scholarly journals Solving the Problem of Aqueous pKa Prediction for Tautomerizable Compounds Using Equilibrium Bond Lengths

2019 ◽  
Author(s):  
Beth A. Caine ◽  
Maddalena Bronzato ◽  
Torquil Fraser ◽  
Nathan Kidley ◽  
Christophe Dardonville ◽  
...  
Keyword(s):  
Ab Initio ◽  
Pka Prediction ◽  
Bond Lengths ◽  
Aqueous Pka

Our new pKa predictor called AIBL outperforms Marvin for the well-known challenge of tautomerizable compounds. The powerful descriptors used here are simply ab initio equilibrium bond lengths. We also correct the literature experimental value for the herbicide Profoxydim, from a previous value 5.91 to a new value of 4.82. This is a fine and rare example of theory correcting experiment.

scholarly journals Solving the Problem of Aqueous pKa Prediction for Tautomerizable Compounds Using Equilibrium Bond Lengths

2019 ◽  
Author(s):  
Beth A. Caine ◽  
Maddalena Bronzato ◽  
Torquil Fraser ◽  
Nathan Kidley ◽  
Christophe Dardonville ◽  
...  
Keyword(s):  
Ab Initio ◽  
Pka Prediction ◽  
Bond Lengths ◽  
Aqueous Pka

Our new pKa predictor called AIBL outperforms Marvin for the well-known challenge of tautomerizable compounds. The powerful descriptors used here are simply ab initio equilibrium bond lengths. We also correct the literature experimental value for the herbicide Profoxydim, from a previous value 5.91 to a new value of 4.82. This is a fine and rare example of theory correcting experiment.

scholarly journals Aqueous pKa prediction for tautomerizable compounds using equilibrium bond lengths

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Beth A. Caine ◽  
Maddalena Bronzato ◽  
Torquil Fraser ◽  
Nathan Kidley ◽  
Christophe Dardonville ◽  
...  
Keyword(s):  
Pka Prediction ◽  
Bond Lengths ◽  
Aqueous Pka

Experiment Stands Corrected: Accurate Prediction of the Aqueous pKa Values of Sulfonamide Drugs Using Equilibrium Bond Lengths

2019 ◽  
Author(s):  
Beth A. Caine ◽  
Maddalena Bronzato ◽  
Paul Popelier
Keyword(s):  
Strongly Correlated ◽  
Pka Values ◽  
Pka Prediction ◽  
Thermodynamic Cycles ◽  
Bond Lengths ◽  
Linear Relationships ◽  
Aqueous Pka ◽  
Experimental Values ◽  
First Time ◽  
Sulfonamide Group

We show here for the first time that strongly correlated linear relationships exist between equilibrium bond lengths of the sulfonamide group and aqueous pKa values. Models are constructed for three variants of the SO2NHR group: primary benzene sulfonamide derivatives (e.g. diuretic drugs furosemide and hydrochlorothiazide), N-phenyl substituted 4-amino-N-phenylbenzenesulfonamide analogues (e.g. the sulfa antibiotic sulfadiazine) and phenylsulfonylureas (e.g. insulin secretogogue, glimepiride). In the context of these compounds, we present solutions to some of the more complex challenges in pKa prediction: (i) prediction for multiprotic compounds, (ii) predicting macroscopic values for compounds that tautomerize, and (iii) quantum chemical pKa prediction for compounds with more than 50 atoms. Using bond lengths as a powerful descriptor of ionization feasibility, we also identify that literature values for drug compounds celecoxib, glimepiride and glipizide are inaccurate. Our newly measured experimental values match our initial predictions to within 0.26 pKa units, whereas previous values were found to deviate by up to 1.68 pKa units. For glimepiride, our corrected value denotes a percentage of ionization at intracellular pH, which is only now in excellent agreement with its known therapeutic efficacy. We propose that linear relationships between bond lengths and pKa should emerge for any set of congeners, thus providing a powerful method of pKa prediction obviating the need for thermodynamic cycles.

Experiment Stands Corrected: Accurate Prediction of the Aqueous pKa Values of Sulfonamide Drugs Using Equilibrium Bond Lengths

2019 ◽  
Author(s):  
Beth A. Caine ◽  
Maddalena Bronzato ◽  
Paul Popelier
Keyword(s):  
Strongly Correlated ◽  
Pka Values ◽  
Pka Prediction ◽  
Thermodynamic Cycles ◽  
Bond Lengths ◽  
Linear Relationships ◽  
Aqueous Pka ◽  
Experimental Values ◽  
First Time ◽  
Sulfonamide Group

We show here for the first time that strongly correlated linear relationships exist between equilibrium bond lengths of the sulfonamide group and aqueous pKa values. Models are constructed for three variants of the SO2NHR group: primary benzene sulfonamide derivatives (e.g. diuretic drugs furosemide and hydrochlorothiazide), N-phenyl substituted 4-amino-N-phenylbenzenesulfonamide analogues (e.g. the sulfa antibiotic sulfadiazine) and phenylsulfonylureas (e.g. insulin secretogogue, glimepiride). In the context of these compounds, we present solutions to some of the more complex challenges in pKa prediction: (i) prediction for multiprotic compounds, (ii) predicting macroscopic values for compounds that tautomerize, and (iii) quantum chemical pKa prediction for compounds with more than 50 atoms. Using bond lengths as a powerful descriptor of ionization feasibility, we also identify that literature values for drug compounds celecoxib, glimepiride and glipizide are inaccurate. Our newly measured experimental values match our initial predictions to within 0.26 pKa units, whereas previous values were found to deviate by up to 1.68 pKa units. For glimepiride, our corrected value denotes a percentage of ionization at intracellular pH, which is only now in excellent agreement with its known therapeutic efficacy. We propose that linear relationships between bond lengths and pKa should emerge for any set of congeners, thus providing a powerful method of pKa prediction obviating the need for thermodynamic cycles.

The Future

1992 ◽  
Author(s):  
John A. Tossell ◽  
David J. Vaughan
Keyword(s):  
Ab Initio ◽  
Quantum Chemical ◽  
Force Fields ◽  
Structural Characteristics ◽  
Future Research ◽  
Quantum Mechanical ◽  
Bond Lengths ◽  
Hartree Fock ◽  
Qualitative Level ◽  
Dynamics Simulations

In this final chapter, an attempt is made to provide an overview of the capabilities of quantum-mechanical methods at the present time, and to highlight the needs for future development and possible future applications of these methods, particularly in areas related to mineral structures, energetics, and spectroscopy. There is also a brief account of some new areas of application, specific directions for future research, and possible developments in the perception and use of quantum-mechanical approaches. The book ends with an epilog on the overall role of “theoretical geochemistry” in the earth and environmental sciences. The local structural characteristics of minerals such as Mg2SiO4, which contain only main-group elements, are reasonably well reproduced by ab initio Hartree-Fock-Roothaan (SCF) cluster calculations at the mediumbasis- set level. Calculations incorporating configuration interaction will inevitably follow and probably lead to somewhat better agreement with experiment. The most pressing needs in this area of study are for the development of systematic procedures for cluster selection and embedding, for a greater understanding of the results at a qualitative level, and for more widespread efficient application of the quantum-chemical results currently available. In the last area, substantial progress has already been made by Lasaga and Gibbs (1987), Sanders et al. (1984), Tsuneyuki et al. (1988), and others, who have used ab initio calculations to generate theoretical force fields which can then be used in molecular-dynamics simulations. If the characteristics of the resultant force fields can be understood at a first-principles level, then it may be possible to understand details of the simulated structures at the same level. Unfortunately, as regards a greater qualitative understanding of the quantum-mechanical calculations, little progress has been made. Rather old qualitative theories describe some aspects of bond-angle variation (Tossell, 1986), but no general model to interpret variations in bond lengths has been developed within either chemistry or geochemistry beyond the model of additive atomic (Slater) or ionic (Shannon and Prewitt) radii. Indeed, global theories of bond-length variations within an ab initio framework seem to be nonexistent. Nonetheless, quantum-chemical studies have shown the presence of intriguing systematics in bond lengths (Gibbs et al., 1987), which had been already noted empirically.

Bond order-bond length relationships in conjugated hydrocarbons - the microwave spectrum and structure of 3,4-dimethylenecyclobutene

1983 ◽  
Vol 36 (4) ◽  
pp. 639 ◽  
Author(s):  
RD Brown ◽  
PD Godfry ◽  
BT Hart ◽  
AL Ottrey ◽  
M Onda ◽  
...  
Keyword(s):  
Dipole Moment ◽  
Ab Initio ◽  
Bond Length ◽  
Bond Order ◽  
Microwave Spectrum ◽  
Basis Set ◽  
Molecular Orbital Calculations ◽  
Bond Orders ◽  
Bond Lengths ◽  
Typical Error

The microwave spectrum of the benzene isomer 3,4-dimethylenecyclobutene including spectra of all possible single 13C-substituted and sufficient singly and doubly D-substituted species to give a complete r5 geometry, have been measured and analysed. An estimate of the re geometry has also been derived. The additional precise CC bond lengths obtained for an unsubstituted, conjugated hydrocarbon enable us to examine bond order-bond length relationships more thoroughly than has previously been possible. The CC bond lengths exhibit a noticeably better correlation with SCFMO bond orders than with simple H�ckel bond orders. Further confirmatory measurements of the dipole moment of dimethylenecyclobutene have been made. Ab initio molecular orbital calculations using a 6-31G basis set give an optimized geometry with CC bond lengths within 2 pm of the r5 values. The computed dipole moment agrees almost exactly with experiment but a corresponding calculation on fulvene is discrepant with experiment by 0.16 D, which is probably a more typical error.

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