Aspirin (acetylsalicylic acid) is an ester of salicylic acid. It has been widely used in medicinal t — Organic Chemistry Chemistry Question
Kinetic analysis of the hydrolysis of aspirin
Aspirin (acetylsalicylic acid) is an ester of salicylic acid. It has been widely used in medicinal treatment. It is an effective analgesic (pain killer) that can reduce the mild pain of headache, toothache, neuralgia (nerve pain), muscle pain and joint pain (from arthritis and rheumatism). Aspirin behaves as an antipyretic drug (it reduces fever), and an anti-inflammatory agent capable of reducing the swelling and redness associated with inflammation. It is an effective agent in preventing strokes and heart attacks due to its ability to act as an anti-coagulant.
Aspirin can be easily synthesized in laboratory by the esterification reaction between salicylic acid and acetic anhydride as shown in the reaction below:
[VISUAL]
In acidic or basic media, aspirin is hydrolyzed to give its active form – salicylic acid. The hydrolysis reaction of aspirin, however, takes place in basic condition much faster than in acidic condition. This illustrates a very important principle: the stability of drugs and their mechanisms strongly depend on the pH condition of the body.
In general, the hydrolysis of esters may be catalyzed by either acid or base. The detailed mechanism of hydrolysis reactions has been the subject of an enormous research effort, since they are of such fundamental importance. The generally accepted mechanism of acid-base-catalyzed hydrolysis is known; however many researchers particularly in biotechnology are applying this fundamental knowledge in new and more complicated systems.
This experiment deals with both the synthesis of aspirin and kinetic study of the hydrolysis of aspirin under a basic condition. Working with synthesis of aspirin, the preparative method uses acetic anhydride and an acid catalyst, concentrated sulfuric acid, to speed up the reaction with salicylic acid. Then the hydrolysis of aspirin will be studied under pseudo-order conditions. This will allow the order with respect to aspirin concentration to be determined. The order with respect to the concentration of hydroxide ions will be given and from this data you will be asked to draw conclusions about the mechanism.
Chemicals and Reagents
* Salicylic acid CH3CO2C6H4CO2H
* Acetic anhydride CH3C2O3CH3
* Concentrated sulfuric acid H2SO4
* Absolute ethanol C2H5OH
* Standard NaOH solution.
Apparatus and glassware
* Vis Spectrophotometer
* Thermostat
* Stirrer hotplate
* Analytical balance (± 0.0001 g)
* Beaker glass, 100 cm3
* Erlenmeyer flask, 100 cm3
* Pipette, 5 cm3
* Büchner flask (Filter flask)
* Büchner filter
* Filter paper
* Glass rod
* Stopwatch
Experimental procedure
Step 1. Synthesis of acetyl salicylic acid
1. Prepare a bath using a 400 cm3 beaker filled about half-way with water. Heat to boil.
2. Weigh 2.0 g salicylic acid using an analytical balance and place it in a 100 cm3 Erlenmeyer flask. Use this quantity of salicylic acid to calculate the theoretical or expected yield of aspirin.
3. Carefully add 5.0 cm3 of acetic anhydride by pipette to the Erlenmeyer flask containing the acid.
4. Add about 5 – 6 drops of concentrated sulfuric acid as catalyst.
Caution! Acetic anhydride could irritate your eyes. Sulfuric acid could cause burns to the skin. Handle both chemicals with care.
5. Mix the reagents and then place the Erlenmeyer flask in boiling water bath. Heat for 15 min. The solid will completely dissolve. Swirl the solution occasionally.
6. Add 10.0 cm3 water to the Erlenmeyer flask, shake the flask thoroughly, and then place it in an ice bath for 10 – 15 min to crystallize out the entire product, acetylsalicylic acid. Collect the crystals by filtration under vacuum. If the crystallization takes place slowly, scratch gently inside the flask with a glass rod.
7. Re-crystallize the crude product as follows: Dissolve the crude product in 10.0 cm3 ethanol, then pour the ethanol solution into 60.0 cm3 warm water and place the obtained solution in the ice water for 10-15 min. Filter off the product.
8. Dry the product in an oven at 100 oC for 30 min. Weigh the dried product.
Step 2. Hydrolysis of acetylsalicylic acid
1. Prepare 50.0 cm3 of a 5 ·10–3 mol dm-3 solution of salicylic acid in 20% ethanol and approx. NaOH 5 ·10–3 mol dm-3 solution as follows:
i) Weigh out the required amount of salicylic acid (M = 138.1 g mol–1) in small beaker on an analytical balance.
ii) Dissolve the weighed acid in 10.0 cm3 of ethanol.
iii) Transfer this quantitatively into a 50 cm3 volumetric flask already containing 5.0 cm3 5 ·10–2 mol dm-3 NaOH, wash the vial several times and add water to the mark.
2. Prepare 50.0 cm3 of a 5 ·10–4 mol dm-3 solution of salicylic acid as follows:
i) Place 10.0 cm3 of ethanol in a 50 cm3 volumetric flask, add by pipette to this flask 5 cm3 solution prepared in step 1.
ii) Add a required amount of 5 ·10–3 mol dm-3 NaOH solution to fill up to the mark. Place the flask in a heated bath at 37 oC.
3. Measure the absorbance at 295 nm. This will be the A∞ in the subsequent calculation (Note: Before measuring the absorbance of salicylic acid, the UV-Vis spectrophotometer should be zeroed with standard sample. Standard sample is a 5 ·10–3 mol dm-3 NaOH solution containing 20% ethanol).
4. Prepare 50 cm3 of a 5 ·10-4 mol dm-3 solution of acetylsalicylic acid (2-CH3CO2C6H4CO2H) as described in parts 1 and 2 above.
5. Place the reaction bottle in a thermostated bath at 37 oC. Start counting the reaction time as soon as the solution is placed in the bath.
6. Five minutes after the start of the reaction, transfer a sufficient amount of the reaction solution into 1 cm UV-Vis absorption cuvette and measure the absorbance at 295 nm.
7. Continue recording the absorbance and write down the obtained experimental data in the table below:
Time/min: 5, 10, 20, 30, 40, 50, 60, ∞
Absorbance A
Calculate the yield of the reaction.
Model Answer
The theoretically obtained amount of aspirin is: n(salicylic acid) = 2.00g / 138.1 = 0.0145 mol. m(aspirin) = 0.0145 mol × 180.2 g mol-1 = 2.6129 g. If, for example, the amount of aspirin obtained experimentally is 2.0132 g, the yield of the reaction is: (2.0132 g / 2.6129 g) × 100 = 77.04 %
Aspirin can irritate the stomach. What is usually done in the preparation of the drug that reduces this side effect?
Model Answer
Magnesium hydroxide, magnesium carbonate and aluminum glycinate, when mixed into the formulation of the aspirin will reduce the irritation.
Calculate the concentration of NaOH in 5 ·10–4 mol dm-3 solution of aspirin.
Model Answer
Ignoring the volume change upon mixing and supposing that aspirin occupies only negligible volume: In the 5 ·10-4 mol dm-3 solution of acetylsalicylic acid, the concentration of NaOH = (5.0 · 10-3 mol dm–3 × 40 cm3) / 50 cm3 – 5.0 · 10-4 mol dm–3 = 3.5 · 10-3 mol dm–3
Plot (A∞ – A) vs. time t, ln(A∞ – A) vs. t, and 1/(A∞ – A) – 1/A∞ vs. t on three separate charts. From these plots determine the order with respect to acetylsalicylic acid.
Model Answer
The UV-Vis absorption obtained in the experiments is given below:
Time/minute: 5, 10, 20, 30, 40, 50, 60, ∞
Absorbance (A): 0.549, 0.829, 1.178, 1.389, 1.506, 1.569, 1.602, 1.653
[VISUAL]
Experimental results showed that the reaction obeyed the pseudo-first-order rate law (plots of ln(A∞ – A) vs. t and ln[(A∞ - At1)/(A∞ - At2)] vs. (t2 – t1) are linear), but not the second-order (plot of 1/(A∞ – A) – 1/A∞ vs. t is curved). Therefore, the reaction is first-order with respect to aspirin.
Determine the value of the pseudo-order rate constant, kobs. Calculate the half-life of the hydrolysis under the reaction condition used. For how many half-lives was the reaction allowed to run?
Model Answer
Based on the equation ln[(A∞ - At1)/(A∞ - At2)] = kt and the plots, we calculate kobs = 0.056 min–1. Hence, the half-life is t1/2 = ln(2)/kobs = 17.85 minutes. The reaction was allowed to run for 60 minutes, which corresponds to 60 / 17.85 = 3.36 half-lives.
In basic solution, acetylsalicylic acid exists as an anion:
[VISUAL]
The following mechanism has been proposed to account for the base catalyzed hydrolysis of aspirin. Based on the order with respect to aspirin, and given the order with respect to [OH–] = 1, derive the rate law and indicate which of the following reactions is the rate - determining step.
[VISUAL]
Model Answer
From the obtained experimental results the reaction is first order with respect to both and [OH–], therefore the rate law may be given as: Rate = k 1[OH–]1.
According to the proposed mechanism, in step 1, the hydroxide nucleophile attacks at the electrophilic C of the ester C=O, breaking the σ bond and creating a tetrahedral intermediate (I). In step 2, the intermediate collapses, reforming the C=O and yielding a product (P). The last step (step 3) is a rapid proton transfer acid-base reaction at equilibrium, so it cannot be rate-determining.
Let us denote the tetrahedral intermediate as I and the salicylate/acetate intermediate species as P. The rate of formation of the product is given by: Rate = d[P]/dt = k2[I].
Two cases are considered for the stability of I:
i) If k-1 >> k2, the rate of reconversion of I into aspirin and hydroxide is much faster than the rate at which it collapses to product. Thus, the concentration [I] can be calculated by pre-equilibrium alone: [I] = K [OH–], where K = k1/k-1. Therefore, Rate = k2K [OH–], which matches the experimental rate law. In this case, step 2 is the rate-determining step.
ii) If intermediate complex I is less stable and steady-state approximation must be applied: d[I]/dt = k1[OH–] - k-1[I] - k2[I] = 0, which yields [I] = k1[OH–] / (k-1 + k2). The rate is then: Rate = k1k2[OH–] / (k-1 + k2). When k-1 >> k2, this expression reduces to the equilibrium treatment in case (i). Thus, step 2 is the rate-determining step under the pre-equilibrium condition.