The Science Snail
  • Home
  • Science
  • Philosophy
  • About
  • Contact
  • Privacy Policy

Benzocaine synthesis from toluene and p-xylene

7/16/2023

0 Comments

 
​Benzocaine is local anesthetic useful as a topical anesthetic and painkiller. In this article I examine two industrially relevant routes to synthesize this drug from widely available petrochemical building blocks: toluene and p-xylene. Where possible, I provide arrow-pushing mechanisms for the reactions used. Benzocaine belongs to the amino ester class of drugs. It has a simple chemical structure, even having a comprehensible IUPAC name: ethyl 4-aminobenzoate. Installation of the amine and ethyl ester are the key transformations required in the production of this drug.
Benzocaine chemical structure

Synthesis of benzocaine from toluene

​First, I discuss the production of benzocaine from toluene. It is helpful to begin with a retrosynthetic analysis to clarify the logic of the synthetic strategy:
Benzocaine retrosynthesis from toluene
We begin with a functional group interconversion on the aryl amine. It can be obtained from a nitro group by reduction. Earlier in the synthesis, the introduction of a nitro group will be a practical way to functionalize para to toluene’s methyl group. Furthermore, unveiling the amine as the final step avoids complications from its reactivity. Next, we disconnect the ethyl ester. It is available from a Fischer esterification of p-nitrobenzoic acid. In turn, oxidation of p-nitrotoluene’s methyl group gives this derivative. Lastly, the required p­-nitrotoluene can be made by nitration of toluene.

​Here is the synthetic route with more detailed reaction conditions:
Benzocaine total synthesis from toluene
​To prepare benzocaine from toluene, the first step is nitration using concentrated sulfuric acid and nitric acid. Though only the para regioisomer p-nitrotoluene is desired for this synthesis, the reaction gives a mixture of ortho and para regioisomers along with a trace of meta [1]. These other nitration products are not a serious problem as they all are valuable building blocks in the chemical industry. They can be separated by fractional distillation and crystallization. Here is an arrow-pushing mechanism for the para-nitration of toluene:
Toluene nitration arrow pushing mechanism
First, protonation of nitric acid and dehydration generates a nitronium ion which is a reactive electrophile. Nucleophilic attack by toluene gives both ortho and para nitrotoluene products. Nitration at these positions is favored over meta due to better resonance stabilization of the arenium ion (the methyl group is electron-donating).

The second step in the synthetic route is the oxidation of p-nitrotoluene to p-nitrobenzoic acid. There are many reactions which would be suitable for this benzylic oxidation. In the condition shown, the reaction is done using oxygen gas and acetic acid as the solvent with catalytic cobalt acetate and potassium bromide [2].

Next, the p-nitrobenzoic acid is esterified with ethanol by Fischer esterification to ethyl p-nitrobenzoate [2]. This reaction is conducted in refluxing ethanol with catalytic sulfuric acid. Toluene is added as a cosolvent to improve solubility. Here is an arrow-pushing mechanism for this Fischer esterification:
Fischer esterification arrow pushing mechanism
​The mechanism begins with protonation of the carbonyl oxygen of the carboxylic acid. This renders the carbonyl carbon electrophilic. Nucleophilic attack by ethanol is followed by dehydration to give the ethyl ester. The reaction is reversible and using a large excess of ethanol is required to drive the equilibrium toward ester formation.

The final reaction in this route is reduction of the nitro group of ethyl p-nitrobenzoate to an amine, giving the desired benzocaine. This can be accomplished by palladium on carbon-catalyzed hydrogenation [3].

Synthesis of benzocaine from p­-xylene​

An alternative industrial route to benzocaine begins with p-xylene. As before, I begin with a retrosynthetic analysis exploring this strategy:
Benzocaine retrosynthesis from p-xylene
This time, we begin the retrosynthesis with the ethyl ester using a Fischer esterification. Next, the amine is disconnected via a Hoffmann rearrangement. The required aryl amide can be produced from monomethyl terephthalate by ammonolysis reaction. Two oxidations and another Fischer esterification leaves us with the starting material p-xylene.

The p-xylene route with detailed reaction conditions follows:
Benzocaine total synthesis from p-xylene
​The first three steps of this route, converting p-xylene to monomethyl terephthalate, are known as the Dynamit-Nobel (Witten) process [4]. First, p-xylene is oxidized at one of its benzylic positions to the benzoic acid derivative p-toluic acid. Though there are many conditions this selective oxidation could be accomplished under, the approach shown uses 8 atm of air (oxygen source), 120 °C, and catalytic cobalt fatty acid salt. Next, the p-toluic acid is esterified with methanol to methyl p­­-toluate. This reaction is done at high temperature (150 – 230 °C) and pressure (15-60 atm), so catalytic strong acid is not required. Mechanistically, this process is equivalent to the Fischer esterification explained above. Another round of air oxidation catalyzed by catalytic cobalt fatty acid salt oxidizes the remaining methyl group, giving monomethyl terephthalate. Ammonolysis with liquid ammonia converts the methyl ester into a primary amide, terephthalic acid monoamide [5].
 
Here is an arrow-pushing mechanism for ammonolysis of the methyl ester:
Ester ammonolysis arrow pushing mechanism
​Attack of ammonia at the carbonyl carbon of the methyl ester gives a tetrahedral intermediate. Loss of methanol gives the primary amide.
 
In the next synthetic step, a Hoffmann rearrangement is used to convert the primary amide into an arylamine. The reaction uses stoichiometric sodium hypochlorite (bleach) and excess sodium hydroxide under aqueous conditions [5]. An arrow-pushing diagram for the rearrangement is shown below:
Hoffmann rearrangement arrow pushing mechanism
The mechanism begins with deprotonation of the amide and chlorination with hypochlorite. Basic conditions promote rearrangement of the bromoamide to an isocyanate. Hydrolysis and decarboxylation affords the amine.
​
The final reaction is another Fischer esterification of the p-aminobenzoic acid with ethanol and catalytic sulfuric acid, giving benzocaine. Though the aryl amine is nucleophilic, the acidic conditions and large excess of ethanol supress formation of amide side product.
0 Comments



Leave a Reply.

    Archives

    July 2023
    December 2022
    April 2022
    December 2021
    December 2020
    September 2020
    August 2020
    December 2019
    June 2019
    February 2019
    January 2019
    December 2018
    October 2018
    August 2018
    July 2018
    February 2018
    December 2017
    December 2016
    April 2016
    January 2016
    August 2015
    July 2015
    February 2015
    December 2014
    August 2013

    Categories

    All
    Biochemistry
    Biology
    Enzymology
    Finance
    Health
    Mathematics
    Organic Chemistry
    Physical Chemistry

    RSS Feed

    List of all articles

    Benzocaine synthesis

    Mathematics of compound interest

    Dynamic nuclear polarization in solid state NMR 

    Modelling a multi-state G protein signalling pathway

    Organic synthesis of Aspirin

    Distinguishing enzyme inhibition mechanisms


    ​Metformin total synthesis
    ​
    ​Ki, Kd, IC50, and EC50 values

    ​
    AZT: mechanism and synthesis


    Forecasting website ad revenue

    Km vs Kd

    The relationship between TV screen size and price

    ​Health benefits of green tea

    Synthesis of ibuprofen from benzene

    ​The mechanism of action of Eflornithine
    ​
    Synthesis of sucralose from sucrose


    Diluting a solution to Avogadro's limit
    ​
    The affect of mutation rate on evolutionary equilibrium

    ​
    Organic synthesis of indomethacin


    Probing protein-protein interactions in the yeast glycolytic metabolon

    Time course enzyme kinetics

    A generalized​ model for enzymatic substrate inhibition
    ​
    ​The basis of high thermostability in thermophilic proteins
    ​

    First order drug elimination kinetics
    ​
    Improving the efficiency of protein dialysis: constant dialysate replacement


    Mathematical modelling of evolution

    Calculating the optimum ddNTP:dNTP ratio in Sanger sequencing

    A mathematical model of hair growth

    Life does not violate the second law of thermodynamics


    Collagen and the importance of vitamin C

    Temperatures below absolute zero are surprisingly hot

    The molecular difference between heat and work

    Want to keep up to date with new articles? Subscribe to the monthly newsletter! ​

Subscribe to Newsletter

​© 2023 Copyright The Science Snail. All rights reserved.