Theoretical Study On The Relationships Between The Acidity And The ~1H NMR Chemical Shieldings Of Protons Of Organic Compounds

The pKa value is one of the fundamental properties of organic compounds.Some important physicochemical properties,such as solubility,permeability,absorption and transportation,are dependent on their pKa values.The pKa values of common compounds can be obtained from database or determined experimentally.However,for reaction intermediates,new compounds,or compounds that are difficult to separate and purify,their pKa values can not be determined directly.Therefore,various empirical formulas emerged to predict pKa values of compounds.However,existing empirical formulas require a large amount of empirical parameters to achieve accurate predictions.In this paper,the ~1H NMR chemical shielding values of acidic protons of organic acids,amines,and ketones were calculated by using a series of quantum chemistry methods.These calculated shielding values were then fitted to the corresponding experimental pKa values by using linear least-squares method,and a series of empirical relationships were obtained.Error analysis shows that the relationships show high correlation coefficients(R~2>0.9)and low standard deviations(RMSD<1.0),and thus bear strong pKa-predicting ability.In addition,these formulas only need chemical masking value to achieve the prediction of acidic proton acidity,and thus could be applied extensively generous compounds.This thesis consists of four chapters,as described below.In the first chapter,we summarize the history of quantum chemistry,popular calculation methods,the relationship between transition state theory and activation energy,various solvation models,and different pKa prediction methods.In addition,chemical isomerization is also briefly introduced.And the content and significance of the research are summed up at the end of this chapter.In the second chapter,we employed various theoretical methods to calculate the NMR chemical shielding values of a series of carboxylic acids and amines in gas phase and aqueous solution.We found that the calculated NMR chemical shielding values of the organic acids and amines in the aqueous solution correlate almost linearly to the corresponding negative logarithm(pKa)of the experimental acid dissociation constants(pK_a),in which the correlation coefficient R~2 is 0.95 for organic acids and is 0.92 for amines.After empirical correction,a general formula covering both species was obtained with a correlation coefficient R~2 values of 0.95 and an RMSD values of 0.63.In the next sections,key factors affecting the theoretical prediction of pKa are discussed.The correlation analysis shows that charges from solvent molecules play a key role in the pKa prediction of the solutes.In the third chapter,we use various theoretical methods to calculate the ~1H NMR chemical shielding values of 30 ketones in different media conditions.At the same time,the chemical shielding values of the enol forms of these compounds were calculated by using the same calculation protocols.Analysis showed that the correlations between the chemical shielding values of the ketone or enol forms and the corresponding pKa values were poor with correlation coefficients R~2 0.48-0.74.When the chemical shielding values of both forms were simultaneously subjected to linear regression against the corresponding pK_a values,a much better correlation coefficient R~2 0.90 was obtained.The predicted pKa values agree well with the experimental pKa,with a standard deviation RMSD 2.5.In addition,the factors that influence the theoretical prediction of pKa are discussed.Among them,the hydrogen bonding interaction between the solvent DMSO molecule and the acidic hydrogen of the solute molecule plays a major role.In addition,the dielectric environment formed by the solvent molecule also has a considerable effect on pKa predicting.In the fourth chapter,we use a series of quantum mechanics methods to study the competitive pathways of 2-nitrocyclohexanone enolization reaction.Reaction coordinate calculations indicate that the competition pathways include intramolecular proton transferring and intermolecular acid-base proton transferring,while the latter is proved to be the fundamental reaction pathway.The energy calculation results demonstrate that in the fundamental pathway the removal of the?-proton by a base is the rate-determining step.Under different solvation surroundings the experimental value of the activation free energy of for 2-nitrocyclohexanone enolization reaction catalyzed by TEA or PRY were respectively reported to be 15.1-18.5 kcal/mol and20.2-22.4 kcal/mol.Our theoretical predictions under the same condition are 14.1-18.6kcal/mol and 16.6-21.3 kcal/mol,respectively.The theoretical value agree well with the corresponding experimental values,proving that the present reaction mechanism calculations are reliable.The prediction of pKa of organic compounds plays an important role in the design of drug molecules.The acidic prediction relationship proposed in this research can provide a new approach for the prediction of pKa of organic compounds.Our study also shows that the protonating form,short-range and long-range electrostatic solute-solvents interactions have a significant impact on the chemical shielding values and the acidity of compounds.Therefore,it is necessary to fully consider the impact of these factor to obtain reasonable?-pKa empirical relationships.