4
$\begingroup$

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?

$\endgroup$
0

2 Answers 2

9
$\begingroup$

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.

The structure of metronidazole

$\endgroup$
3
  • $\begingroup$ Ok thanks! I just don't get it why the pKa of metronidazole is so low (2.57) when the pKa of imidazole is 7? $\endgroup$
    – user139229
    Nov 5, 2023 at 15:11
  • 4
    $\begingroup$ The nitro group is strongly electron withdrawing which reduces the basicity of the imidazole ring $\endgroup$
    – Waylander
    Nov 5, 2023 at 15:20
  • $\begingroup$ @user139229 If you are happy with the reply please accept it $\endgroup$
    – Waylander
    Nov 6, 2023 at 16:05
5
$\begingroup$

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).
$\endgroup$

Your Answer

By clicking “Post Your Answer”, you agree to our terms of service and acknowledge you have read our privacy policy.

Not the answer you're looking for? Browse other questions tagged or ask your own question.