scholarly journals Accurate reaction barrier heights of pericyclic reactions: Surprisingly large deviations for the CBS-QB3 composite method and their consequences in DFT benchmark studies

2015 ◽  
Vol 36 (9) ◽  
pp. 622-632 ◽  
Author(s):  
Amir Karton ◽  
Lars Goerigk
Keyword(s):  
Large Deviations ◽  
Pericyclic Reactions ◽  
Reaction Barrier ◽  
Composite Method ◽  
Barrier Heights

scholarly journals A Computational Investigation of the Uncatalysed and Water-Catalysed Acyl Rearrangements in Ingenol Esters

2018 ◽  
Vol 71 (4) ◽  
pp. 212 ◽  
Author(s):  
Asja A. Kroeger ◽  
Amir Karton
Keyword(s):  
Ring Opening ◽  
Density Functional ◽  
Skin Lesions ◽  
Functional Theory ◽  
Reaction Barrier ◽  
Barrier Heights ◽  
Rate Determining Step ◽  
Proton Transfers ◽  
Biological Potency ◽  
Hybrid Density Functional

Ingenol esters have been identified as potent anticancer and HIV latency reversing agents. Ingenol-3-angelate was recently approved as a topical treatment for precancerous actinic keratosis skin lesions. It was found, however, that ingenol esters can undergo a series of acyl rearrangements, which may affect their biological potency and the shelf-life of drug formulations. We use double-hybrid density functional theory to explore the mechanisms for the uncatalysed and water-catalysed acyl migrations in a model ingenol ester. The uncatalysed reaction may proceed either via a concerted mechanism or via a stepwise mechanism that involves a chiral orthoester intermediate. We find that the stepwise pathway is kinetically preferred by a significant amount of ΔΔH‡298 = 44.5 kJ mol−1. The uncatalysed 3-O-acyl to 5-O-acyl and 5-O-acyl to 20-O-acyl stepwise rearrangements involve cyclisation and ring-opening steps, both concomitant with a proton transfer. We find that the ring-opening step is the rate-determining step for both rearrangements, with reaction barrier heights of ΔH‡298 = 251.6 and 177.1 kJ mol−1 respectively. The proton transfers in the cyclisation and ring-opening steps may be catalysed by a water molecule. The water catalyst reduces the reaction barrier heights of these steps by over 90 kJ mol−1.

Assessment of Multireference Perturbation Methods for Chemical Reaction Barrier Heights

2015 ◽  
Vol 119 (21) ◽  
pp. 5490-5495 ◽  
Author(s):  
Francesco Fracchia ◽  
Renzo Cimiraglia ◽  
Celestino Angeli
Keyword(s):  
Chemical Reaction ◽  
Perturbation Methods ◽  
Reaction Barrier ◽  
Barrier Heights
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