Equation 1: Overall Synthesis Reaction of Benzocaine




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НазваниеEquation 1: Overall Synthesis Reaction of Benzocaine
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Single Step Synthesis of Benzocaine

Christopher Nusbaum

Dates Performed: 9-21 July 2010

Date Submitted: 26 July 2010


Purpose: The purpose of this experiment was to synthesize benzocaine, a common topical anesthetic, via acid-catalyzed Fisher esterfication of p-aminobenzoic acid and ethanol

Results and Discussion: Benzocaine is an ester and can be prepared via acid-catalyzed Fisher esterfication from p-aminobenzoic acid and ethanol, both of which are readily available starting materials. The overall reaction is shown below as Equation 1.

Equation 1: Overall Synthesis Reaction of Benzocaine.

O

OH

C

NH2

+ HOCH2CH3

1. H2SO4

2. Na2CO3

O

OCH2CH3

C

NH2

+ H2O


Although the synthesis reaction proceeded to completion, its mechanism was actually a series of equilibrium reactions. The equilibrium was made to lie far to the right by using acid in excess and carrying out the reaction in ethanol. Using one reactant as the solvent reduced possibilities for side reactions and ensured it was present in sufficient excess to drive the reaction to completion.

1.03g (7.51x10-3 mol) of p-aminobenzoic acid was added to 10.01mL (0.2874 mol) of absolute ethanol, and dissolved by slow stirring. 1mL (2x10-2 mol) of 18M sulfuric acid was added to the mixture and an unexpected heavy white precipitate was observed to form.

Initially it was thought the precipitate was some sort of sulfate salt, but further research1 revealed it was a zwitterion. Although zwitterions are more commonly associated with amino acids, any compound that bears a carboxylic group and an amine group can form zwitterions under suitable conditions. The overall equation of zwitterion formation of p-aminobenzoic acid is shown as Equation 2.

Equation 2: Zwitterion Formation of p-Aminobenzoic Acid

O

O-

C

NH3+

O

OH

C

NH2

H2SO4


In a suitably acidic environment, the carboxylic group donates a proton to the solvent, while the lone pair of the amine group, acting as a Lewis base, accepts a proton. The overall effect is that p-aminobenzoic acid donates a proton to itself and takes on a form that bears both a negatively charged carboxylic group and a positively charged amine group. Zwitterionic compounds are usually soluble in water and insoluble in organic solvents; the p-aminobenzoic acid used in this experiment followed this pattern and precipitated out of the solution.

Conversion of a compound to its zwitterionic form is an equilibrium process. Thus, some amount of non-ionic p-aminobenzoic acid remained in solution, and as it was consumed by the reaction the zwitterionic p-aminobenzoic acid dissolved to replace it. This is fortunate as the mechanism of Fisher esterfication is inhibited by the zwitterionic form of p-aminobenzoic acid.

The reaction mixture was heated under reflex with fast stirring for approximately thirty minutes, during which time the esterfication reaction took place. The following equations detail the mechanism of this reaction, starting with Equation 3.

HO—CH2CH3 + H—OSO2OH

H2O—CH2CH3 + - OSO2OH

:

:

:

:

+

:

:

:

:

Equation 3: Ethyloxonium Formation


The first step in the Fisher esterfication reaction was the donation of a proton to ethanol by the acid catalyst.

Equation 4: Protonation of p-Aminobenzoic Acid

+ H—OHCH2CH3

:

+

O

OH

:

:

C

NH2

:

OH

OH

C

NH2

+

+ HOCH2CH3


The second step of the mechanism was the donation of a proton by ethyloxonium ion to p-aminobenzoic acid.


+ HO—CH2CH3

:

:

:

OH

OH

C

NH2

+

+

O CH2CH3

OH

OH

C

NH2

:

H

Equation 5: Nucleophilic Addition of Ethanol to p-Aminobenzoic Acid


The nucleophilic oxygen of ethanol bonded to p-aminobenzoic acid. Although the most stable resonance structure of the previous step showed oxygen bearing a positive charge, it was a poor electrophile when it was already bonded to two other atoms. The positive charge was delocalized over both hydroxyl groups and the carbon that bore them. The carbocation character of the carbon made it an excellent electrophile, thus the nucleophilic oxygen of ethanol bonded to it.

+

O CH2CH3

OH

OH

C

NH2

:

H

+ HO—CH2CH3

:

:

OCH2CH3

OH

OH

C

NH2

+ H2O—CH2CH3

+

:

Equation 6: Deprotonation of Tetrahedral Intermediate


The intermediate formed as shown in Equation 5 was very unstable as it contained a tri-substituted oxygen. This oxygen donated its excess hydrogen to the solvent.

:

:

+ H—OHCH2CH3

+

:

OCH2CH3

OH

C

NH2

OH

OCH2CH3

HOH

OH

C

NH2

:

+

Equation 7: Protonation of Tetrahedral Intermediate Hydroxyl Group


:

:

:

OCH2CH3

HOH

OH

C

NH2

:

+

OH

OCH2CH3

C

NH2

+ H2O

+

Equation 8: Dehydration of Tetrahedral Intermediate Hydroxyl Group


The tetrahedral intermediate formed as shown by Equation 6 immediately dehydrated in the acidic solution. As there was a greater amount sulfuric acid present than p-aminobenzoic acid (2x10-2 mol sulfuric acid verses 7.51x10-3 mol p-aminobenzoic acid) and sulfuric acid is a much stronger acid than p-aminobenzoic acid, the reaction stopped at this stage and protonated benzocaine remained in solution.

After reacting under reflux for approximately thirty minutes, 20.0mL of 10% by mass (2.0x10-2 mol) Na2CO3 was added to the reaction mixture to neutralize the remaining sulfuric acid and force the benzocaine product out of solution as described by Equation 9.

:

O—H

OCH2CH3

C

NH2

+

O

OCH2CH3

C

NH2

+ HCO3-

+ - OCOO

:

:

:

Equation 9: Neutralization of Conjugate Acid of Benzocaine


The protonated acidic form of benzocaine was neutralized by bicarbonate ions. Benzocaine is normally highly soluble in ethanol, but in this experiment sodium carbonate was added in excess and the benzocaine precipitated out of solution. Benzocaine bears two functional groups capable of accepting a proton with relative ease, a carbonyl group and an amine group. Thus, pure benzocaine is weakly basic; the excess base prevented its re-ionization and forced it out of solution.

The raw benzocaine was collected by vacuum filtration, washed with deionized water, and allowed to dry. 0.75g (4.5x10-3 mol) of raw benzocaine was collected, a raw yield of 60%.

The raw benzocaine was purified by recrystallization. It was mixed with approximately 30mL of deionized water and heated to approximately 60°C. 9.8mL of methanol was added dropwise until the benzocaine was observed to fully dissolve. The mixture was cooled in an ice bath for approximately fifteen minutes to recrystallize the benzocaine, which was then separated from the mixture by vacuum filtration. The benzocaine was washed with deionized water and allowed to dry. 0.56g (3.4x10-3 mol) of benzocaine was recovered, a net yield of 45%.

The melting point of the final product was tested to verify its identity and purity. The product melted over a one degree range of 88°-89°C, an excellent match for the literature value of 88°-90°C2. This confirmed the identity of the product as benzocaine and indicated that it was pure.

IR spectra of the product and its starting materials were taken and compared with reference spectrums. These spectrums are shown below as Figures 1 through 6.

Figure 1: Synthesized Benzocaine IR Spectrum

benzocaine_ir.tif


Figure 2: Ethanol IR Spectrum

absolute_ethanol_ir_sample2.tif

Figure 3: p-Aminobenzoic Acid IR Spectrum

p-aminobenzoicacid_ir_sample2.tif


Figure 4: Benzocaine Reference IR Spectrum3

benzocaine_irref.gif

Figure 5: Ethanol Reference IR Spectrum3

ethanol_ir_reference_aist.gif


Figure 6: p-Aminobenzoic Acid Reference IR Spectrum3

p-aminobenzoicacic_ir_ref.gif

Multiple methods were employed to obtain the best IR spectra possible of the solid benzocaine product and p-aminobenzoic acid starting material; the vice yielded the best results for both. A full analysis of the benzocaine spectrum is given in Table 1.



Table 1 – IR Spectral Analysis of Synthesized Benzocaine

Peak

Analysis

Match with Reference

2350

No interpretation

No

1690

C=O

Yes

1275

Both of these bands together are consistent with an ester attached to an aromatic ring.

Yes

1175

Yes

850

Para-substituted benzene ring

Yes

725

No interpretation. This portion of the spectrum is missing from the reference

No



Because of the high amount of noise, misshapen nature of the graph, and the small number of peaks actually able to be compared to a reference, the IR spectrum obtained from the synthesized benzocaine was determined to be inconclusive.

The identity and purity of the starting materials was known in advance, making a peak-by-peak analysis of the starting materials unnecessary. The ethanol spectrum was a match to the reference spectrum; the p-aminobenzoic acid spectrum could only be tentatively matched to the reference spectrum due to its poorer quality.

NMR spectra of the product and its starting materials were also taken and compared with references. These spectra are shown as Figures 7 through 12.


Figure 7: Synthesized Benzocaine NMR Spectrum

nmr_benzocaine_clean.tiff

Figure 8: Ethanol NMR Spectrum

nus_eth_fullclean.tiff

Figure 9: p-Aminobenzoic Acid NMR Spectrum

p-aminobenzoicacid_inacetoned_fullclean.tiff

Figure 10: Benzocaine NMR Reference Spectrum3

benzocaine_nmrref.gif

Figure 11: Ethanol NMR Reference Spectrum3

ethanol_nmr_reference_aist.gif

Figure 12: p-Aminobenzoic Acid NMR Reference Spectrum3

p-aminobenzoicacid_nmr_ref.gif

A full analysis of the spectrum obtained for the synthesized benzocaine is shown in Table 2.

Table 1 – NMR Spectral Analysis of Synthesized Benzocaine

Peak

Type

Analysis

Match with Reference

1.368

Triplet

Terminal CH3. It was only slightly deshielded by the adjacent CH2, which caused the chemical shift to be fairly small. This peak represents three hydrogens, and is thus the largest peak on the graph.

Yes

4.056

Singlet

NH2. The hydrogens this peak represented were deshielded by the electronegative nitrogen, though less so than the peaks corresponding to CH2 and the benzene hydrogens. The nitrogen that was the hydrogen’s parent atom was bonded to the benzene ring, which cannot bear a hydrogen at any point that bears a substituent because it is sp2 hybridized. The nearest hydrogen was two groups (four atoms) away and did not cause any spin-spin coupling.

Yes

4.325

Quartet

CH2. Inductive effects from the adjacent carbonyl group significantly deshielded these hydrogens, and the adjacent CH3 group caused the expected splitting pattern of four peaks.

Yes

6.647

Doublet

This peak corresponded to the two hydrogens bonded to the two carbons in the benzene ring adjacent to the carbon that bore the nitrogen. Nitrogen has a lone pair and acts as an electron-releasing substituent on the benzene ring, causing these two protons to be less deshielded than the protons on the carbons adjacent to the carbonyl. Doublet splitting was observed because each hydrogen is bonded to a carbon that is adjacent to a carbon that only bears one hydrogen.

Yes

7.32

Singlet

Unknown trace contaminant. The peak at this position was inconsistent with water and the starting materials.

No

7.870

Doublet

This peak corresponded to the two hydrogens bonded to two carbons in the benzene ring adjacent to the carbon that bore the carbonyl group. Carbonyl is strongly electron-withdrawing and caused this pair to be more deshielded than the pair at 6.647. Doublet splitting was observed for the same reason as the peak at 6.647.

Yes



The NMR spectrum obtained for benzocaine was determined to match the reference spectrum for benzocaine. The unexpected small singlet at 7.32 was attributed to an unknown contaminant. Based on the melting point data, the sample was determined pure to two significant figures, 1.0 parts benzocaine per 1 part product, or greater than 95% benzocaine. A more accurate assessment of purity could have been obtained by obtaining a GCMS spectrum of the benzocaine, identifying the impurity, and then quantitatively determining its concentration.

The identity and purity of the starting materials was known in advance, making a peak-by-peak analysis of the starting materials unnecessary. It was noted that the O-H peak in the known sample of p-aminobenzoic acid showed considerably better definition than the reference, likely due to its low concentration and the choice of acetone-D rather than chloroform-D as the solvent. More interestingly, the ethanol spectrum showed two fewer peaks than expected in the splitting of the peak corresponding to CH2 hydrogens; a quartet was expected, but a doublet was observed.

Experimental: 1.03g of p-aminobenzoic acid and 10.01mL of absolute ethanol were placed in a round-bottom flask with a stirbar. The mixture was stirred until all the p-aminobenzoic acid had dissolved, at which time 1mL of 18M sulfuric acid was added dropwise. A heavy white precipitate was observed to form.

A condenser was set up above the flask and the mixture was heated with rapid stirring under reflux, during which time the precipitate dissolved again. After 35:10 had elapsed, the flask was removed and immersed in an ice bath for 4:03.

The flask was emptied into a beaker and rinsed with 2mL of deionized water. 20.0mL of 10% by mass Na2CO3 was added to the beaker with stirring, and a white precipitate was observed to form. The pH was checked by dipping a capillary tube in the mixture and then dabbing it on pH paper; the pH was determined to be approximately 8.

The mixture was separated by vacuum filtration. The beaker was rinsed with three 10mL portions of deionized water and the stirbar removed with forceps. The stirbar was rinsed with rinse water from the beaker before it was set aside. The raw product was left on the vacuum to dry for approximately fifteen minutes before it was weighed, and found to be 0.75g.

The raw product was mixed with 20mL of deionized water. The filter assembly and sides of the beaker were rinsed with an additional 10mL portion which was added to the 20mL already present. The mixture was heated to approximately 60°C, and 9.8mL of methanol was added with stirring dropwise to the mixture at which time all the product was observed to have dissolved.

The beaker containing the solution was immersed in an ice bath for approximately fifteen minutes to recrystallize the benzocaine, which was separated by vacuum filtration. The beaker was washed with approximately 10mL of deionized water; the benzocaine was washed with a different 10mL portion of deionized water, then allowed to dry under vacuum for approximately fifteen minutes. The mass was again measured and found to be 0.56g.

The melting point was tested on a sample of the benzocaine and found to be 88°-89°C. IR spectra were taken on the final product and starting materials. Several methods were employed to obtain the most useful IR spectra of the solid materials, and the vise was found to give the best unambiguous spectra. NMR spectra were taken on the final product and starting materials, with CDCl3 being used as the solvent for all of the samples except p-aminobenzoic acid. p-Aminobenzoic acid was insoluble in CDCl3 and was run in acetone-D instead.

Conclusion: Benzocaine was synthesized via Fisher esterfication of p-aminobenzoic acid and ethanol in the presence of a sulfuric acid catalyst. The benzocaine product was purified via recrystallization in a solution of methanol and water, and was isolated in 45% yield. The product was analyzed by melting point determination and IR and NMR spectroscopy. The product was determined to be pure by melting point determination, but was shown to be impure by NMR analysis. Thus, it was determined pure to the limit of accuracy of the melting point apparatus, 1.0 parts benzocaine to 1 part product, or greater than 95% benzocaine.

References

  1. Carey, Francis; Giuliano, Robert. Organic Chemistry, 8th Edition; McGraw-Hill: New York, NY, 2011; pp 1124-1127.

  2. The Merck Index, 14th Edition; Heckelman, P.E., Koch, C.B., O’Neil, M.J., Roman, K.J.; Merck Research Laboratories: Whitehouse Station, NJ, USA, 2006.

  3. National Institute of Advanced Industrial Science and Technology. SDBSWeb. http://riodb01.ibase.aist.go.jp/sdbs/ (accessed 7 14, 2010).

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