Priori Prediction Research Articles

Understanding the Cis-Trans Amide Bond Isomerization of N,N'-Diacylhydrazines to Develop Guidelines for A Priori Prediction of Their Most Stable Solution Conformers.

N,N'-diacylhydrazines (R1CO-NR3-NR4-COR2) are a class of small molecules with a wide range of applications in chemistry and biology. They are structurally unique in the sense that their two amide groups are connected via a N-N single bond, and as a result, these molecules can exist in eight different isomeric forms. Four of these are amide isomers [trans-trans (t-t), trans-cis (t-c), cis-trans (c-t), and cis-cis (c-c)] arising from C-N bond restricted rotation. In addition, each of these amide isomers can exist in two different isomeric forms due to N-N bond restricted rotation, especially when R3 and R4 groups are relatively bigger. Herein, we have systematically investigated the conformations of 55 N,N'-diacylhydrazines using a combination of solution NMR spectroscopy, X-ray crystallography, and density functional theory calculations. Our data suggest that when the substituents R3 and R4 on the nitrogen atoms are both hydrogens. These molecules prefer twisted trans-trans (t-t) (>90%) geometries (H-N-C═O ∼ 180°), whereas the N-alkylated and N,N'-dialkylated molecules prefer twisted trans-cis (t-c) geometries. Herein, we have analyzed the stabilization of the various isomers of these molecules in light of steric and stereoelectronic effects. We provide a guideline to a priori predict the most stable conformers of the N,N'-diacylhydrazines just by examining their substituents (R1-R4).

A Priori Prediction of Mass Spectrometric Product Patterns of Photoinitiated Polymerizations.

We introduce a method for the a priori prediction of mass spectra of complex poly(methyl methacrylate)s initiated by photoinitiators featuring multiple cleavage points. The method is based on permutation mathematics using multinomial coefficients to predict the probability of each poly(methyl methacrylate) species' isotopic pattern contribution to the overall mass spectrum. The method assumes a statistical behavior for the cleavage of the photoinitiator. The excellent agreement of the predicted mass spectrum based on multinomial coefficients with the experimental mass spectrum confirms a multipoint cleavage mechanism of the assessed photoinitiators. We exemplify our method for the prediction of mass spectra of poly(methyl methacrylate)s initiated by four tetraacylgermane derivates and one bisacylgermane, recorded after visible light pulsed-laser polymerization by high resolution Orbitrap electrospray ionization mass spectrometry (ESI-MS). The excellent agreement of our approach with experimental data suggests that a wide array of polymer mass spectra of polymers initiated by initiators capable of multiple cleavage events can be quantitatively predicted.

A Priori Prediction of Dissociation Phenomena and Phase Behaviors of Ionic Liquids

Many unique properties of ionic liquids (ILs) are closely related to the extent of dissociation (α) in solution. However, most of the existing models for ILs assume either full dissociation or full nondissociation regardless of mixture compositions. In this work, the dissociation of ILs (CA = C+ + A–) is described as a chemical reaction. Together with the predictive COSMO-SAC model, the dissociation constant can be determined based on the value of α in the pure state. Our results show that the predicted composition dependence of α is in good agreement with experiment over the entire concentration range. We further examine the prediction of a variety of thermodynamic properties and phase behaviors of IL solutions, covering high (infinite dilution activity coefficient of solvent), medium (vapor–liquid and liquid–liquid), and low (osmotic coefficient and mean ionic activity coefficient) IL concentrations (a total of 9857 data points). Our results show that the composition dependence of IL dissociation has a ...

A Priori Prediction of Heats of Vaporization and Sublimation by EFP2-MD

New theoretical procedures were proposed for the heats of vaporization (ΔHvap) and sublimation (ΔHsub) predictions by adopting effective fragment potential version 2-molecular dynamics (EFP2-MD) simulations. The particular EFP2, as generated by HF/6-31++G(2d,2p), yielded excellent results in the predictions of ΔHvap, where mean absolute deviation (MAD) and root-mean-square deviation (RMSD) for 16 molecules were 0.34 and 0.44 kcal/mol, respectively. By introducing a uniform scaling factor, we further derived a prediction procedure for ΔHsub, where its MAD and RMSD were 0.76 and 0.90 kcal/mol, respectively. Because EFP2-MD does not require any ab initio computations during simulation, computational overhead of our procedures is minimal. We believe that our new procedures for the ΔHvap and ΔHsub predictions could be widely applicable in the areas where accurate chemical information for virtual molecules is critical.

A Priori Prediction of Tumor Payload Concentrations: Preclinical Case Study with an Auristatin-Based Anti-5T4 Antibody-Drug Conjugate

The objectives of this investigation were as follows: (a) to validate a mechanism-based pharmacokinetic (PK) model of ADC for its ability to a priori predict tumor concentrations of ADC and released payload, using anti-5T4 ADC A1mcMMAF, and (b) to analyze the PK model to find out main pathways and parameters model outputs are most sensitive to. Experiential data containing biomeasures, and plasma and tumor concentrations of ADC and payload, following A1mcMMAF administration in two different xenografts, were used to build and validate the model. The model performed reasonably well in terms of a priori predicting tumor exposure of total antibody, ADC, and released payload, and the exposure of released payload in plasma. Model predictions were within two fold of the observed exposures. Pathway analysis and local sensitivity analysis were conducted to investigate main pathways and set of parameters the model outputs are most sensitive to. It was discovered that payload dissociation from ADC and tumor size were important determinants of plasma and tumor payload exposure. It was also found that the sensitivity of the model output to certain parameters is dose-dependent, suggesting caution before generalizing the results from the sensitivity analysis. Model analysis also revealed the importance of understanding and quantifying the processes responsible for ADC and payload disposition within tumor cell, as tumor concentrations were sensitive to these parameters. Proposed ADC PK model provides a useful tool for a priori predicting tumor payload concentrations of novel ADCs preclinically, and possibly translating them to the clinic.

A Priori Prediction of Thermodynamic Properties of Electrolytes in Mixed Aqueous–Organic Solvents to Extreme Temperatures

The unified theory of electrolytes (J. Phys. Chem. B 2009, 113, 2398-2404) for predicting the standard state thermodynamic properties of aqueous electrolytes has been extended to include mixed solvent systems. The solubility of solid sodium chloride in mixed solvents (methanol/water concentration up to 75% w/w) was also measured up to 466 K and pressures near 7 MPa. The present model, together with a simple modification of Pitzer's thermodynamic treatment of aqueous solutions, allows a priori prediction of solubility of electrolytes in aqueous/organic systems to extreme temperatures and pressures. Solubility is predicted for sodium chloride and potassium chloride in mixed solvents (methanol/water, ethanol/water) over a wide range of temperatures and compositions from the extension of the unified theory of electrolytes to mixed solvents. Comparisons indicate good agreement in all cases to well within the uncertainties of the experimental data. The stoichiometric activity coefficients of saturated solution of sodium chloride in methanol/water mixed solvents were calculated up to 473.15 K. The stoichiometric activity coefficients, as a function of temperature at all concentrations (0 ≤ m ≤ m(sat)) and the entire range of mole fraction of methanol, were also calculated up to 473.15 K. The novelty of the present approach is that no additional parameters are required to account for the medium effect.

Water Clusters on Graphite: Methodology for Quantum Chemical A Priori Prediction of Reaction Rate Constants

The properties, interactions, and reactions of cyclic water clusters (H(2)O)(n=1-5) on model systems for a graphite surface have been studied using pure B3LYP, dispersion-augmented density functional tight binding (DFTB-D), and integrated ONIOM(B3LYP:DFTB-D) methods. Coronene C(24)H(12) as well as polycircumcoronenes C(96)H(24) and C(216)H(36) in monolayer, bilayer, and trilayer arrangements were used as model systems to simulate ABA bulk graphite. Structures, binding energies, and vibrational frequencies of water clusters on mono- and bilayer graphite models have been calculated, and structural changes and frequency shifts due to the water cluster-graphite interactions are discussed. ONIOM(B3LYP:DFTB-D) with coronene and water in the high level and C(96)H(24) in the low level mimics the effect of extended graphite pi-conjugation on the water-graphite interaction very reasonably and suggests that water clusters only weakly interact with graphite surfaces, as suggested by the fact that water is an excellent graphite lubricant. We use the ONIOM(B3LYP:DFTB-D) method to predict rate constants for model pathways of water dissociative adsorption on graphite. Quantum chemical molecular dynamics (QM/MD) simulations of water clusters and water addition products on the C(96)H(24) graphite model are presented using the DFTB-D method. A three-stage strategy is devised for a priori investigations of high temperature corrosion processes of graphite surfaces due to interaction with water molecules and fragments.

Structure, Modified Scaled Quantum Mechanical Force Field and A Priori Prediction of Vibrational Spectra and Their Assignment and Exponential Scaling of Frequencies of Triphenylene

The structure, force field and vibrational spectra of triphenylene are studied by B3LYP/6-31G*(5d) level of theory. The results are compared to those of the related system, phenanthrene. The scale factors in nonredundant local coordinates obtained after fitting the DFT frequencies to the experimental numbers of phenanthrene-d0 and -d10 are transferred to predict the spectra and assignment of triphenylene for in-plane modes. The frequencies based on scaling methodology due to Lee et al. are also obtained. These frequencies are compared with the predicted numbers based on scale factors from phenanthrene. Probable assignment for out-of-plane modes is proposed based on simple scaling of Scott and Radom (scale factor 0.9614) as well as by scaling methodology by Lee et al.

A Priori Prediction of Tissue:Plasma Partition Coefficients of Drugs to Facilitate the Use of Physiologically‐Based Pharmacokinetic Models in Drug Discovery

The tissue:plasma (Pt:p) partition coefficients (PCs) are important drug‐specific input parameters in physiologically based pharmacokinetic (PBPK) models used to estimate the disposition of drugs in biota. Until now the use of PBPK models in early stages of the drug discovery process was not possible, since the estimation of Pt:p of new drug candidates by using conventional in vitro and/or in vivo methods is too time and cost intensive. The objectives of the study were (i) to develop and validate two mechanistic equations for predicting a priori the rabbit, rat and mouse Pt:p of non‐adipose and non‐excretory tissues (bone, brain, heart, intestine, lung, muscle, skin, spleen) for 65 structurally unrelated drugs and (ii) to evaluate the adequacy of using Pt:p of muscle as predictors for Pt:p of other tissues. The first equation predicts Pt:p at steady state, assuming a homogenous distribution and passive diffusion of drugs in tissues, from a ratio of solubility and macromolecular binding between tissues and plasma. The ratio of solubility was estimated from log vegetable oil:water PCs (Kvo:w) of drugs and lipid and water levels in tissues and plasma, whereas the ratio of macromolecular binding for drugs was estimated from tissue interstitial fluid‐to‐plasma concentration ratios of albumin, globulins and lipoproteins. The second equation predicts Pt:p of drugs residing predominantly in the interstitial space of tissues. Therefore, the fractional volume content of interstitial space in each tissue replaced drug solubilities in the first equation. Following the development of these equations, regression analyses between Pt:p of muscle and those of the other tissues were examined. The average ratio of predicted‐to‐experimental Pt:p values was 1.26 (SD = 1.40, r = 0.90, n = 269), and 85% of the 269 predicted values were within a factor of three of the corresponding literature values obtained under in vivo and in vitro conditions. For predicted and experimental Pt:p, linear relationships (r > 0.9 in most cases) were observed between muscle and other tissues, suggesting that Pt:p of muscle is a good predictor for the Pt:p of other tissues. The two previous equations could explain the mechanistic basis of these linear relationships. The practical aim of this study is a worthwhile goal for pharmacokinetic screening of new drug candidates. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:16–35, 2000

A Priori Prediction of Substituent and Solvent Effects in the Basicity of Nitriles

The relative basicity of a series of nitriles in the gas phase, chloroform, and aqueous solution is studied using ab initio and state of the art SCRF methods. Theoretical results reproduce well the available experimental data for a large series of nitrile derivatives. The origin of basicity differences in solution within the series is analyzed. The impact of the results in the understanding of nitrile chemistry is discussed.

A Priori Prediction of Propagation Rate Coefficients in Free-Radical Polymerizations: Propagation of Ethylene

A method is derived for calculating Arrhenius parameters for propagation reactions in free-radical polymerizations from first principles. Ab initio molecular orbital calculations are carried out initially to determine the geometries, vibrational frequencies, and energies of the reactants and the transition state. Transition state theory then yields the Arrhenius parameters. The lowest frequencies are replaced by appropriate (hindered or unhindered) internal rotors, to better model these modes in the calculation of frequency factors. It is found that a high level of molecular orbital theory (e.g., QCISD-(T)/6-311G**) is required to produce reasonable activation energies, whereas satisfactory frequency factors can be obtained at a relatively simple level of theory (e.g., HF/3-21G), because the frequency factor is largely determined by molecular geometries which can be reliably predicted at such a level. Obtaining reliable frequency factors for quite large systems is thus possible. The overall procedure is illustrated by calculations on the propagation of ethylene, and the results are in accord with literature experimental data. Means are also derived for extending the results from propagation of monomeric radicals to propagation of polymeric radicals, without additional computational requirements. The method is expected to be generally applicable to those propagation reactions that are not significantly influenced by the presence of solvent (i.e., relatively nonpolar monomers in nonpolar solvents). The calculations show that the magnitude of the frequency factor is largely governed by the degree to which the internal rotations of the transition state are hindered. They also suggest that there can be a significant penultimate unit effect in free-radical copolymerization. Furthermore, the calculations explain the rate-enhancing effect found upon deuteration of the monomers and explain why the rate coefficient for the first propagation step is larger than that for the long-chain propagation step.

Meissl Memorial Senior Scientist

Beginning in 1976, the Committee on Geodesy of the National Academy of Sciences/National Research Council has administered a Senior Scientist Program supported by the National Geodetic Survey of the National Oceanic and Atmospheric Administration (NOAA). Under this program, awardees have spent up to a year in residence at the National Geodetic Survey, conducting research in geodesy and related fields. Through the summer of 1984, 15 prominent scientists have participated, producing more than 20 papers published in a NOAA publications series or in professional journals.The second awardee was Peter Meissl, Professor of Geodesy at the Technical University of Graz, Austria, who spent 8 months during 1977 at the National Geodetic Survey. His work, “A Priori Prediction of Roundoff Error Accumulation in the Solution of a Super‐Large Geodetic Normal Equation System,” was released as a NOAA professional paper, published hardbound as an acknowledgment of the permanence of the achievement. His contribution was so outstanding that he was invited to return for the summer of 1982. But, tragically, in May 1982 he was killed in a mountain‐climbing accident near Graz.