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If I have a diprotic acid that is +1 positively charged in its fully protonated state, I can figure out the apparent equilibrium constants by titration with base. The net charge will be neutral after losing one proton, and -1 after losing the second proton.

Examples would be the hydronium ion or the amino acid glycine at a pH < 2.

How could you determine whether the single-protonated state is a zwitterion (glycine in neutral aqueous solution) or a molecule without charged functional groups (glycine in neutral polar aprotic solvent, or water at neutral pH)?

Is it necessary to do an experiment, or is there a simple rule to figure out whether a zwitterion is expected?

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    $\begingroup$ Well, in principle there will always an equilibrium between at least four species (zwitterion, cation, anion and uncharged molecule), which makes it seem difficult to characterize. I'm also interested to know how reliable of a picture you can get with simple rules, and I'm especially curious about whether they can compensate for solvent effects. $\endgroup$ Commented Dec 31, 2022 at 0:45
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    $\begingroup$ Inspired by this closed question: chemistry.stackexchange.com/q/89937/72973 $\endgroup$
    – Karsten
    Commented Dec 31, 2022 at 3:30
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    $\begingroup$ One has to consider nature of both protonated groups. In case of glycine, there is no reason to assume R-NH3+ is more acidic than R-COOH. OTOH, it is funny to assume H3O+ dissociate to a zwitterion. $\endgroup$
    – Poutnik
    Commented Dec 31, 2022 at 6:01
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    $\begingroup$ Related: Charge distribution in molecules $\endgroup$
    – Karsten
    Commented Dec 31, 2022 at 14:51

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That is a very difficult problem worth a PhD project in physical chemistry. Intially, I thought one could try capillary electrophoresis at different pHs and if the analyte travels with the electrosmotic flow marker at a certain pH, one can say a zwitterion has existed (or a neutral form) by inference. However, you query is about distinguishing the neutral state and the zwitterionic state. One has to think about spectroscopic techniques that rely on dipole moments. Since you are interested in aqueous phase, gas phase microwave spectroscopy of amino-acids is out of question (there are papers on it). Since zwitterion ions can possess large dipole moments as compared to their neutral counterparts, two remaining ones are infrared and photoelectron spectroscopy.

Zwitterion formation in hydrated amino acid, dipole bound anions: How many water molecules are required? J. Chem. Phys. 119, 10696 (2003); https://doi.org/10.1063/1.1620501

We utilize the facts that zwitterions possess very large dipole moments, and that excess electrons can bind to strong dipole fields to form dipole bound anions, which in turn display distinctive and recognizible photoelectron spectral signatures. The appearance of dipole-bound photoelectron spectra of hydrated amino acid anions, beginning at a given hydration number, thus signals the onset of greatly enhanced dipole moments there and, by implication, of zwitterion formation.

IR would be finiky with water, but there are reports that water bound to zwitterions has a different vibrational frequency

Stability and IR Spectroscopy of Zwitterionic Form of β-Alanine in Water Clusters, J. Phys. Chem. B 2019, 123, 20, 4392–4399, https://doi.org/10.1021/acs.jpcb.9b00654

We perform an experimental and computational study on the number of water molecules needed for zwitterion formation of β-alanine. Our density functional theory investigation reveals that a minimum of five water molecules are required to form and stabilize the zwitterion. A characteristic connecting water molecule located between the COO– and NH3+ groups is found to enhance the stability. This water molecule is also involved in a characteristic infrared active vibration at ≈1560 cm–1, which is slightly shifted with the number of surrounding water molecules and is located in a spectral region outside of water vibrations.

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  • $\begingroup$ Additionally, I assume measurement of permitivity spectrum of protic and aprotic solvents, with and without glycine, could confirm the zwitterion nature of glycine solution in water. $\endgroup$
    – Poutnik
    Commented Dec 31, 2022 at 13:14
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    $\begingroup$ Poutnik, Have you checked relevant literature? I didn't, but that is an interesting idea. $\endgroup$
    – AChem
    Commented Dec 31, 2022 at 15:26
  • $\begingroup$ I have not, was just wondering..... $\endgroup$
    – Poutnik
    Commented Dec 31, 2022 at 15:58
  • $\begingroup$ Would NMR be capable of distinguishing zwitterions vs neutral molecules? As an example, one would expect 3 different peaks for glycine's neutral form vs 2 for the zwitterionic form on proton NMR, right? $\endgroup$
    – user73910
    Commented Jan 1, 2023 at 7:45
  • $\begingroup$ @user73910, I do not know. In solution there is perhaps very, very little neutral glycine. NMR is fundamentally an insensitive technique. Feel free to do a literature search on Google Scholar. $\endgroup$
    – AChem
    Commented Jan 1, 2023 at 16:32

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