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

Organic synthesis of Aspirin from benzene

12/29/2020

0 Comments

 
Aspirin (acetylsalicylic acid) is a nonsteroidal anti-inflammantory drug (NSAID) useful for alleviating pain, fever, and inflammation. In addition to being one of the most widely used drugs (44,000 tons consumed globally per year), it is also one of the earliest pharmaceuticals developed, being named “Aspirin” by Bayer in 1899 [1]. In this article, I explore the industrial production of Aspirin, showing how it can be synthesized from benzene in three steps.
Aspirin chemical structure (acetylsalicylic acid)
A retrosynthetic analysis is presented below, accessing acetylsalicylic acid from benzene:
Aspirin retrosynthetic analysis
Recognizing the acetyl group in Aspirin, this can be prepared by acetylating salicylic acid. Salicylic acid, in turn, is available from ortho-carboxylation of phenol. Lastly, phenol synthesis is possible through hydroxylation of benzene. I will go through these transformations in detail, explaining the reaction conditions and providing arrow-pushing mechanisms for each.

ARTICLE CONTINUES BELOW ADVERTISEMENT

Phenol synthesis from benzene

Industrially, phenol is mainly produced through the Cumene process [2]. This transforms benzene and propylene (widely available petrochemicals) into phenol and acetone.
Phenol synthesis from benzene by Cumene process
First, benzene is converted to cumene (isopropylbenzene) by Friedel-Crafts alkylation with propylene. Protonation of propylene favors the more stable secondary carbocation, resulting in selective alkylation of benzene with an isopropyl group instead of a linear propyl group:
Friedel-Crafts alkylation of benzene arrow-pushing mechanism
Next, cumene is oxidized by air to cumene hydroperoxide. Mechanistically, a benzylic radical of cumene is formed which then reacts with molecular oxygen to give the hydroperoxide:
Cumene oxidation arrow-pushing mechanism
Phenol is obtained by decomposing the cumene hydroperoxide in the presence of dilute aqueous acid. The mechanism for this transformation begins with protonation of the hydroperoxide. This allows expulsion of a water molecular with rearrangement to an isopropyl carbocation ether. Attack of a water molecular at this carbocation center is followed by decomposition to the products acetone and phenol:
Hydrolysis arrow-pushing mechanism for cumene hydroperoxide

Salicylic acid synthesis by the Kolbe-Schmitt reaction

In the next step of industrial Aspirin production, phenol is ortho-carboxylated to salicylic acid. This is accomplished by a Kolbe-Schmitt reaction, using strong base and carbon dioxide gas [3].
Kolbe-Schmitt reaction for salicylic acid synthesis
Treatment of phenol with sodium hydroxide generates an electron rich sodium phenolate. This species reacts as an enolate nucleophile, doing a nucleophilic attack on the carbon dioxide. The ortho regiochemistry is favored over para by coordination of the incoming CO2 by the sodium cation. An acidic work-up protonates the carboxylic acid and allows tautomerization to restore aromaticity. An arrow-pushing mechanism is proposed below:
Kolbe-Schmitt reaction arrow-pushing mechanism

Acetylation of salicylic acid

The final step of Aspirin synthesis is acetylation of the salicylic with acetic anhydride or acetyl chloride. Various acid or base catalysts can be used to promote this chemistry. In a patented procedure shown below [4], salicylic acid is reacted with one equivalent of neat acetic anhydride in the presence of zinc oxide:
Acetylation of salicylic acid with acetic anhydride
The reaction is exothermic, spontaneously heating up and proceeding to completion quickly. The zinc oxide catalyzes the acetylation by coordinating the carbonyl oxygen of acetic anhydride, increasing its electrophilicity. Thus, a nucleophilic attack at this carbon center by the phenol of salicylic acid is promoted. Zinc oxide also acts as a base in this reaction, giving zinc acetate as a by-product.
Salicylic acid acetylation arrow-pushing mechanism

Summary: total synthesis of Aspirin from benzene

Total synthesis of Aspirin from benzene
First, benzene is alkylated to cumene (isopropylbenzene) by Friedel-Crafts reaction. Oxidation by air gives cumene hydroperoxide, which is then hydrolyzed to phenol by treatment with aqueous acid. Salicylic acid is obtained by othro-carboxylation with carbon dioxide in a Kolbe-Schmitt reaction. Lastly, acetylation with acetic anhydride affords acetylsalicylic acid (Aspirin).


0 Comments
<<Previous

    Archives

    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

    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

​© 2020 Copyright The Science Snail. All rights reserved.