Submitted on 12/9/15

Synthesis of 4-Morpholinosulfonyl Aniline

S. O. Boatemaa, J. L. Dauberman, R. E. Horton, and J. Paredes School of Science & Technology, Georgia Gwinnett College,

Lawrenceville, GA 30043

Procedure

All of the reactants and equipment used for each step

was supplied by Georgia Gwinnett College Organic Chemistry

Department. Step one began with adding 2ml of analine into an

Erlenmeyer flask. Then 15 ml of water is added to the flask.

While stirring the solution 2.4ml of acetic anhydride is also

mixed into Erlenmeyer flask. When acetic anhydride, the

mixture turned a cloudy eggshell color. After adding the acetic

anhydride, 37.5ml was stirred into the mixture. Then the final

mixture was stirred while heating around 95 °C Celsius until

everything was dissolved. After everything was dissolved, the

solution was cooled to room temperature and placed in an ice

bath. Finally the formed crystals were vacuumed and washed

with distilled water. Then they were put under a heat lamp to

dry. The resulting crystals, or acetanilide, was a light eggshell

color (Figure 1).

For step 2 the acetanilide made from step 1 was slowly

mixed with 3.78ml of chlorosulfonic acid in an Erlenmeyer

flask. This was done under a fume hood, using a glass pipet with

great caution. The resulting mixture was a viscous brown and

pink liquid. Next the mixture was left to cool underneath the

fume hood. Then the oil was carefully pipetted into ice distilled

water very slowly. The Erlenmeyer flask was then washed out

with the chilled distilled water to react any remaining oil and

then poured out into the beaker of water. The product, p-

acetamidobenzenesyulfonyl chloride, was filtered using a

vacuum. Finally the precipitant was dried under a heat lamp

(Figure 3).

Step three must be performed in a fume hood as

pyridine is highly toxic. In a reaction flask .435g of p-

acetamidobenzesulfonyl chloride were combined with 4.3mL

of acetonitrile (1mL: 100mg of p-acetamidobenzesulfonyl

chloride) and allowed to dissolve. In a separate flask .174g of

morpholine and .696mL of pyridine (1mL: 250mg morpholine)

were also combined until dissolved. Then, both mixtures were

combined at stirred at room temperature for several minutes. A

precipitate did not form, therefore, the reaction mixture needed

to by acidified with 6 molar hydrochloric acid. Well over 60mL

were used until an acidic pH could be reached. The mixture

was then extracted with ethyl acetate. The organic layer was

then washed with distilled water and saturated aqueous sodium

chloride. The mixture was washed three times to ensure purity.

Anhydrous magnesium sulfate was used as a drying agent. The

product was then left to recrystallize over a period of no less

than seven days. The total amount of the 4-morpholin -4-

ylsulfonylphenolacetamide product retrieved was .320g (see

flow chart figure 5).

In step 4, using an Erlenmeyer flask, the product from

step three was mixed with six drops of six molar hydrochloric

acid. The mixture was then heated with a stir bar present to a

boiling temperature so that all of the solid dissolved. The liquid

was then cooled to room temperature and s aturated sodium

bicarbonate was added to the solution until a neutral pH was

present. The product was then cooled in an ice bath and vacuum

filtered. Liquid waste was disposed of properly and the solid

product was left to dry in a fume hood for no less than five days.

Abstract

4-morpholinosulfonyl aniline is a compound that belongs to a family of drugs called sulfa drugs or

sulfonamides. These drugs are known for their many properties and for its capability of treating a wide array for diseases. The goal of this synthesis experiment is to develop a procedure for and to achieve the

synthesis of a sulfonamide. 4-morpholinosulfonyl aniline was synthesized in four steps starting from

aniline. This experiment will specifically attempt to synthesize a pure sample of 4-(morpholinosulfonyl) aniline. The starting material is aniline. Additionally, intermediate products will be isolated and

analyzed. The products of each step were analyzed using thin layer chromatography, mel-temp analysis, IR, and H’NMR. The final product, 4-(morpholinosulfonyl), will be further analyzed for purity.

The total amount of 4-morpholinosulfonyl aniline produced

was .146g (Figure 7)

Results

Step one resulted in 1.972g of acetanilide. The melting

point from the melting point analysis was 115.2°C (Table 1).

The TLC had an Rf value of .636 (Table 1). An IR and an

HNMR was also retrieve and shown in the figures and tables

section. (Figure 12, Figure 13).

Step two resulted in .435g of p-

acetamidobenzenesulfonyl chloride. The experimental melting

point was 140°C (Table 1).

Step 3 resulted in .320g of p- morpholin-4-

ylsulfonylphenol acetamide. The experimental melting point

was 120.9 (Table 1). The TLC resulted in an Rf value of .552

(Table 1). The IR and HNMR is featured on the figured and

tables page (Figure 14, Figure 15).

Step 4 resulted in .146g of 4-

morpholinosulfonylbenzene. The melting point of this product

was 215°C (Table 1). The TLC resulted in an Rf value of .54

(Table 1). The IR and HNMR is also feature in the figures and

tables page (Figure 16, Figure 17).

Discussion

The purpose of the overall experiment was to use

proper lab techniques to synthesize a sulfonamide from analine.

The specific sulfonamide that was synthesized was p-

morpholinosulfonyl analine.

For step one, the amount of product that was extracted

was 1.972g of acetanilide. The calculated theoretical yield was

2.906g. That gives a percent yield of 67.9%. The sweat point of

product was 113.9 °C. The melting point was 115.2 °C. The

change in temperature is less than two °C which indicates that

the product is pure. It was also very close to the literary melting

point of 114.3°C. The thin layer chromatography or TLC also

showed that the product was pure. It had one spot and had an

Rf value of .636. The acetanilide was then processed through

mass spectroscopy by running IR and NMR. The IR was found

to have possible nitrogen-hydrogen bonds at 3289.87cm-1. A

benzene ring is present at 1595.99cm-1. The carbon double

bonded oxygen may be found at 1660.72m-1, which is also

consistent with the structure of acetanilide (see fig. 12).

The NMR peaks were found to be at 2.02ppm and 7.28ppm.

The first peak is most likely attributed to the aldehyde portion

of the acetanilide compound. The second peak is most likely

the benzene ring portion, which is usually found between six

and eight ppm. These spectroscopy images support the

structure of an acetanilide compound (see fig. 13).

Step two resulted in getting .435g of

pacetamidobenzenesulfonyl. The calculated theoretical mass of

step 2 was 2.664g. The resulting percent yield for this step was

16.3%. The sweat point of the product was 138.4°C and the

melting point was 140 °C. The change in temperature is less

than 2 °C. This indicates that the product was a pure substance.

The literary melting point was 146°C which is very close to the

tested melting point.

For step three the amount on product synthesized was

.320g. The theoretical yield for this step was .529g. This means

that there was a percent yield of 60%. The sweat point of this

product was 120.5°C and the melting point was 120.9°C. The

results of the melt-temp showed an overall change in

temperature of .5 °C. This indicates that the product is a pure

substance. However, the experimental melting point is about

22°C away from the literary melting point which was 142-145.

This could be due to a small amount of water mixed in with the

product. The TLC plate also indicated that the product w Spectroscopy was obtained by running an IR and NMR of the

4-morpholin-4-ylsulfonylphenolacetamide product. The IR

was found to have a carbon double oxygen bond at 1669.61c m-

1 and a benzene ring at 1606.87cm-1. The nitrogen-hydrogen

bond may be found at 3445.09cm-1, however, it is not entirely

clear, as there are also bonds at 3253.26cm-1 and 3103.51c m-

1. A carbon-hydrogen bond may also be present between

2500cm-1 and 3000cm-1 (see figure 14). This is consistent

with the compound’s structure (also included in figure 14). The

NMR found peaks at 8.44, 7.27, and 5.17ppm. The 5.17ppm

peak could be a double oxygen bonded to a carbon, but it is

unclear (see figure 15). Further testing and research would need

to be completed to determine if the NMR spectroscopy is

accurate.

For step four, the total amount of product extracted

was .146 g. The theoretical amount of product was .451 g. The

overall percent yield of our final product was 32.4%. The sweat

point of the product was 214.6°C and the sweat point was

215°C. The results of the melt-temp had a change in temp of

.4°C. This shows that our product was a pure substance. The

literary melting point is 216°C, which is very close to the

experimental melting point. The TLC plate showed one spot,

and had an Rf value .540. This also indicates that our product

was a pure substance. Spectroscopy was obtained by running

an IR and NMR of the 4-morpholinosulfonyl aniline product.

The IR was found to have possible nitrogen-hydrogen bonds at

3441.59cm-1 and at 3363.3cm-1. A benzene ring is also present

at 1640.80cm-1. The carbon-hydrogen bond may be found at

2845.64cm-1, which is also consistent with the structure of this

compound (see fig. 16). This is consistent with the compound’s

structure (also included in figure 16). The NMR found peaks

at 2.20, 2.91, 3.72, 6.16, 6.92, and 7.61ppm. The 2.20ppm peak

may be a carbon-hydrogen bond and the 3.72 and 2.91ppm

peaks may be the morpholine group. The higher peaks may

refer to a split nitrogen group, however, testing and research

would need to be completed to determine if the NMR

spectroscopy is accurate.

Some possible sources is error could be from using the

HMNR. There were some difficulties when trying to get the

step 3 and 4 into the machine. This could have affected the

results of the peaks. Another source of error could have resulted

in having a little water in the step 3 product while testing its

melting point. Our experiment could be improved by making

sure our product was completely dry before analyzing its

melting point. Another thing that could be improved is the use

of the HNMR. One further a direction for this experiment

would be to synthesize other sulfadrugs using a different

starting material.

Conclusion

Through this synthesis laboratory experiment it is

concluded that aniline can by synthesized to form 4-

morpholinosulfonyl aniline; the targeted sulfonamide

compound. The IR spectroscopy of the step four product

matched published spectroscopy for the the same compound.

(insert footnote for pharmacie globale article, weird spelling).

However, more research should be completed to ascertain if the

spectroscopy is accurate for each structure.

Table 1: Overall Results for Steps 1-4

Table 2: Overall IR Spectroscopy for Steps 1-4

Figure 1

Figure 2: Mechanism for Aniline → Acetanilide

Armstrong, K. Synthesis of Bromoaniline

http://www.foothill.edu/psme/armstrong/mssbromoaniline.shtml (accessed May 1, 2015).

Figure 3

Figure 4: Mechanism for Acetanilide → p-acetamidobenzenesulfonyl chloride

sulfamechanism http://www.organicchem.org/oc2web/lab/exp/sulfa/sulfamechanism.html (accessed

May 1, 2015).

Figure 5

Figure 6: Mechanism for p-acetamidobenzenesulfonyl chloride → p-morphilin-4-ylsulfonylphenol acetamide

sulfamechanism http://www.organicchem.org/oc2web/lab/exp/sulfa/sulfamechanism.html (accessed

May 1, 2015).

Figure 7

Figure 8: Mechanism for p-morphilin-4-ylsulfonylphenol acetamide → 4-morpholinosulfonyl aniline

sulfamechanism http://www.organicchem.org/oc2web/lab/exp/sulfa/sulfamechanism.html (accessed

May 1, 2015).

Figure 9: Calculations for theoretical yield & percent yield

Figure 10: Calculations for theoretical yield & percent yield

Figure 11: Calculations for theoretical yield & percent yield

Figure 12: IR of Acetanilide Product

Figure 13: H-NMR of Acetanilide

Figure 14: IR of p-morphalin-4-ylsulfonalphenyl acetamide

Figure 15: H-NMR of p-morphalin-4-ylsulfonalphenyl acetamide

Figure 16: IR of 4-morphalinosulfonyl aniline

Figure 17: H-NMR of IR of 4-morphalinosulfonyl aniline