Experiment 3 Part B: Preparation of Lidocaine from αChloro-2,6-dimethylacetanilide and Diethylamine
INTRODUCTION
This step of the synthesis involves the reaction of α-chloro-2, 6dimethylacetanilide, prepared in the previous part (Experiment 3A) and used without
further purification, with excess diethylamine, (CH3CH2)2NH.
CH3
N
H
CH3
CH3
O
2 (CH3CH2)2NH
Cl
diethylamine
!-chloro-2,6-dimethylacetanilide
O
N
N
H
(4)
CH3
Lidocaine
+ (CH3CH2)2NH2
Cl
diethylammonium
chloride
Diethyl amine serves three roles in this reaction: (a) as a nucleophile to displace
chloride anion from –CH2Cl in the α-chloro-2, 6-dimethylacetanilide by an SN2 type
reaction; (b) as a base to absorb the HCl that is formed in the nucleophilic substitution
reaction leading to Lidocaine; and (c) as a solvent for the reaction. The reaction of αchloro-2, 6-dimethylacetanilide with diethylamine represents another example of
selection reaction because nucleophilic substitution occurs exclusively at the carbon
alpha to the carbonyl. Nucleophilic attack by the amine on the carbonyl carbon of the
amide group is not favored relative to reaction at the carbon alpha to the carbonyl,
which bears the chlorine atom. If substitution were to occur at the carbonyl carbon, it
would disrupt the resonance associated with the amide linkage.
Examination of equation (4) shows that a minimum of two moles of diethylamine is
required for each mole of α-chloro-2, 6-dimethylacetanilide used. One mole is needed
for the SN2 reaction and a second mole absorbs the HCl that is liberated in the
substitution reaction; diethylammonium chloride, (CH3CH2) 2NH2 Cl, is formed along
with Lidocaine, and no HCl is ever formed directly in the reaction. The mechanism for
the substitution reaction between an alkyl halide and an amine may be found in lecture
textbooks and/or discussed by your instructor.
In this reaction, the starting chloroamide, α-chloro-2, 6-dimethylacetanilide, is
placed in a vial with the diethylamine solvent/nucleophile and the solution is allowed to
react in the vial. As the reaction proceeds, the formation of a salt, diethylammonium
⊕
1
chloride, is observed. After several days, the solution is carefully vacuum filtered to
remove the salt and the excess diethylamine is removed by evaporation using the vacuum
system. The compounds remaining in the filtration flask are: (a) traces of diethylamine,
(b) any unreacted α-chloro-2, 6-dimethylacetanilide and (c) Lidocaine, the desired
product. To isolate Lidocaine, the solids left behind by the evaporation process are
dissolved by aqueous HCl solution, which converts Lidocaine into its water-soluble
hydrochloride salt. Diethylammonium chloride is formed from the reaction between
aqueous HCl and traces of unreacted diethylamine, and is soluble in aqueous HCl solution.
Any unreacted chloroamide, α-chloro-2, 6-dimethylacetanilide, is insoluble in aqueous
HCl and remains a solid that is removed from the acidic aqueous solution by a second
vacuum filtration.
CH3
O
N
N
H
H
CH3
HCl
Reaction
Mixture
Cl
Soluble in HCl solution
(CH3CH2)2NH2 Cl
H2O
CH3
N
H
O
Cl
Insoluble in HCl solution
CH3
The HCl extracts are made distinctly basic (pH ~ 14) to liberate Lidocaine from
its water-soluble hydrochloride salt and to reconvert diethylammonium chloride to
diethylamine. Lidocaine is extracted from the basic aqueous solution with several
portions of petroleum ether, which is a mixture of low-boiling hydrocarbons.
CH3
N
H
CH3
O
N
H
CH3
(CH3CH2)2NH2 Cl
Cl
KOH
H2O
O
N
H
CH3
(CH3CH2)2NH
N
insoluble in
basic aqueous
solution, but
soluble in
pet ether
slightly soluble
in basid aqueous
solution
2
The petroleum ether extracts containing the Lidocaine are combined and washed
with several portions of cold water to remove traces of diethylamine and inorganic salts
and bases. The petroleum ether layer is dried with anhydrous potassium carbonate
(K2CO3), which is a basic drying agent that will not react with basic organic compounds
such as Lidocaine. This minimizes the loss of Lidocaine in the procedure. A little
decolorizing carbon is then added to the petroleum ether solution to remove colored
impurities. Gravity filtration is used to remove the drying agent and decolorizing
charcoal. The ether is allowed to evaporate in the hood until the next lab period to give
solid Lidocaine.
REAGENT/PRODUCT TABLE:
Reagents
diethylamine
MW (g/mol) MP (ºC)
73.14
-50
alpha-chloro-2, 6-dimethylacetanilide 197.6
petroleum ether
Product
lidocaine
BP (ºC)
55
Density
0.707
35-60
0.64
MW (g/mol) MP (ºC)
234.33
68-69
EXPERIMENTAL PROCEDURE:
FOR YOUR SAFETY
Keep the bottle containing the diethylamine in the hood at all times. Take your reaction
vial to the hood when adding diethylamine to it.
1. Obtain a clean, dry large sample vial from your locker. Check that the cap you
selected for the vial has a lid liner in place to seal the vial shut. Preweigh the cap and
empty sample vial. Transfer all of the α-chloro-2, 6-dimethylacetanilide obtained
from the previous step (Expt 3A) to the vial. Reweigh the vial to determine the
amount of α-chloro-2, 6-dimethylacetanilide added to the vial.
2. To the large sample vial containing the chloroamide, add 5 mL of diethylamine. Using
a spatula, stir to mix thoroughly, cap tightly and place in locker until the next lab
period. (END DAY 1)
3. Set-up the porcelain Hirsh funnel and 50 mL filter flask provided for you, for a
vacuum filtration. The filter flask should be clamped so it is placed down inside an
empty 250 mL beaker, which will be used in Step 8 to hold a water bath. Make sure a
microfilter paper is placed in the funnel. This apparatus will be used to vacuum filter
your reaction mixture in the large sample vial from Step 2.
3
4. Use a 5 mL syringe to obtain 5 mL of dry petroleum ether from the hood. Make
sure the shield is on the needle. Take it back to your bench.
5. Turn the vacuum on to about half strength (NOT full strength), wet the microfilter
paper with a few drops of pet ether to seat the paper and check that the vacuum
is indeed pulling through the funnel (gently place your hand on top of the funnel to
see if the vacuum is on).
6. Caution: You must do this next step VERY SLOWLY into the filter for filtration to
occur, due to the low boiling point of diethylamine and the reduced pressure in the
filter flask. Pour the reaction mixture SLOWLY into the Hirsh funnel. As the
solution starts to filter through the Hirsh funnel, it will “flash up” in the filter flask.
If you pour too quickly, the vacuum will suck up the liquid containing your product out
the side arm of the filter flask and into the vacuum line! The filtrate/filter flask
will quickly get cold and it may even form some ice on the outside of the flask.
If/when that happens, don’t worry – it’s expected.
7. After all of the liquid from the reaction mixture has been filtered, rinse the
reaction sample vial up to five times with 1 mL portions of pet ether using the 5
mL syringe (Step 4). With each portion, try to rinse the reaction vial well each time
so all solid material will be transferred to the Hirsh funnel.
8. Once the filter flask is cold, turn on the vacuum full strength and fill the 250 mL
beaker with room temperature (not hot!) water so the filter flask is submerged up to
the filtration arm. Allow the vacuum to remain on for at least 30 minutes, to
evaporate off the diethylamine from your filtrate. This will leave only crude
Lidocaine and any unreacted chloroamide inside your filtration flask.
9. While waiting, obtain 3-4 mL of 3M HCl and 3 mL of 8M KOH, in separate large
sample vials, labeled appropriately. Place them in an ice bath to cool.
10. After the diethylamine has evaporated, the inside of the filtering flask should
contain a solid, which would be your impure Lidocaine. The Hirsch funnel also has a
solid in it, which are the by-product diethylammonium salts that formed during the
reaction. Turn off the vacuum, remove the Hirsch funnel and obtain a crude weight
on the diethylammonium salts. The crude weight of the by-product salt may be used
to calculate an approximate yield of your Lidocaine. Rinse the Hirsh funnel several
times with water to clean it. It does not have to be dry before you use it again.
11. Turn on your hot plate to a heat setting of 1.5-2 for use later in Step 18.
12. Add the 3-4 mL of the cold 3M HCl into the filter flask. ALL solids inside the flask
should dissolve in the acidic solution so try to “wash” down the sides of the filtering
flask and gently swirl the flask so the acid comes in contact with all solids in order to
dissolve them entirely. The possible solid that may not dissolve is unreacted αchloro-2, 6-dimethylacetanilide. If the reaction was nearly complete, very little, if
any, solid should be observed. If solid is observed, see your instructor.
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13. Transfer the contents of the filter flask to a large sample vial and rinse the filter
flask with 2 mL of water, which will be added to the large sample vial also. Clean the
filter flask prior to the next step.
14. Vacuum filter the acidified reaction mixture through the Hirsch funnel (do not
forget the microfilter paper) into the clean filter flask. Wash the large sample vial
with 3 mL of 3 M HCl and pour it through the funnel.
15. Discard any filtered solid in the “solid organic waste container” and transfer the
contents of the filter flask to a clean, large sample vial (Vial #1). Place the vial in a
small beaker containing ice and water, and while in the ice-water bath, add about 3
mL of 8 M KOH solution to the vial, and stir with a spatula or a glass stirring rod to
ensure thorough mixing. Test the basicity of the solution with pH paper. If the pH
is not about 14, add KOH drop-wise and with stirring until the pH is ~ 14. The
contents of the vial will appear milky and if any crystals form, they will be removed in
the next step. Remove the vial from the ice bath and allow it to warm back to room
temperature.
16. NOTE: In this step, you may find it convenient to label and number the vials to
avoid getting them mixed up. Fill a clean, dry large sample vial about two-thirds
full with petroleum ether for use in the following extractions. Label the vial
“petroleum ether”. Add about 4 mL of petroleum ether to the original cold vial (Vial
1) from Step 14, cap it tightly (make sure the cap has an insert in it so the seal will
be good), and shake it gently (wear gloves!) with frequent venting. All of the solids
that formed in the previous step MUST be dissolved before performing the next
separation. Do not attempt to separate until everything is dissolved.
Using a Pasteur pipette, remove the lower aqueous layer and transfer it to a second
large, clean vial (Vial 2). Keep the upper layer in Vial 1; it contains most of your
product, Lidocaine. Repeat this procedure (removal of Lidocaine) one more time by
now extracting the basic aqueous layer in Vial 2 with another 4 mL portion of
petroleum ether. Remove the lower, basic layer and place it in a large sample vial (Vial
3, a waste container). Vial 2 now contains the upper layer, with more of your product.
At the completion of these extractions, you will have two large sample vials (Vial 1
and Vial 2), each of which contains petroleum ether extracts with Lidocaine.
Combine the two petroleum ether extracts (total volume ~ 8 mL) together into
the same sample vial by pouring Vial 2 into Vial 1). The third large vial (Vial 3) will
contain “aqueous basic waste” and it should be saved and used for further waste
collection until product is obtained.
17. Add about 3 mL of ice water to the combined petroleum ether extracts (Vial 1). Cap
the vial and shake it vigorously. Allow the layers to separate and carefully remove
the bottom waste layer with a Pasteur pipette. Place the water in the “waste”
5
beaker (Vial 3). Repeat this washing process of vial 1 with an additional 3 mL portion
of ice water, again placing the aqueous layer in Vial 3.
18. Add enough anhydrous K2CO3 to cover the bottom of Vial 1 containing the petroleum
ether and Lidocaine. Cap and gently swirl the vial. If some of the drying agent does
not move freely when the vial is swirled, add a little more of it. The petroleum ether
layer should appear clear, not cloudy. Then add a couple of microspatulas of
decolorizing carbon to the vial, cap it, and swirl it gently. Remove the cap and warm
the vial on the hot plate until the petroleum ether is slightly warmed. This takes
just a minute or so. Don’t over-heat, as the petroleum ether can boil over, sending
decolorizing carbon all over your hot plate. (Don’t walk away while this is heating, as
the solution may erupt like a volcano.) Allow the vial to cool briefly to room
temperature.
19. Pre-weigh a clean and dry large sample vial (Vial 4). Gravity filter the contents of
Vial 1, using a short-stemmed glass funnel and fluted filter paper, into pre-weighed
Vial 4. Wash the vial once with a 3-mL portion of petroleum ether (swirl around to
help remove all traces of Lidocaine left behind), and pour this through the filter as
well. Rinse the fluted filter paper well and also the inside of the glass funnel so all
rinses are collected in Vial 4. Any white, cloudy crystal formations on the glass are
Lidocaine and should be rinsed into Vial 4. Vial 4 now contains all of your Lidocaine,
along with petroleum ether.
20. Label a 30 mL beaker with your name and place Vial 4 containing the petroleum ether
and Lidocaine inside the 30 mL beaker (to prevent Vial 4 from spilling). Vial 4 should
remain uncapped. See your instructor regarding which designated hood you must
leave the beaker/Vial 4 in until the next laboratory period. The ether will evaporate
during this time.
21. Clean and return to the bench top all equipment provided for you: porcelain Hirsch
funnel with black adapter cone, 50 mL filter flask, 250 mL beaker and 5 mL syringe.
22. Reweigh the large sample to determine the total weight of the Lidocaine and then
scrape down the sides of the vial to obtain crystals and get a melting point and IR (if
desired) on your crystals. Hand in product, properly labeled.
WASTE DISPOSAL
Place the aqueous basic extracts and the water extracts in the “aqueous basic waste”
container.
6
90
85
80
75
70
65
%Transmittance
60
55
50
45
40
35
30
25
20
15
10
5
4000
3500
Date: Wed Dec 16 10:51:20 2009 (GMT-05:00)
Scans: 4
Resolution: 4.000
3000
diethylamine
2500
2000
Wavenumbers (cm-1)
1500
1000