Mõnede lämmastiku, fosfori ja süsiniku aluste aluselisus atsetonitriili keskkonnas

Väitekirja elektrooniline versioon ei sisalda publikatsiooneHappelisus ja aluselisus on keemiliste ühendite ühed olulisemad omadused. Hape-alus tasakaalud toimuvad suuremal või vähemal määral peaaegu kõigis keemilistes protsessides ja tihti mõjutavad nende käike oluliselt. Happelisuse ja aluselisuse uuringuid vesikeskkonnas on läbiviidud juba pikka aega ja hapete ning aluste käitumine selles on hästi teada. Paljud protsessid, kus ained käituvad hapete või alustena toimuvad mittevesikeskkondades. Sellistes keskkondades avaldub ainete happelisus või aluselisus oluliselt erinevalt. Mittevesikeskondade eeliseks on see, et neis saab läbi viia väga tugevate või nõrkade hapete ning aluste pKa uuringuid. Käesoleva doktoritöö eesmärgiks oli erinevate aineperekondade esindajate aluselisuse väärtused atsetonitriili keskkonnas. Nendeks aineperekondadeks olid triarüülfosfaanid, arüülhüdrasoonid, pentafulveenid ja lämmastikheterotsüklid. Atsetonitriil on solvent, mida kasutakse laialdaselt erinevates keemia valdkondades. Uuritud ainetest on lämmastikheterotsüklid, mis on kõige levinumad. Neid esineb looduses, ravimites, pestitsiidies ja nad leiavad rakendust ka paljudes muudes vadkondades. Kui võrrelda doktortöö raames määratud heterotsüklite pKa väärtusi atsetonitriili keskkonnas arvutatud gaasifaasi aluselisuse väärtustega ja kirjandusest leitud pKa väärtustega vees on võimalik teha järeldusi erinevate struktuuriefektide kohta, mis mõjutavad lämmastikeheterotsüklite aluselisust. Nendeks struktuurseteks tunnusteks on peri vesiniku olemasolu, sisemolekulaarne vesinikside, täiendavalt liidetud aromaatne tuum, lämmastike suhteline asukoht tsüklis ja tsükli suurus. Selle tulemusena leiti, et need efektid toimivad kõigis kolmes keskkonnas, aga erineval määral. Leiti, et pKa väärtused vees ja atsetonitriilis korrelleeruvad hästi lämmastikheterotsüklite puhul. Näidati, et arüülhüdrasoonide ja pentafulveenide pKa väärtused korrelleeruvad hästi Hammetti substituendi konstantidega. Töös esitatud korrelatsioonid ja struktuuri mõjutuste uuringut aluselisusele saab edaspidi kasutada sarnaste ühendite pKa väärtuste ennustamiseks.The acidity and basicity are among the most important properties of chemical compounds. The acid-base equilibria take place at least to some extent in almost all chemical processes and often decisively influences the course of these processes. Acidity and basicity studies in water has a long history and the behaviour of acids and bases in this medium is well known. Many processes where compounds behave as acids or bases take place in non-aqueous media. In non-aqueous media molecules display acidity and basicity often quite differently. The benefit of non-aqueous solvents in the acid-base equilibria studies is that very strong or weak acids and bases and water sensitive compounds can be studied. The aim of this thesis was to determine the basicities of members of different compound families – triarylphosphanes, arylhydrazones, pentafulvenes and nitrogen heterocycles - in acetonitrile. A solvent that is widely used in many different fields of chemistry. Of the studied compounds nitrogen heterocycles are the most widespread figuring in nature, medicine, pesticides and finding use in many other fields. The determined pKa values in acetonitrile combined with computed gas phase basicities and pKa values in water from literature made it possible to rationalize structure effects influencing the basicity of these compounds. These structural features were the presence of the peri hydrogen, intramolecular hydrogen bond, fusion of additional benzene ring, relative position of nitrogen atoms in the ring and the ring size. It was found that these effects are present in all studied media but to a different extent. It was shown that the pKa values of nitrogen heterocycles correlate well in water and acetonitrile. The pKa values of substituted penatafulvenes and arylhydrazones correlate well with the Hammett substituent parameters. The obtained correlations, as well as rationalization of structure-basicity relationships can be used for pKa estimations of similar compounds

On the Basicity of Conjugated Nitrogen Heterocycles in Different Media

In this work we explored the relationship between the structure and solvent effects on the basicity of a large selection of conjugated N-heterocyclic nitrogen bases in different media: the polar aprotic solvent acetonitrile, the polar protic solvent water and the gas phase. Altogether, 58 previously unpublished basicity values in different media for 39 compounds are presented, including 30 experimentally determined pKa values in acetonitrile. We present the pKa and gas-phase basicity values for quino[7, 8-h]quinoline, which is one of the most basic conjugated nitrogen heterocyclic compounds without basicity-enhancing substituents. The trends in basicity are rationalized by comparing the basicity data of related compounds in different solvents, as well as by using isodesmic reactions. The gas-phase basicity is predominantly determined by the ability of a molecule to disperse the excess positive charge over a large number of atoms. In solution the situation is less clear and smaller systems with localized charge often lead to higher basicities because of solvent effects. In particular, it was found that the fusion of an additional benzene ring does not always lead to an increase in basicity in solution: its effect can be either basicity-increasing or -decreasing, depending on the ring size, number and position of nitrogen atoms and medium. A correlation between the measured pKa values in MeCN and in water suggests that these two different solvents exert a similar effect on the basicity of the studied heterocycles

Prediction of pKa values using the PM6 semiempirical method

The PM6 semiempirical method and the dispersion and hydrogen bond-corrected PM6-D3H+ method are used together with the SMD and COSMO continuum solvation models to predict pKa values of pyridines, alcohols, phenols, benzoic acids, carboxylic acids, and phenols using isodesmic reactions and compared to published ab initio results. The pKa values of pyridines, alcohols, phenols, and benzoic acids considered in this study can generally be predicted with PM6 and ab initio methods to within the same overall accuracy, with average mean absolute differences (MADs) of 0.6–0.7 pH units. For carboxylic acids, the accuracy (0.7–1.0 pH units) is also comparable to ab initio results if a single outlier is removed. For primary, secondary, and tertiary amines the accuracy is, respectively, similar (0.5–0.6), slightly worse (0.5–1.0), and worse (1.0–2.5), provided that di- and tri-ethylamine are used as reference molecules for secondary and tertiary amines. When applied to a drug-like molecule where an empirical pKa predictor exhibits a large (4.9 pH unit) error, we find that the errors for PM6-based predictions are roughly the same in magnitude but opposite in sign. As a result, most of the PM6-based methods predict the correct protonation state at physiological pH, while the empirical predictor does not. The computational cost is around 2–5 min per conformer per core processor, making PM6-based pKa prediction computationally efficient enough to be used for high-throughput screening using on the order of 100 core processors

Proton Transfer Chemistry in the Gas Phase. Is a Spontaneous \u27Neutralization\u27 Reaction a Myth or a Reality?

Relying on physicochemical knowledge, the proton cannot be spontaneously transferred from a gaseous mineral acid (HF, HCl, HBr, HI, HNO3, H2SO4, or HClO4) to a gaseous nitrogen base (NH3, alkylamine, aniline, pyridine, amidine, or guanidine). For example, the full proton-transfer from HCl to NH3, followed by the separation of Cl- and NH4+ requires more than 500 kJ mol-1. The same is true for a spontaneous intramolecular proton-transfer for gaseous amino acids, aminophenols and other amphiprotic compounds. From the gas-phase acidity parameter of COOH and the gas-phase basicity parameter of NH2 (or other more basic group in the side chain), it appears that proton transfer is endothermic or endergonic. For arginine, an amino acid with a highly basic guanidine function, this difference is still larger than about 300 kJ mol-1. Only solvation of the acid-base system by neutral species (e.g., one or more water molecules), complexation by ions (e.g., ionic acids or bases, metal cations) or even electrons may reduce the energetic barrier and facilitate the proton-transfer. Recent extension of the gas-phase acidity-basicity scale toward superacids and superbases, and recent development of spectroscopic techniques adapted to the gas phase for less volatile organic compounds give some perspectives for observing the full intermolecular proton-transfer between a molecular Brønsted-Lowry superacid and a molecular Brønsted-Lowry superbase

Ionisatsiooni efektiivsus elektropihustusionisatsiooni allikas, seosed analüüdi füüsiko-keemiliste omadustega

Väitekirja elektrooniline versioon ei sisalda publikatsiooneVedelikkromatograafi-massispektromeetria (LC-MS) võimaldab tuvastada erinevates proovides väga erinevaid ühendeid ja on tõusnud praegusel ajal domineerivaks analüüsimeetodiks orgaaniliste ühendite madalate sisalduste määramisel. Selle süsteemi üks võtmekomponente on ioonallikas, mida kasutatakse LC-MS aparatuuri juures nende kahe liidesena. Elektropihustusionisatsiooni (ESI) ioonallikas on tänu sellele, et võimaldab ioniseerida ja analüüsida väga laia omaduste spektri ja massivahemikuga ühendeid üks enimkasutatavaid ioonallikaid massispektromeetrias. Vaatamata ESI populaarsusele, ei ole siiani päris selge, millised ühendite füsiko-keemilised omadused määravad aine ioniseerumise effektiivsuse ESI allikas. Nimelt, erinevad ühendid võivad anda sama kontsentratsiooni juures massispektris väga erineva intensiivsusega signaale. Käesoleva töö peamiseks eesmärgiks oli jõuda seosteni, mis määravad ühendi ionisatsiooni efektiivsuse ESI allikas lähtudes ühendi füsiko-keemilistest parameetritest. Selleks töötati välja metoodika analüüsimaks erinevaid ühendeid samadel tingimustel ESI massispektromeetriga. Selle tulemusena on loodud suhteliste ionisatsioonieffektiivsuste skaala (solvendisüsteemis 80% - atsetonitriili, 20% - 0.1% sipelghappe vesilahust), mis hetkel sisaldab 344 väga erinevate füsiko-keemiste omadustega ühendit. Kaasates kõiki analüüsitud ühendeid ja nende 11 parameetrit (aluselisus vees, atsetonitriilis ja gaasifaasis, osakese pindala, ruumala, molekulmass, dipoolmoment, polaarse pinna suurus, lipofiilsus/hüdrofoobsus, protoneerumistsenter ja laengu jaotumist iseloomustav parameeter) viidi läbi multilineaarne regressioonanalüüs (MLR) leidmaks peamised seosed mainitud parameetrite ning ühendi ionisatsioonieffektiivsuse vahel ESI allikas kasutatud tingimustel. Kuna kõigi analüüsitud ühendite jaoks ei ole eksperimentaalseid parameetrite väärtuseid, siis käesoleva töö raames arvutati puuduvad väärtused kõigile ühenditele ja kasutati neid MLR analüüsis. MLR analüüsi tulemusena joonistuvad selgelt välja seosed ühendi ionisatsioonieffektiivsuse (ESI allikas antud tingimustel) ning kolme füsiko-keemilise omaduse vahel: aluselisus (vesilahuses), molekuli/iooni suurus ja iooni lipofiilsus/hüdrofoobsus. Mida tugevamini väljendunud on ainel need kolm omadust, seda intensiivsemalt see ESI allikas ioone annab. Käesolev töö on suure olulisusega kõigile, kes töötavad LC-ESI-MS meetodiga.Liquid chromatography mass spectrometry (LC-MS) enables to identify various compounds from different samples and it is currently the dominant method for detecting organic compounds in low concentrations. Ion source is the interface between the LC and MS and is a key component of an LC-MS apparatus. One of the most widely applied ionization source in mass spectrometry is electrospray ionization source (ESI) due to its capability to ionize and analyse different compounds with wide span of parameters’ values. Despite of the commonness of ESI-MS the relationships between the ionization efficiency and compounds’ physico-chemical parameters have still not been fully elucidated. The signals in mass-spectrum of different compounds having the same concentration in the sample can vary strongly. The main purpose of this study was to analyse the relationships between ionisation efficiencies and physico-chemical properties of analytes and find out which physico-chemical parameters influence ionization efficiency the most. The ESI-MS method for analysing the ionization efficiencies of various compounds under the same experimental conditions and the scale of relative ionization efficiencies of 344 compounds with widely differing physico-chemical parameter values (in solvent system 80% - acetonitrile, 20% - 0.1%formic acid aqueous solution) was developed. Multilinear regression analysis involving all the analysed compounds and the 11 physico chemical parameters (basicity in acetonitrile, in water and gas phase basicity, the area and the volume of the particle, molecular mass, dipole moment, polar surface area, lipophilicity/hydrophobicity, protonation centre and the (de)localization of the charge on the surface of the particle) was used to determine the most relevant relations between ionization efficiencies and those parameters. Since the experimental data on some of those parameters is not available, the computational values were calculated for all the compounds and used in multilinear regression analysis when experimental values were not available. The results of MLR analysis enable concluding that three main descriptors of compound determine its ionization efficiency in ESI source under the used conditions: the basicity on aqueous solution, the size of the ion/molecule and the lipophilicity/hydrophobicity of the ion. The more strongly these mentioned parameters of compounds are expressed, the more intensive is ionization in ESI source. This study is expected to be significant to all chemists and researchers working with the LC-ESI-MS method.https://www.ester.ee/record=b544943

Theoretical pKa prediction of the α-phosphate moiety of uridine 5′-diphosphate-GlcNAc

The pKa value of the α-phosphate moiety of uridine 5\u27-diphosphate-GlcNAc (UDP-GlcNAc) has been successfully calculated using density functional theory methods in conjunction with the Polarizable Continuum Models. Theoretical methods were benchmarked over a dataset comprising of alkyl phosphates. B3LYP/6-31+G(d,p) calculations using SMD solvation model provide excellent agreement with the experimental data. The predicted pKa for UDP-GlcNAc is consistent with most recent NMR studies but much higher than what it has long been thought to be. The importance of this study is evident that the predicted pKa for UDP-GlcNAc supports its potential role as a catalytic base in the substrate-assisted biocatalysis

Soluut-solvent vastasmõjude eksperimentaalne uurimine ja modelleerimine

Väitekirja elektrooniline versioon ei sisalda publikatsiooneEnamik praktilist tähtsust omavatest keemilistest protsessidest toimub vedelikes – mitte ainult tööstuslik süntees ja laborikeemia, vaid ka bioloogilised protsessid nagu rakkude hingamine toimuvad molekulaarsel tasemel keerulise koostisega lahustes. Neist protsessidest arusaamine ja molekulide käitumise ennustamine lahustes on tähtis arvukate uurimisvaldkondade jaoks, meditsiinist ja farmakoloogiast naftakeemiani. Kahjuks on ainete omaduste ennustamine vedelikes arvutuskeemia jaoks üks keerulisemaid ülesandeid. Käesolevas töös hinnati olemasolevate arvutusmetoodikate sobivust vesiniksideme tekke kirjeldamiseks orgaanilistes lahustites ning molekulide jaotuse kirjeldamiseks kahe vedeliku vahel (sisuliselt vedelik-vedelik ekstraktsiooni modelleerimiseks). Peamine kasutatud arvutusmeetod oli COSMO-RS (Conductor-like Screening Model for Real Solvents), valitud oma erakordse sobivuse tõttu kontsentreeritud ja mitmekomponendiliste lahuste omaduste ennustamiseks ja molekulaardisainiks. Töö käigus leiti, et vesiniksidemed neutraalsete molekulide vahel on kirjeldatavad suhteliselt hästi, kuid vaadeldud arvutusmetoodikad pole piisavalt täpsed negatiivselt laetud vesiniksidemega komplekside modelleerimiseks. Vedelik-vedelik ekstraktsiooni tulemuste ennustamine COSMO-RS meetodiga oli üldjuhul edukas. Saadud tulemustele (nii lõpp- kui vahepealsetele parameetritele) saadi täpsuse hinanngud. Peale selle arendati uus metodoloogia tundmatute ühendite jaotuse ennustamiseks kahe mitteseguneva vedeliku vahel ilma vajaduseta ühendeid identifitseerida. See lihtsustab parima lahusti valikut ainete isoleerimiseks või puhastamiseks, vähendades töö- ja kemikaalide kulu ning jäätmete kogust.The majority of practically relevant chemical processes occur in liquids. Those are not limited to industrial synthesis and laboratory chemistry – biological processes such as cellular respiration on molecular level take place in complex solutions. Understanding and being able to predict the behaviour of molecules in solutions is essential for numerous branches of science, ranging from medicine and pharmacology to petroleum chemistry. However, predicting the behavior of chemical compounds in liquids, especially in many-component solutions, is one of the most challenging tasks for computational chemistry. In this work existing computational methodologies were tested for suitability for describing hydrogen bond formation in organic solvents and distribution of organic compounds between liquids (essentially modeling of liquid-liquid extraction). The main computational method in this work is COSMO-RS (Conductor-like Screening Model for Real Solvents), chosen for its unequalled ability to predict properties of concentrated and multicomponent solutions and usability in molecular design. It was found that properties of hydrogen bonds between uncharged molecules can be predicted relatively well, but the tested computational approaches were not accurate enough for description of hydrogen bonds involving negatively charged ions. Modeling of liquid-liquid extraction using COSMO-RS was generally successful. Accuracy of the predictions and intermediate parameters was evaluated and problematic cases identified and discussed. Also, a new methodology was developed for predicting the distribution of unknown compounds between immiscible solutions without need for compound identification. It allows simplifying the solvent selection for compound isolation or purification, reducing the workload, expenses and waste amount

Nucleophilicities of Amines, Amino Acids and Pyridines

In line with earlier work of the Mayr group, diarylcarbenium ions (benzhydryl cations) Ar2CH+ have been employed as reference electrophiles for the construction of nucleophilicity scales for amines, amino acids, some di- and tripeptides, and pyridines using the relationship eq. (0.1). log k20° C = s(N + E) (0.1) k = second-order rate constant in M-1 s-1 s = nucleophile specific slope parameter N = nucleophilicity parameter E = electrophilicity paramete