Lecture 8a

Synthesis of Lidocaine (Step 3)

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

Theory II
O
HN
H3C

O
Cl
CH3

HN
HNEt 2

H3C

NEt2
CH3

Lidocaine

+ Et 2NH2+ Cl -

HN
HCl

Diethylammonium
chloride

H3C

HNEt 2+ ClCH3

KOH

Lidocaine

Acid extration
soluble in aqeous layer

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

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: pK a=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

Experiment I
Dissolve the dry anilide in toluene Why is toluene used here?
Because of its high boiling
point (111oC)
Add three equivalents of the amine
Reflux the mixture vigorously for Can the student use more?
NO
about 90 min
What does this imply?
The mixture has to boil and
a reflux ring has to be observed
After cooling the mixture, extract
the mixture with water

Which observations should the

student
Usuallymake?
a white precipitate forms
How
3*10 much
mL water is used?

Experiment II
Extract the organic layer
with 3 M hydrochloric acid

Why is this step performed?

How much is used here?

2*10 mL

Which layer
has to belayer
kept
The bottom
here?

Combine the two aqueous

extracts and place the
solution in an ice-bath
Add 8 M KOH until the
solution is strongly basic

Which pH-value is the student

pH>10
looking for?
How is the pH-value measured?

Experiment III
Place the mixture in an
ice-bath

Why is this step performed?

What should be done if
the compound does not
solidify?

Scratch the inside of the beaker

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

What is a fritted funnel?

Why is it used here?

The strongly basic solution

disintegrates the filter paper

Why is the solid pressed?

To remove the bulk of the water

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?
The aqueous and organic solution
have to be cleanly separated

Why is the volume reduced?

Which equipment should be used

here?
Hirsch funnel

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

Characterization II
Melting point
Infrared spectrum (anilide)

(NH)=3214 cm-1
(C=O)=1648 cm-1
(NH, amide II)=1537 cm-1
Oop (1,2,3)=762 cm-1

(NH)
Anilide

(C=O)

(NH)

oop

Infrared spectrum (lidocaine)

(NH)=3260 cm-1
(C=O)=1654 cm-1
(NH, amide II)=1500 cm-1
Oop (1,2,3)=766 cm-1
Note that the (CH, sp3) peak
grew compared to the NH peak!

(NH)
Lidocaine

(C=O)

(NH)

oop

Characterization III
1H-NMR Spectrum (CDCl3)

(NH)=8.92 ppm
(COCH2)=3.22 ppm
(CH2CH3)=2.69 ppm
(CH2CH3)=1.13 ppm

CH2

NH

CH2CH3

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?

Characterization III

13

C-NMR spectrum

CH2CH3

(C=O)=170 ppm
(CH2CO)=58 ppm
(CH2CH3)=49 ppm

CH2CO

C=O

The 1H-NMR and the 13C-NMR spectrum of the lidocaine for the post-lab can
be found at
www.chem.ucla.edu/~bacher/General/30CL/spectra/lidoH.html

Characterization IV
Mass spectrum (sample has to be submitted for analysis)
Question: The EI 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 February 6, 2015

at 5 pm. Any samples that are submitted later will not receive any credit.