More than 9000 quality-evaluated pK_a values of more than 5000 acids in 7 dipolar aprotic solvents (DMSO, MeCN, DMF, pyridine, acetone, propylene carbonate and THF) have been collected from around 800 original works and are now available as an IUPAC technical report Acid dissociation constants in selected dipolar non-hydrogen-bond-donor solvents. Pure and Applied Chemistry. 2025, https://doi.org/10.1515/pac-2024-0276. The widest possible selection of compound classes is covered (Table below). The results of this large-scale pK_a data collection and evaluation work are now available for the scientific community to use in reaction mechanism analysis and modelling, catalyst design, computational method development, etc.

Very importantly, the collected pK_a data have been critically evaluated based on predefined quality criteria and depending on situation, kept as they were originally published, flagged as doubtful/unreliable (around 2700 values) or corrected (around 2500 values) (Figure above).

To enable automated processing and data mining, as well as other kinds of cheminformatics, the data are presented as a set of spreadsheets, together with structural codes (SMILES and InChI strings), compound class qualifiers and comments.

The published IUPAC Technical Report contains also comprehensive educational background information on the acid-base processes in non-aqueous media, as well as brief descriptions of the main measurement methods, with focus on the reliability of the data and sources of uncertainty.

The data collection has been deposited in the Zenodo repository and is freely available at https://doi.org/10.5281/zenodo.12608876.

The work has been carried out in the framework of the IUPAC project 2015-020-2-500. It was additionally funded by numerous sources, most importantly the EMPIR programme (project 17FUN09 “UnipHied”, www.uniphied.eu), by the Estonian Research Council grant (PRG690) and by the Estonian Ministry of Education and Research (TK210).

In a recent publication Universal Reversible Hydrogen Potential for Electrocatalytic Ammonia Splitting Reactions in Nonaqueous Solvents from Unified pH Measurements. Inorg. Chem. 2025, https://doi.org/10.1021/acs.inorgchem.5c02177, jointly with colleagues from Michigan State University, we have used careful pH_abs measurements of dilute NH₄⁺/NH3 buffer solutions in four nonaqueous solvents – acetonitrile (MeCN), Tetrahydrofuran (THF), dimethylformamide (DMF), and propylene carbonate (PC) – to determine the pH_abs^H2O values aligned to the aqueous pH scale (see the resulting pH_abs “ladder” in the graph below). From those measurements (combined with some other experiments) it was possible to determine the reversible hydrogen potential E°_H+/H2 in these four solvents relative to the aqueous standard hydrogen electrode (SHE) and, most importantly, ensuring comparability across the different solvents. As an independent method, Open Circuit Potential measurements were carried out in the same solvents titrated with NH₄⁺/NH₃ to obtain alternative values for the reversible hydrogen potential in these solvents. The results of the two methods agreed well.

The reversible hydrogen potential values were then used to obtain, for the first time, the overpotential for ammonia oxidation as a function of solvent, with a recently discovered ruthenium catalyst. I.e., it is now for the first time possible to rigorously compare the oxidation process of NH₃ to N₂ between different solvents!

This work is a clear demonstration of the usefulness of the unified pH (pH_abs) concept in understanding and modelling electrocatalysis processes!

Many thanks, Jaan for performing the extremely difficult pH_abs measurements, Agnes for leading this pH_abs/electrocatalysis topic in our group and Michigan colleagues for the great collaboration!

The ninth edition of the online course LC-MS Method Validation is open for registration (registration link is here)! The course will be offered as a Massive Open On-line Course (MOOC) during November 26, 2024 – February 7, 2025.

This is a practice-oriented on-line course on validation of analytical methods, specifically using liquid chromatography-mass spectrometry (LC-MS) as technique, mostly (but not limited to) using the electrospray (ESI) ion source. The scope of the course is sufficiently broad, so that it will be useful also to chromatography practitioners using other detector types. The course introduces the main concepts and mathematical apparatus of validation, covers the most important method performance parameters and ways of estimating them. More information about the course can be found in Course introduction page.

Participation in the course is free of charge. Receiving digital certificate (in the case of successful completion) is also free of charge. Printed certificate (to be sent by post) is available for a fee of 60 EUR. Registration is possible until the start of the course. The course materials are available from the above address all the time and can be used via web by anyone who wishes to improve the knowledge and skills in analytical method validation (especially when using LC-ESI-MS).

Märt Lõkov works in our group focusing on investigations of acid-base equilibria – first of all, determination of acidity and basicity constants (pK_a values) of molecules – in nonaqueous solutions. This is a core research direction in our group and he is one of the key people in advancing it.

He has made significant contributions to the self-consistent acidity scale and self-consistent basicity scale in acetonitrile, containing pK_a values 231 acids and pK_aH values of 279 bases, respectively. Because of how these values have measured (“multiple overlapping” relative spectrophotometric measurements), these scales are widely regarded as the most reliable sets of pK_a values in acetonitrile. Thus, assembling those scales was to a large extent also a revision of existing pK_a values for many compounds and assigning new values to them.

Märt has mastered the art of pK_a measurements in nonaqueous media to the highest degree and is right now one of the most skilful people on planet Earth in performing nonaqueous pK_a measurements. Besides doing these measurements himself, he has supervised and is supervising numerous master’s and doctoral students who measure pK_a values in their degree projects. Thus, indirectly, via the supervised students, his contribution is even larger.

Perhaps the most ambitious endeavour that Märt is now engaged in is a large-scale re-evaluation and revision of pK_a values of carboxylic acids in three nonaqueous solvents – acetonitrile, DMSO, dimethylformamide. The analysis of available pK_a data that we have carried out in the framework of the IUPAC project 2015-020-2-500 Critical compilation of acid pK_a values in polar aprotic solvents reveals that the non-aqueous pK_a values available in the literature for this very important compound class are often significantly in error, sometimes by several orders of magnitude. The revision will involve measurements and analysis of literature data. Märt has assembled a group of people involving several students and the expected outcome will be a large amount of high-quality nonaqueous pK_a data of carboxylic acids.

These contributions have been noticed by the International Union of Pure and Applied Chemistry (IUPAC) and Märt has been awarded the Balarew Award for an Outstanding Young Scientist working in the field of critical evaluation of solubility and/or related chemical equilibria!

Märt, please accept our warm congratulations!

(A part of this research was supported by grant PRG690 from the Estonian Research Council)

At the recent Balticum Organicum Syntheticum conference Ivo Leito made a presentation titled How to make maximum use of the available pKa data in non-aqueous solvents? (Photo on the left)

The presentation started with how acid and base strengths, typically expressed as pK_a values (acids) or pK_aH values (bases), depend on solvation of the proton, as well as of the neutral and ionized forms of the acid/base. Every solvent has different solvation properties. Thus, the pK_a values for the same acid/base in different solvents are also different (often dramatically different).

In principle, whenever using pK_a values for predicting or rationalizing chemical processes, the pK_a values determined in the same solvent should be used. In some solvents, e.g. water, DMSO or acetonitrile large bodies of pK_a data exist, while in most solvents either very few pK_a values are available or none at all. This leads to the frequent need of estimating pK_a values in one solvent from the data in other solvent(s) (Picture on the right). An additional consideration is the (often problematic) quality of pK_a data in the literature.

When estimating pK_a values in one solvent based on the data in another solvent it is important to clearly define the aim. Is it needed to have the absolute pK_a value or is it rather necessary to have the acidity/basicity differences (or acidity/basicity order) within a set of compounds? Perhaps the question is just “can base B deprotonate acid A in solvent S”? If absolute pK_a value is needed then what accuracy is necessary? Depending on the aim, there are different possibilities of estimating pK_a and pK_aH values in a solvent on the basis of data in other solvents.

The presentation gave an overview to what extent such estimates can be usefully done, highlighting both successes and failures, as well as how to recognize clearly erroneous pK_a data. The presentation also highlighted the IUPAC project Critical compilation of acid pKa values in polar aprotic solvents that is nearing completion. The critically evaluated pK_a data of acids in dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, pyridine, acetone, propylene carbonate, tetrahydrofuran are available from Ivo Leito on request.

The presentation turned out to be highly interesting for the participants, receiving a large amount of questions, which extended well into the coffee break!

(This research was supported by grant PRG690 from the Estonian Research Council)

On 7th of August, 2024, Kerli Martin successfully defended her PhD dissertation titled Recognition of carboxylates by synthetic receptors – from structure-affinity studies to solid-contact anion-selective electrode prototyping.

This dissertation begins with the observation that while polymer membrane ion-selective electrodes (ISEs) have been well known and widely used for decades to detect small cations, determining organic anions with ISEs remains a challenge, essentially without a solution. The dissertation presents a journey starting with the study of the interactions between small monocarboxylates and numerous anion receptors – potential new ionophores.

By measuring the binding constants of eight carboxylates (formate, acetate, pivalate, lactate, ibuprofen, ketoprofen, glucuronate, and benzoate) to 44 synthetic receptor molecules using nuclear magnetic resonance, Kerli constructed eight binding affinity scales where all the binding affinities are comparable. These results were then assembled into a large overall map of the receptor-anion binding constants (Figure on the right). The results revealed that the selected synthetic hydrogen-bond donor receptors can distinguish between carboxylates with different structures.

As a result of this binding study, a 1,3-bis(carbazolyl)urea derivative (receptor 13 in the Figure on the right) was selected as the hydrogen-bonding ionophore to create prototypes of ion-selective electrodes that can detect acetate. The electrodes built by Kerli displayed a unique selectivity pattern for different anions. The addition of this ionophore to the electrode membrane significantly (by up to several orders of magnitude) reduced the interference from other common ions such as chloride, bromide and nitrate. Kerli’s work is an important step forward in designing ionophores that can specifically bind carboxylates and building sensitive and selective ion-selective electrodes for different anions.

The defence procedure itself was quite a battle for Kerli! It started with the detailed questioning by the opponent prof. Claudia Caltagirone (University of Cagliari, Italy) on all the aspects of the thesis. Particularly interesting and difficult were some of her highly technical questions regarding the fluorescence measurement of binding affinities. Then there was a long string of questions from the defence committee members. The topics of Kerli’s thesis ranged from receptor-anion binding to computational chemistry and from materials science to hard-core electrochemistry. Thus, most committee members found something familiar and worth asking about. Kerli managed nicely with all the questions and left a very good impression on everybody in the room!

Please accept our warm congratulations, Kerli!

On February 8, 2024 the on-line course (MOOC) LC-MS Method Validation offered by the University of Tartu finished successfully.

Eventually, altogether 1014 people registered from 109 countries. Around half of them, 508 participants actually started the course (i.e. tried at least one graded test at least once) and out of them 311 successfully completed the course. The overall completion rate was 31%. The completion rate of participants who started the studies was 61%. The completion rates of active participants (i.e. who started the course) seems to have stabilized at around 60%, which can be considered good. In addition, the overall completion rate is starting to increase again. In any case, there is some food for thought for us on how we could improve the overall completion rate…

At the same time, those participants who actually took part in the course, were very active and asked lots of questions. The questions were often very much to the point and addressed things that are really important to analysts in their everyday work. The course has several forums (general and by topic) and during the course period the overall number of forum posts was above 400 (!) (overall number of posts, both from participants and from teachers) and the forums are still active and posts are still coming in.

This active participation made teaching of this MOOC a great experience also for us, the teachers. The discussion threads gave a lot of added value to the course and some of them triggered making important modifications to the course materials, even during the course. Importantly, thanks to active participants, several mistakes were found and corrected in the course materials. As a result, the overall quality of the course improved.

We want to thank all participants for helping to make this course a success!

We plan to repeat this course again in Autumn 2024.

The eighth edition of the online course LC-MS Method Validation is open for registration (registration link is here)! The course will be offered as a Massive Open On-line Course (MOOC) during Nov 21, 2024 – Feb 02, 2024.

This is a practice-oriented on-line course on validation of analytical methods, specifically using liquid chromatography-mass spectrometry (LC-MS) as technique, mostly (but not limited to) using the electrospray (ESI) ion source. The scope of the course is sufficiently broad, so that it will be useful also to chromatography practitioners using other detector types. The course introduces the main concepts and mathematical apparatus of validation, covers the most important method performance parameters and ways of estimating them. More information about the course can be found in Course introduction page.

Participation in the course is free of charge. Receiving digital certificate (in the case of successful completion) is also free of charge. Printed certificate (to be sent by post) is available for a fee of 60 EUR. Registration is possible until the start of the course. The course materials are available from the above address all the time and can be used via web by anyone who wishes to improve the knowledge and skills in analytical method validation (especially when using LC-ESI-MS).

We are also glad to announce, that the course has been added into the BIPM (Bureau International des Poids et Mesures) e-learning platform. The BIPM is the most important international metrology organization established by the Metre Convention, through which Member States act together on matters related to measurement science and measurement standards. BIPM is also the home of the International System of Units (SI) and the international reference time scale (UTC). The Institute of Chemistry of University of Tartu is a designated institute by the BIPM since 2010.