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Amines
Amine Synthesis
INTRODUCTION (1 page max)
Abstract:
Reductive amination was the specific reaction performed. It is a process that is typically
used for making primary, secondary, and tertiary amines in high yield. This experiment
began with p-vanillin and benzylamine reacting (with the nucleophilic nitrogen of the
amine to the electrophilic carbon of the aldehyde) to form the intermediate imine. Then,
sodium borohydride (NaBH4) was added to reduce the imine to the corresponding amine.
The product can be characterized through IR, yield, melting point, and look. The IR shows
the imine product formed through production of the imine C=N stretch at 1634cm-1, and
production of the amine through production of the secondary N-H stretch at 3356cm-1.
The yield of the imine was 105%, showing the presence of impurities, and the yield of the
amine was 80%. The imine and amine melting point was as expected as well, and the
imine was yellow-ish powder, and the amine was white powder.
Background Information:
Taken from the lab manual, amines are the ‘jack of all trades’ of organic functional groups
because they behave as nucleophiles, bases, and activating groups, and also leaving
groups and deactivating groups (when protonated or quaternized). Specifying to reductive
amination, this can be used for primary, secondary, and tertiary amines in high yield. This
reaction is important because direct alkylation of amines with alkyl halides is a difficult
reaction to control in that it is common to accidentally produces multiple alkylations. 1 This
reaction also holds importance in pharmaceutical and medicinal chemistry due to the
applicability to biologically active compounds (especially in the C-N bond construction). 2
Enzymatic reductive amination is a direct, selective, and green methodology that is
emerging as a powerful tool for the synthesis of chiral alkylated amines.3
1. Ashenhurst, Reductive Amination Reductive Amination, and How It Works – Master Organic
Chemistry
2. Afanasyev et al, Reductive Amination in the Synthesis of Pharmaceuticals Reductive Amination
in the Synthesis of Pharmaceuticals - PubMed (nih.gov)
3. Kumar et al, Biocatalytic reductive amination from discovery to commercial manufacturing
applied to abrocitinib JAK1 inhibitor Biocatalytic reductive amination from discovery to
commercial manufacturing applied to abrocitinib JAK1 inhibitor | Nature Catalysis
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Amines
EXPERIMENTAL & RESULTS (1.5 pages max)
Figure 1. Reaction scheme for amines experiment
1. 1.0eq
Hot hexanes (10min)
1.0 eq
2. 3.2eq NaBH4
EtOH (10min)
Quench (cold) H2O
Figure 2. 1H NMR signal assignment of 4-((benzylamino)methyl)-2-methoxyphenol
Table 1. 1H NMR data of 4-((benzylamino)methyl)-2-methoxyphenol (500 MHz, CDCl3)
Label
Chemical
Shift (ppm)
Multiplicity
Coupling
Constant (Hz)
Observed
Integration
Number of
Hydrogens
A
7.34-7.33
M
-
4.89
5
B
6.89
D
2.0
1.20
1
C
6.86
D
8.5
1.21
1
D
6.80
DD
7.8, 1.8
1.17
1
E
3.89
S
-
3.00
3
F
3.81
S
-
2.04
2
G
3.74
S
-
2.18
2
Sample Calculations:
Chemical shift = (6.813ppm + 6.794ppm) /2 = 6.80
Coupling Constant:
J13 = 6.813ppm – 6.798ppm = 0.015ppm
J24 = 6.810ppm – 6.794ppm = 0.016ppm
(0.015 + 0.016)/2 = 0.0155 * 500Hz
= 7.8Hz
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J12 = 6.813ppm – 6.810ppm = 0.003ppm
J34 = 6.798ppm – 6.794ppm = 0.004ppm
(0.003 + 0.004)/2 = 0.0035 * 500Hz
=1.8Hz
J= 7.8, 1.8Hz
Amines
CHEM 222/244
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Amines
SPECTRA (2 pages max)
Supplementary Figure 1. Annotated NMR spectrum of the amine, 4-((benzylamino)methyl)-2methoxyphenol.
Supplementary Figure 2.
Annotated IR spectrum of the purified imine, (E)-4-((benzylimino)methyl)-2-methoxyphenol.
CHEM 222/244
Report Sheet
Amines
**no IR obtained due to burned experiment. Was supposed to use a friend’s IR, but was unable to
obtain in time.
What I expect to see:
Expected frequency: 3500-330
Expected frequency
Observed frequency
3500-3300
3356
3100-3000
3026
3000-2900
1600-1450
2934
1642
900-860
850
770-730
751
Bond type
Secondary N-H stretch
Aromatic Sp2 C-H
stretch
Sp3 C-H stretch
Aromatic sp2 C=C
stretch
1, 2, 4, trisub. Arom.
C-H bend
Monosub. Arom. C-H
bend
Signal appearance
Broad, strong
Sharp, weak
Sharp, weak
Sharp, weak
Sharp, medium
Sharp, strong
Supplementary Figure 3. Annotated IR Spectrum of the amine, 4-((benzylamino)methyl)-2methoxyphenol.
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DISCUSSION (1 page max)
IR analysis of imine and amine products:
The imine IR spectrum does not see the C=O carbonyl stretch of the aldehyde form the pvanillin, and there is also no C-H aldehyde stretch, and there is the occurrence of the C=N
stretch. This shows that the imine was formed as these were the known changes to prove
the product.
The amine IR spectrum should show a new observed frequency at 3300-3500 showing the
formation of a N-H secondary stretch, proving the formation of the amine from the imine.
NMR analysis of amine product:
There are 7 NMR signals that agree with how many should be found on the amine without
the OH and NH.
A at 7.3ppm with integration of 5.00 shows the 5 hydrogens of the aromatic ring of
benzylamine.
E is the 3 hydrogens on the sp3 carbon the ether because it is a singlet and has an
integration of 3.01.
F & G as singlets show the best proof of product formation because the integration of
about 2 means they are both sp2. Signal F would have a higher chemical shift because it is
closer to the benzene ring with the alcohol and ether.
B, C, D: are the aromatic hydrogens and so are at 7-9ppm. The ether and OH are electron
withdrawing, so signals B and C have the highest chemical shift and signal D is a doublet of
doublets and has the lowest chemical shift due to location in comparison to EWG.
Amines
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DISCUSSION: PART 2 (1 page max)
Mechanism:
Application of reductive amination:
Fluoxetine.
This drug is the active ingredient in Prozac, a common anti-depressant that works by
inhibiting serotonin reuptake. This drug is synthesized by:
With reductive amination being shown in the second step with NaBH4. 4
Amines
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REFERENCES
1. Ashenhurst, J. Reductive Amination
Reductive Amination, and How It Works – Master Organic Chemistry (accessed
2023-02-23)
2. Afanasyev. Reductive Amination in the Synthesis of Pharmaceuticals Reductive
Amination in the Synthesis of Pharmaceuticals - PubMed (nih.gov) (accessed 202302-23)
3. Kumar. Biocatalytic reductive amination from discovery to commercial
manufacturing applied to abrocitinib JAK1 inhibitor Biocatalytic reductive
amination from discovery to commercial manufacturing applied to abrocitinib JAK1
inhibitor | Nature Catalysis (accessed 2023-02-23)
4. Meaghan B. Three Step Synthesis of Fluoxetine A Three-Step Synthesis of
Fluoxetine (stkate.edu) (accessed 2023-02-23)
****Please don’t take marks off for being late… I was in Boston Friday-Sunday for a first
responder conference and the wifi was spotty and I thought these uploaded, but when
checking to make sure my tutorial mark went into crowdmark just now I saw the warning
that this wasn’t completed. Sorry.
Amines