1

Austin Goewert, Chem 213

Synthetic #1 FFR

Chitosan Catalyzed Synthesis of Imines

Introduction

An imine is a chemical compound that contains a carbon-nitrogen double bond. The synthesis of

imines is important in organic chemistry because imines are precursors to numerous biological and

industrial products. The carbon double bonded to nitrogen serves as an electrophile in many of these

reactions.1

Imines have important biological properties as well. The lone pair on the nitrogen serves as a

nucleophile in addition to organometallic compounds. These metallic-imine complexes reduce the

spread of cancerous tumors and serve as antioxidants. Certain imines also neutralize radicals which

otherwise would oxidize, and deteriorate DNA.2

Synthesis of imines can be accomplished by many different pathways. Common methods of

creating imines include “condensation of aldehydes/ketones with amines, addition of aryl halides and

liquid ammonia to aldehydes/ketones, hydroamination of alkynes, oxidative coupling of amines to give

imines, oxidative coupling of alcohols and amines, dehydrogenation of secondary amines, coupling of

aldehydes/ketones with nitro compounds, and the reaction between chemical equivalents of

aldehydes/ketones and amines.”1 The method used in this experiment is condensation of an aldehyde by

an amine. As this reaction is reversible and tends to favor the products, distillation or a catalyst is

necessary to push this reaction toward completion. Several sustainable catalysts have been tested,

including microwaves, ultrasound, and solvent free catalysts.1One possible catalyst is chitosan, which

contains amino groups and hydroxyl groups, allowing it to activate both nucleophillic and electrophilic

compounds. Chitosan has been used efficiently as a solvent free catalyst in an aldol condensation, which

2

has a similar mechanism to carbonyl-amine imine synthesis.3Additionally, chitosan is found naturally in

shrimp, and thus is a byproduct of fishing industry. It is abundant, cheap, non-toxic, and biodegradable.4

Chitosan is therefore a “green” catalyst, as it is cheap, environmentally friendly, and produces less

chemical waste when used under solvent-free conditions. Alternative catalysts may include silica gel

supported sodium hydrogen sulfate and extract from Sapindus trifoliatus.5,6

Scheme 1. Mechanism of chitosan catalyzed imine synthesis from aniline and vanillin.

First, vanillin is protonated by chitosan, resulting in a positively charged primary carbon (2). The

lone electron pair on the aniline nitrogen attacks this positive carbon, forming a carbon-nitrogen

bond(3). Next, chitosan deprotonates the nitrogen (3) and re-protonates the oxygen (4), forming a water

leaving group. As the water group leaves, a lone electron pair on nitrogen forms a double bond with the

primary carbon (5). Finally, chitosan deprotonates the positively charged nitrogen (6), and the imine

product is produced (7).

Imines are useful both as reactants and for their biological properties. The purpose of this

experiment is to synthesize an imine using chitosan as a catalyst. The imine will then be purified via

recrystallization. The final product will be analyzed by 1H NMR,

13C NMR, IR, and melting point.

3

Experimental

Phenol, 2-methoxy-4-[(phenylimino)methyl]- (55). Chitosan (16mg), vanillin (152mg, 0.999mmol),

and aniline (.091mL, .998mmol) were added to 4:1 ethanol to water (5mL). As the solution was stirred

for 40 minutes at room temperature, a cloudy white precipitate formed. Upon completion of the

reaction, as indicated by TLC (50% ethyl acetate/50% hexanes), distilled water (10mL) was added to the

solution. The solution was cooled in an ice bath for 20 minutes, and the product was separated using

vacuum filtration. Recrystallization (2:1 hexanes/ethyl acetate) afforded 55 as shiny, flaky, yellow-tan

crystals (159.7mg, 70.5%), mp 159-163oC;

1H NMR (400MHz, CDCl3) δ8.3412 (s, 1H), 7.6264 (s, 1H),

7.4032-7.3644 (t, 2H), 7.2572-7.1879 (m, 4H), 6.9909-6.9707 (d, 1H), 6.1031 (s, 1H), 3.9495 (s, 3H);

13C NMR (400MHz, CDCl3) δ160.1461, 152.1185, 149.0268, 147.0983, 129.0821, 125.5559, 125.2549,

120.8242, 114.1580, 108.3857, 77.2835, 76.9656, 76.6484, 55.9710; IR (ATR)ɤmax(cm-1

) 3029.0,

2960.3, 1580.5.

Results and Discussion

Phenol, 2-methoxy-4-[(phenylimino)methyl]-was synthesized at room temperature from vanillin

and aniline. Upon completion of the reaction, the product was purified via recrystallization. The final

product was analyzed using 1H NMR,

13C NMR, IR, and melting point analyses.

An important factor of this experiment was the use of chitosan as a catalyst. Due to amino and

hydroxyl substituents, chitosan is a versatile catalyst capable of both protonating with its hydroxyl

hydrogens, and deprotonating with its lone electron pairs. As shown by the mechanism titled Scheme 1

above, this synthesis utilized chitosan as both an acid and a base. As the reaction progressed, it was

monitored with TLC using 50:50 ethyl acetate:hexanes as the mobile phase. The reaction was run for 40

4

minutes. The solution was yellow in color throughout the reaction, which is consistent with Waszczak’s

results.4

After the crude solid was collected, recrystallization with 2:1 hexanes:ethyl acteate proved useful

in purifying the product. As solvent was added, an insoluble tan solid was observed in the solution. This

was most likely chitosan, as it is insoluble in this particular solution.4 No boiling stick was used which

resulted in bumping while boiling off excess solvent. After slow cooling and vacuum filtration, shiny,

flaky, yellow-tan crystals remained. The identity of these crystals was determined using the analyses

mentioned previously.

The melting point of the product was 159-163oC. This is consistent with the literature value of

159oC for phenol, 2-methoxy-4-[(phenylimino)methyl]-.

4 IR analysis (Figure 1) displays a broad O-H

peak at 3092cm-1

, which shows that the hydroxyl substituent from vanillin remains on the imine product.

Aromatic hydrogen peaks are present on top of this O-H peak, around 2960.3cm-1

. The carbon-nitrogen

double bond peak is present at 1580.5cm-1

. The primary difference between starting material IR and

product IR is the elimination of the aldehyde substituent on vanillin, and thereby the removal of one

carboxyl and one carbon-hydrogen bond. Since there is no carboxyl peak between 1730-1705cm-1

,

vanillin is not present in the product. The absence of a carbonyl peak and the presence of the three

expected peaks suggests the presence of the imine product.

Further analysis was performed with 400MHz 1H NMR spectra (Figure 3). The essential

difference between reactant and product spectra is the presence of the vinylic hydrogen marked in

Figure 3 as hydrogen c in the product. Before the reaction, this hydrogen was part of an aldehyde

substituent on vanillin. After the reaction, this hydrogen is part of the imine. Figure 3 shows this

hydrogen as a 1H singlet at 6.1031 ppm, proving the reaction did occur, as an aldehyde hydrogen would

5

absorb further downfield (9-10 ppm). Figure 3 shows that the methoxy substituent from vanillin is still

present on the product by the 3H singlet at 3.9495 ppm. The hydroxyl substituent is still present as well,

as shown by the 1H singlet at 8.3412 ppm. The aromatic hydrogens were not affected by the reaction.

All eight aromatic hydrogens can be observed from 6.9-7.7 ppm. This NMR result is similar to the NMR

for phenol, 2-methoxy-4-[(phenylimino)methyl]- published by Advanced Chemistry Development,

Inc.,and thus it proves the presence of phenol, 2-methoxy-4-[(phenylimino)methyl]-.7

13

C NMR also proved useful in analyzing the product (Figure 4). The presence of product can be

verified by the presence of a primary carbon peak at 160.1461 ppm. Before the reaction, this carbon was

the carboxyl carbon on vanillin. A carboxyl carbon’s 13

C peak is located further downfield then 160

ppm. The presence of this peak at 160 ppm proves the electrophilic attack of vanillin’s carboxyl carbon

by aniline, and the loss of the carboxyl oxygen via a water leaving group. The other 13 carbons involved

in this reaction essentially maintained the same substituents before and after the reaction. The three

aromatic carbons attached to the three substituents (imino, methoxy, and hydroxyl) are present from

147-153 ppm. The remaining 10 aromatic carbons are shown by 10 peaks between 76-130ppm. This 13

C

NMR also is similar to the 13

C NMR for phenol, 2-methoxy-4-[(phenylimino)methyl]- published by

Advanced Chemistry Development, Inc.7

Following the results from IR, NMR, and melting point data, it can be concluded that phenol, 2-

methoxy-4-[(phenylimino)methyl]- was successfully synthesized. The percent yield for the product was

70.5%. This is a fair yield, however it is noticeably lower then the 95% yield obtained by Pore in a

similar experiment.6The primary source of error in this experiment was the bumping of the liquid during

recrystallization. This bumping happened 3-4 times, and each time solution was lost from the flask. In

addition to this loss, residual losses occurred in the flask after running the reaction, and in the Hirsch

funnel after vacuum filtration.

6

In order to obtain better results in future experiments, a boiling stick should be used during

recrystallization to prevent bumping. Small residual losses in certain cases cannot be avoided. Overall,

the experiment was successful in producing a 70.5% yield of pure phenol, 2-methoxy-4-

[(phenylimino)methyl]- from vanillin and aniline, with the use of chitosan as a catalyst. The reaction

went to completion, as shown by TLC. The crude product was successfully purified using

recrystallization. Its identity was validated by melting point, IR, 1H NMR, and

13C NMR.

References

1. Patil, R.D.; Adimurthy, S; Asian J.of Organic Chem. 2013, 2, 726-744.

2. Zhao, F.; Liu, Z.Q.; J. Phys. Org. Chem.2009, 22, 791-798.

3. Tharun, J.; Sudheesh, N.; Ram, S.; Journal of Molecular Catalysis A: Chemical.2010, 333,

158-166.

4. Waszczak, Z.; Green Chem. 2013, 15, 811.

5. Gopalakrishnan, M.; J. of Chem. Research. 2005, 5, 299-303.

6. Pore, S.; Chem. and Biodiversity. 2010, 7, 1796-1800.

7. Advanced Chem. Development, Inc. Predicted NMR data 1994-2013.