Synthesis of Methyl anthranilate

Name: Alejandro Fernandez Zaitsev

Student number: S5678862
Assistants: David Grantz, Vasilis Koutsogiannopoulos
Date: 17/18-10-2024

Reaction Overview:

Figure 1: The synthesis of methyl anthranilate using phthalimide as starting material

Abstract:
Methyl anthranilate was synthesized by performing a Hoffman rearrangement of
phthalimide, followed by an esterification using methanol. The product was purified
and analyzed using 1H-NMR and FTIR to find that methyl anthranilate was formed
with a yield of 17%.

Introduction:
The goal of this experiment is to determine whether the devised procedure will indeed
synthesize methyl anthranilate. The procedure starts with a Hoffman rearrangement
of phthalimide to give anthranilic acid, followed by an esterification using methanol,
to give as a product methyl anthranilate. The product and the intermediate after the
Hoffman rearrangement will both be analyzed to determine whether indeed this is a
viable route to synthesize methyl anthranilate.
Theory:

Figure 2: Mechanism of synthesis of methyl anthranilate from phthalimide

The mechanism for this reaction has two parts, the first one is a Hoffman
rearrangement, and the second one is a esterification. So following Figure 2 it can be
seen that the first step is the deprotonation of phthalimide, forming a compound with
multiple resonant structures (Resonance 1), one of these further reacts with Cl-OH, in
Step 1.2. Then once a good leaving group has been formed a hydroxide ion attacks one
amide carbon and the amine leaves while making a double bond with the other amide
carbon. This structure has resonance (Resonance 2) and so one of these is what will
react further through a Hoffman rearrangement in Step 1.4. The newly formed
isocyanate then reacts with a hydroxide ion to form a carboxylate and a secondary
amine, which in Step 1.6, the carboxylate ion leaves as carbon dioxide and leaves
behind an imide which then is simply protonated in the next step, forming the
intermediate, anthranilic acid. Then in the esterification process, the intermediate is
protonated, and in the next step a methanol molecule attacks the activated carboxylic
acid, forming a tetrahedral intermediate. In Step 2.3, a proton exchange occurs, and in
Step 2.4 the water molecule is eliminated, and finally in Step 2.5 after a deprotonation,
the product, methyl anthranilate, is formed.

Experimental:
Phthalimide (10.03 g, 68.2 mmol, 1.0 eq) and NaOH (11 M, 25 mL, 275 mmol, 4.0 eq)
were stirred together for 5 min, afterwards the mixture was in an ice bath and NaOCl
(60 mL, 81.6 mmol, 1.2 eq) was added, and the orange mixture was stirred for 3 h and
30 min, after which the solution was tar like in color. The solution was quenched with
sodium bisulfite, and HCl was added afterwards dropwise. The intermediate was
extracted using diethyl ether (4 × 60 mL) and washed with brine (1 × 80 mL). Then
the pale yellow solution was dried using magnesium sulfate and concentrated in
vacuo. The pale yellow solid intermediate was analyzed using 1H-NMR and FTIR. The
intermediate was then refluxed with MeOH (70 mL) and sulfuric acid (25 mL, 466
mmol, 6.8 eq) for 16 h. The solution was then quenched to pH 6 using saturated
sodium bicarbonate, and solid NaOH. The colorless solution was then split into two
equal batches and each of these underwent the following steps. The product was
extracted using diethyl ether (4 × 100 mL), washed with water (1 × 100 mL), washed
with brine (1 × 100 mL), dried using magnesium sulfate and concentrated in vacuo.
The batches were then recombined and analyzed using 1H-NMR, FTIR and the yield
was found to be 17%.
The FTIR of the intermediate was as follows:
−1
FTIR: 𝑐𝑚 3472 (N-H), 3620 (C-H(ar)), 3588-1800 (O-H), 1667 (C=O), 1511 (N-H
primary), 1417 (C(ar)-N), 1241 (C-O).
The 1H-NMR of the intermediate was as follows:
1H-NMR (100 MHz, DMSO) δ 3.32 (s), 2.55 (s).
The FTIR of the product was as follows:
−1
FTIR: 𝑐𝑚 3481 (N-H), 3470 (C-H(ar)), 2981 (C-H(al)), 1697 (C=O), 1615 (N-H
primary), 1295 (C(ar)-N), 1245 (C-O).
The 1H-NMR of the product was as follows:
1H-NMR (100 MHz, DMSO) δ 7.82 (d, 1H, J = 9 Hz), 7.29 (t, 1H, J = 8 Hz), 6.90 (d, 1H, J
= 8 Hz), 6.68 (s, 2H), 6.58 (d, 1H, J = 8 Hz), 3.82 (s, 3H), 3.55 (s), 2.86 (s), 2.54 (s), 1.43
(s).
Analysis & Discussion:

Figure 3: FTIR spectrum of intermediate

The FTIR spectrum of the intermediate shown in Figure 3 has all the expected peaks
that anthranilic acid should have, showing there is an amine, and that it’s connected
to an aromatic ring, that there is a C=O and C-O implying the presence of a carboxylic
acid derivative, but the lack of C-H(al) peaks means that it’s not an ester. But there is
no obvious O-H peak, which says that it is not a carboxylic acid. The most glaring
detail is the wide O-H peak for water, which means that the intermediate was not
properly dried. The lack of O-H peak could be due to a few possibilities: the peak is
drowned by the water peak or the pH of the product was too high, so the carboxylic
acid was deprotonated, and no O-H peak would be seen.
 Figure 4: 1H-NMR of the intermediate in 100 MHz and DMSO as solvent

The figure above (Figure 4) shows a 1H-NMR spectrum of the intermediate, which
displays two peaks, a water peak at 3.32 ppm and a singlet at 2.55 ppm, which is most
likely due to the amine. The lack of aromatic peaks between 6.5 ppm and 8.2 ppm is
what is most disturbing. Additionally, the lack of a solvent peak (DMSO), is surprising.

Figure 5: FTIR of the product

In Figure 5, no unexpected results are observed, as it is simply all the peaks from the
intermediate with the addition of an aliphatic C-H peak, which means that an ester
was formed, and the lack of peak of impurities suggests that the product does not
contain significant amounts of water. This suggests that the desired product was
obtained, but there is not enough evidence to conclude that it is indeed the desired
product, or whether it is pure.

Figure 6: 1H-NMR of the final product at 100 MHz, in DMSO

The spectrum shown in Figure 6 shows a total of 6 significant peaks, and a few
negligible impurity peaks. The singlet at 3.82 ppm is a methyl group as it integrates to
3H and does not have neighboring hydrogens, so it is caused by carbon 11. The next
peak, at 6.68 ppm, is also a singlet, and it integrates to 2H, it is most likely caused by
the amine group 7, as all the criteria fit, including the position, as N is more
electronegative than C, so the peak is more to the left, and additionally it is next to an
aromatic ring, which further deshields the hydrogens. Then there are the 3 doublets
and 1 triplet between 6.50 ppm and 7.82 ppm, which all integrate to 1H. They are all
within the expected range for aromatic protons (6.5 ppm to 8.2 ppm) so they are most
likely caused by the four aromatic protons 1, 2, 5 and 6. With the peaks assigned from
left to right as follows: 5, 1, 2, 6; the splitting patterns match up, except for 6, which
should be a triplet, but it is likely absorbed by the amine singlet. Lastly there are the
impurity peaks, which includes the DMSO peak at 2.54 ppm, and a water peak at 2.86
ppm, which suggests that the product was thoroughly dried, but not completely.
Finally there are the two peaks at 3.55 ppm and 1.43 ppm, which are likely caused by
residual diethyl ether.

An improvement to be made in the procedure is to use less sulphuric acid during the
esterification, and quench the solution afterwards using a solid base such as NaOH, to
not increase the volume of the solution to unnecessary degrees. Another improvement
is to dry the intermediate more thoroughly, to remove all water from the product,
making the esterification easier.

Conclusion:
Methyl anthranilate was synthesized from phthalimide through a Hoffman
rearrangement followed by an esterification, with a low yield of 17%. This suggest that
the synthesis route could be viable but improvements first have to be implemented
and tested to verify this hypothesis.