction and make a quick and direct comparison, you
should, for every 15-30 minutes, run your starting material right next to (on the
same TLC plate) your reaction mixture collected in the following steps.
3. Fit the flask with a reflux condenser, add a boiling stone, and reflux vigorously.
4. The progress of the reaction can be measured conveniently at 15 to 30-minute
intervals by TLC. (TLC solvent: Chloroform)
5. After the starting materials are consumed (based on the TLC results), or after 90
minutes of refluxing, whichever comes first, cool the mixture to room temperature,
and then in ice bath, and filter out the crystals.
6. Rinse the crystals with small amount of pentane, let air dry, and weigh. At the same
time, proceed to step 7 with the filtrate.
7. Transfer the filtrate to a separatory funnel and extract with two 10 mL portions of 3
M HCl solution.
8. Cool the acidic aqueous layer in an Erlenmeyer flask and add 30% KOH solution
until the mixture is strongly basic.
9. Extract with two 10 mL portions of pentane.
10. Rinse the pentane layer with six 10 mL portions of water to remove unreacted
diethylamine, dry over sodium carbonate (Na2CO3) and concentrate in a tared flask.
11. Measure the mass of the product.
Chemistry 212 Laboratory
For your report report all melting points taken and discuss. Calculate your percent yield for
each step and discuss each step. Calculate your overall percent yield and discuss this value.