Probably the most commonly used drug of all time is acetylsalicylic acid (ASS), which was released o — Analytical Chemistry Chemistry Question
Pain Reliefers
Probably the most commonly used drug of all time is acetylsalicylic acid (ASS), which was released on the market as a pain reliefer under the trade name Aspirin® by a German company in 1899. Now, billions of tablets are sold each year. Acetylsalicylic acid can be synthesized according to the following scheme:
[VISUAL]
ONa
CO2
125 °C, 100 atm
A + H+
B
+ H3C O CH3
O O
H3PO4
ASS C9H8O4
Give structural formulas for A, B and ASS.
Model Answer
The first step is the Kolbe–Schmitt reaction in which - after protonation - salicylic acid (B) forms. The reaction with acetic anhydride results in the formation of acetylsalicylic acid ASS. [VISUAL]
Structural representations based on the solution:
- A: Sodium salicylate
- B: Salicylic acid
- ASS: Acetylsalicylic acid (2-acetoxybenzoic acid)
Decide whether the following statements concerning acetylsalicylic acid are true, false or whether no decision is possible:
- ASS is more soluble in water at a pH of 2 than at a pH of 9.
- A further electrophilic substitution will occur ortho to the COOH group.
- The conjugate base is less water soluble than the acid.
- The NMR spectrum shows only two CH signals in the aromatic region.
- The 1 H NMR in D2O/DMSO mixtures shows 5 signals.
Model Answer
- ASS is more soluble in water at a pH of 2 than at a pH of 9: false (The anion (pH = 9) is more soluble than the acid)
- A further electrophilic substitution will occur ortho to the COOH group: false (COOH directs meta and OAc para attack at C4)
- The conjugate base is less water soluble than the acid: false (the carboxylate is negatively charged and hence more polar and soluble)
- The NMR spectrum shows only two CH signals in the aromatic region: false (ASS shows 4 CH signals)
- The 1 H NMR in D2O / DMSO mixtures shows 5 signals: true (The COOH proton is exchanged for D)
Phenacetin:
One of the first synthetic drugs, that has been commercially available since 1888, is Phenacetin, a mild analgesic. Due to side effects, it was removed from the market in 1986. Phenacetin E can be synthesized according to the following scheme:
NO2
SnCl2, H+
A SO3/H2SO4
B
NaOH
300 °C
C
Et-Br
+ Ac2O
D C10H13NO2E
The 1 H NMR spectrum of E is shown on the next page. [VISUAL]
Write down structural formulas for A to E. Assign the NMR signals in the figure to the corresponding protons in the structure of E. Explain the splitting pattern of the signals. (table of 1 H–NMR chemical shifts on page 24)
Intensity 1 2 2 2 3 3
Model Answer
Reaction sequence: reduction of the nitro group to the amine (A), acylation (B) and sulfonation in the para position to form C (ortho substitution is not consistent with the symmetric NMR, because that would require 4 CH signals (see spectrum)). The reaction with NaOH under harsh conditions results in the formation of the phenol D which is finally alkylated to ether E (Williamson ether synthesis).
Structural formulas:
- A: Aniline
- B: Acetanilide
- C: p-Acetamidobenzenesulfonic acid
- D: p-Acetamidophenol (Paracetamol)
- E: Phenacetin (p-Ethoxyacetanilide)
NMR Assignments for Phenacetin (E):
- signal a: NH (~7.9 ppm, broad singlet, intensity 1)
- signal b: OCH2CH3 (~4.0 ppm, quartet, intensity 2)
- signals c, d: Aromatic CH protons (~6.8 and ~7.3 ppm, two doublets, intensity 2 each). Note: An unambiguous assignment of c and d is not possible from the given NMR spectrum.
- signal e: COCH3 (~2.1 ppm, singlet, intensity 3)
- signal f: OCH2CH3 (~1.3 ppm, triplet, intensity 3)
If you compare acetylsalicylic acid (ASS) and phenacetin (E), which of the following statements are true, false or can not be evaluated?
- At pH = 9 phenacetin is more polar than acetylsalicylic acid
- Both compounds can be deprotonated by NaHCO3
- The aromatic ring in phenacetin is more electron–rich than in acetylsalicylic acid
- None of them is chiral
- On a silica gel TLC plate, developed with 5% acetic acid in ethyl acetate, the Rf value for phenacetin is larger than for acetylsalicylic acid
Model Answer
- At pH = 9 phenacetin is more polar than acetylsalicylic acid: false (ASS can be deprotonated to form an anion, phenacetin not)
- Both compounds can be deprotonated by NaHCO3: false
- The aromatic ring in phenacetin is more electron rich than in acetylsalicylic acid: true (two donor substituents, ASS has two acceptor groups)
- None of them is chiral: true
- On a silica gel TLC plate, developed with 5% acetic acid in ethyl acetate, the Rf value for phenacetin is larger than for acetylsalicylic acid: true (ASS is more polar than E, hence has a lower Rf)