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Theory I
The third step of the reaction sequence is a SN2 reaction on the
CH2Cl function
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
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
Experiment II
Extract the organic layer
with 3 M hydrochloric acid
2*10 mL
Which layer
has to belayer
kept
The bottom
here?
Experiment III
Place the mixture in an
ice-bath
Experiment IV
Dissolve the crude product in
about 10 mL of hexane
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
(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?