A computer-aided method for controlling chemical resistance of drugs using RRKM theory in the liquid phase

The chemical resistance of drugs against any change in their composition and studying the rate of multiwell-multichannel reactions in the liquid phase, respectively, are the important challenges of pharmacology and chemistry. In this article, we investigate two challenges together through studying drug stability against its unimolecular reactions in the liquid phase. Accordingly, multiwell-multichannel reactions based on 1,4-H shifts are designed for simplified drugs such as 3-hydroxyl-1H-pyrrol-2(5H)-one, 3-hydroxyfuran-2(5H)-one, and 3-hydroxythiophen-2(5H)-one. After that, the reverse and forward rate constants are calculated by using the Rice Ramsperger Kassel Marcus theory (RRKM) and Eckart tunneling correction over the 298–360 K temperature range. Eventually, using the obtained rate constants, we can judge drug resistance versus structural changes. To attain the goals, the potential energy surfaces of all reactions are computed by the complete basis set-quadratic Becke3 composite method, CBS-QB3, and the high-performance meta hybrid density functional method, M06-2X, along with the universal Solvation Model based on solute electron Density, SMD, due to providing more precise and efficient results for the barrier heights and thermodynamic studies. To find the main reaction pathway of the intramolecular 1,4-H shifts in the target molecules, all possible reaction pathways are considered mechanistically in the liquid phase. Also, the direct dynamics calculations that carry out by RRKM theory on the modeled pathways are used to distinguish the main reaction pathway. As the main finding of this research, the results of quantum chemical calculations accompanied by the RRKM/Eckart rate constants are used to predict the stability of drugs. This study proposes a new way to examine drug stability by the computer-aided reaction design of target drugs. Our results show that 3-hydroxyfuran-2(5H)-one based drugs are the most stable and 3-hydroxythiophen-2(5H)-one based drugs are more stable than 3-hydroxy-1H-pyrrol-2 (5H)-one based drugs in water solution.

A unified statistical RRKM approach to the fragmentation and autoneutralization of metastable molecular negative ions of hexaazatrinaphthylenes

Experimental data on the formation and delayed decay of isolated negative ions are analyzed through the prism of statistical RRKM theory.

Mass spectrometry evidence for self-rigidification of π-conjugated oligomers containing 3,4-ethylenedioxythiophene groups using RRKM theory and internal energy calibration

The self-rigidification of ionized π-conjugated systems based on two combinations of thiophene (T) and 3,4-Ethylenedioxythiophene (E) is investigated using mass-analyzed ion kinetic energy spectrometry (MIKES) of ions produced from electron impact ionization at 70 eV. The m/z 446 radical cations of the two isomers ETTE and TEET lead to detect m/z 418 and 390 daughter ions. The MIKE spectra differ only by the intensities of these fragment ions. As the m/z 418 daughter ion is produced through a same retro-Diels Alder reaction whatever the fragmenting isomer, the difference in daughter ion intensities is interpreted in term of unimolecular dissociation rate constants ( k( Eint)) ratios. Considering that the transition state (TS) of such reaction is attributed to a quinoid form, equivalent vibration modes are assumed for the TS of both dissociating ETTE and TEET radical cations. As a result, by using the Rice–Ramsperger–Kassel–Marcus (RRKM) theory, the difference in daughter ion intensities is interpreted by considering that the fragmenting ion is more or less ordered in its ground state than at the transition state, resulting from the influence of the number of the S…O interactions in the planarization of the TEET ion toward the ETTE charged species. The comparison of this behavior in MIKES experiments is supported by the modeling of ion behavior in mass spectrometer and the calibration in internal energy of the radical cations produced in an EI source.

Benton Seymour Rabinovitch. 19 February 1919 — 2 August 2014

Benton Seymour Rabinovitch was one of the pioneers of chemical dynamics. His brilliant experiments performed during his four decades as a Professor of Chemistry at the University of Washington in Seattle provided most of our early quantitative measurements of the efficiency with which energy is transferred between molecules in gas-phase molecule–molecule collisions and in collisions of molecules with solid surfaces. More importantly, his work provided quantitative estimates of the rates with which vibrational energy deposited locally within a molecule is redistributed among the many vibrational modes within that molecule, proving that the equilibration of this vibrational energy among these modes almost always occurs in approximately one picosecond. He further showed that this validates (in most cases) the assumptions of Rice–Ramsperger–Kassel–Marcus (RRKM) theory. He also developed several widely used mathematical shortcuts for using RRKM theory to make important predictions about physical chemistry. These shortcuts greatly increased both the applications and impact of RRKM theory, so that it has become one of the most important theories of physical chemistry. It continues to guide much of our fundamental understanding of chemical dynamics and reaction kinetics even today. In addition to being a great scientist, Seymour Rabinovitch was a devoted husband and father. He raised four accomplished children, and later in life became an expert in the art of silversmithing, a writer of children's books, and a philanthropist. His offspring are following beautifully in his footsteps in their kindness to fellow human beings, their excellence in scholarship, science and art, and in their energetic dedication to improving the world through teaching, research, service and philanthropy. The same can be said for his academic offspring as well.