1. Synthesis of Lidocaine (Step 3)
Lecture 8a
Synthesis of Lidocaine (Step 3)

2. Theory I
The third step of the reaction sequence is a SN2 reaction on the CH2Cl function
Diethylamine is moderately strong nucleophile because it is neutral
The chloride ion is a moderately good leaving group in SN2-reactions
More rigorous conditions are needed i.e., higher temperature and longer reaction time to observe a good conversion rate
The reflux is very important to produce any reasonable amounts of lidocaine

3. Theory II
The presence of water in the reaction mixture poses a significant problem because it reacts with the amine  the amide has to be dry
In theory, the reaction requires two equivalents of the amine, but for practical purposes three equivalents of the amine are used
The reaction leads to the formation of diethylammonium chloride, which precipitates from the non-polar solution as a white solid

4. Theory III
Upon completion, the reaction mixture contains lidocaine, some unreacted anilide, the excess amine and the ammonium salt
The separation of these compounds is based on the different solubilities in water and hydrochloric acid
1st extraction: the water removes the ammonium salt and the excess of the diethylamine
2nd extraction: the hydrochloric acid moves the lidocaine into the aqueous layer due the protonation of the diethylamine function
The unreacted anilide remains in the organic layer because it is significantly less basic than the amine (lidocaine: pKa=7.9)
The sequence of extractions is very important here!
The lidocaine is recovered by addition of a strong base (KOH) to the aqueous extract from the combined extracts from the 2nd extraction step

5. Experiment I Dissolve the dry anilide in toluene
Add three equivalents of the amine
Reflux the mixture vigorously for about 90 min
After cooling the mixture, extract the mixture with water
Why is toluene used here?
Can the student use more?
What does this imply?
Which observations should the student make?
How much water is used?
Because of its high boiling point (111oC) NO
The mixture has to boil
Usually a white precipitate forms
3*10 mL

6. Experiment II Extract the organic layer with 3 M hydrochloric acid
Combine the two aqueous extracts and place the solution in an ice-bath
Add 8 M KOH until the solution is strongly basic
Why is this step performed?
How much is used here?
Which layer has to be kept here?
Which pH-value is the student looking for?
How is the pH-value measured?
2*10 mL
The bottom layer
pH>10

7. Experiment III Place the mixture in an ice-bath
Isolate the white solid by vacuum filtration using a fritted funnel or fritted crucible
Wash the solid with water
Press the solid in the funnel
Why is this step performed?
What should be done if the compound does not solidify?
What is a fritted funnel?
Why is it used here?
Why is the solid pressed?
Scratch the inside of the beaker
The strongly basic solution disintegrates the filter paper
To remove the bulk of the water

8. Experiment IV Dissolve the crude product in about 10 mL of hexane
Add anhydrous sodium sulfate
Reduce the volume of the solution to 3-4 mL using an air stream
Allow to the compound to crystallize
Isolate the solid by vacuum filtration
Why is the solid dissolved again?
What is the exact procedure here?
Why is the volume reduced?
Which equipment should be used here?
The aqueous and organic solution have to be cleanly separated
Hirsch funnel

9. Characterization I X-Ray Structure
Trans amide configuration (like in the chloroanilide)
The NH and CO functions are opposite of each other
d(N3-N4)=269.5 pm
The short contact is due to an intramolecular H-bond
<(N3-C23-C24-N4)=13o
The amide function is almost planar
d(C23-O2)=122.8 pm
The C=O bond is slightly longer than in acetone (121.3 pm)
d(C23-N3)=134.0 pm
Very short C-N bond indicative of a partial C-N double bond
d(O1-H)=214 pm
Intermolecular hydrogen bonding observed the solid leading to the formation of a chain with alternating orientation of the aromatic ring
The distance is about 10 pm longer than in the chloroanilide resulting in a lower melting point for lidocaine compared to the chloroanilide

10. Characterization II Melting point Infrared spectrum (anilide)
n(NH)=3214 cm-1
n(C=O)=1648 cm-1
d(NH, amide II)=1537 cm-1
Oop (1,2,3)=762 cm-1
Infrared spectrum (lidocaine)
n(NH)=3260 cm-1
n(C=O)=1654 cm-1
d(NH, amide II)=1500 cm-1
Oop (1,2,3)=766 cm-1
Note that the n(CH, sp3) peak grew compared to the NH peak!
n(NH)
n(C=O)
d(NH)
oop
Anilide
n(NH)
n(C=O)
Lidocaine
d(NH)
oop

11. Characterization III 1H-NMR Spectrum (CDCl3)
d(NH)=8.92 ppm
d(COCH2)=3.22 ppm
d(CH2CH3)=2.69 ppm
d(CH2CH3)=1.13 ppm
The main difference is the presence of the two signals due to the diethylamine group
Submit NMR sample (50 mg/mL CDCl3)
Question: Why is the NH peak so far downfield here?
CH2 NH
CH2CH3

12. Characterization III 13C-NMR spectrum d(C=O)=170 ppm d(CH2CO)=58 ppm
d(CH2CH3)=49 ppm
The 1H-NMR and the 13C-NMR spectrum of the lidocaine for the post-lab can be found at
CH2CH3
CH2CO
C=O

13. Characterization IV
Mass spectrum (sample has to be submitted for analysis)
Question: The mass spectrum of lidocaine is dominated by a peak at m/z=86. Which fragment can this be attributed to?
The final product has to be submitted to the TA by November 5, at 5 pm. Any samples that are submitted later will not receive any credit.