Acidity of metronidazole

Question

Metronidazole has two $\mathrm{p}K_\mathrm{a}$ values: $2.57$ and $15.42.$ The basic group is the imidazole moiety. Does metronidazole have acidic groups?

Answer 1

There are no acidic groups in metronidazole. The $\mathrm{p}K_\mathrm{a}$ you are quoting relates to the protonated form of the molecule (usually hydrochloride or benzoate). The most easily removed proton will be the $\ce{-OH}$ which is no more acidic than a standard alkyl alcohol.

Answer 2

As Waylander correctly predict that presence of no acidic groups in metronidazole framework. The reported $\mathrm{p}K_\mathrm{a}$ value is related to the protonated hydrophilic form of the molecule (e.g., usually hydrochloride salt).

Metronidazole is a imidazole-based compound, namely 2-(2-methyl-5-nitroimidazole-1-yl)ethanol. All reported $\mathrm{p}K_\mathrm{a}$ values of the imidazole-based compounds are attributed to the protonated nitrogen atom at position 3 $(\ce{N-3})$ of the imidazole ring (Ref.1). Again, as Waylander pointed out, excerpts from Ref.2 suggest following:

Owing to the −NO2 group attached to the $\ce{C-5}$ position, metronidazole shows a weak basic character compared to the $\mathrm{p}K_\mathrm{a}$ value of the imidazole ring with a $\ce{N-3}$ atom ($\mathrm{p}K_\mathrm{a}$ 7). The introduction of an electron-donating group at the $\ce{N-1}$ and $\ce{C-2}$ positions of the imidazole ring of metronidazole increases the $\mathrm{p}K_\mathrm{a}$ value, but this effect is obstructed by the electron-withdrawing $\ce{−NO2}$ group.

The $\mathrm{p}K_\mathrm{a}$ value of metronidazole was reported as 3.039 in Ref.2. In a different study using the capillary electrophoresis method, the $\mathrm{p}K_\mathrm{a}$ value of metronidazole was determined in the aqueous $30−60\% (v/v)$ methanol media (Ref.3). The average $\mathrm{p}K_\mathrm{a}$ value was calculated to be 2.49. A closely related value of $2.43 \pm 0.03$ has also been reported, which had been determined by the spectrophotometric method in a solution containing methanol−dioxane, acetonitrile, and water (Ref.4).

References:

1. Sheng-Feng Cui, Li-Ping Peng, Hui-Zhen Zhang, Syed Rasheed, Kannekanti Vijaya Kumar, and Cheng-He Zhou, "Novel hybrids of metronidazole and quinolones: Synthesis, bioactive evaluation, cytotoxicity, preliminary antimicrobial mechanism and effect of metal ions on their transportation by human serum albumin," European Journal of Medicinal Chemistry 2014, 86(30), 318-334 (DOI: https://doi.org/10.1016/j.ejmech.2014.08.063).
2. Kader Poturcu and Ebru Çubuk Demiralay, "Determination of $\mathrm{p}K_\mathrm{a}$ Values for Some Benzimidazole and Imidazole Group Drugs Using the Reversed-Phase Liquid Chromatography Method," Journal of Chemical & Engineering Data 2020, 65(11), 5617-5626 (DOI: https://doi.org/10.1021/acs.jced.0c00764).
3. Marina Shalaeva, Jeremy Kenseth, Franco Lombardo, and Andrea Bastin, "Measurement of Dissociation Constants ($\mathrm{p}K_\mathrm{a}$ Values) of Organic Compounds by Multiplexed Capillary Electrophoresis Using Aqueous and Cosolvent Buffers," Journal of Pharmaceutical Sciences 2008, 97(7), 2581–2606 (DOI: https://doi.org/10.1002/jps.21287).
4. Gergely Völgyi, Rebeca Ruiz, Karl Box, John Comer, Elisabeth Bosch, and Krisztina Takács-Novák, "Potentiometric and spectrophotometric $\mathrm{p}K_\mathrm{a}$ determination of water-insoluble compounds: Validation study in a new cosolvent system," Analytica Chimica Acta 2007, 583(2), 418-428 (DOI: https://doi.org/10.1016/j.aca.2006.10.015).