On the structure of 3‐acetylamino‐5‐methyl‐1,2,4‐oxadiazole and on the fully degenerate rearrangements (FDR) of its anion: a stimulating comparison between the results of ‘in‐silicon chemistry’ and ‘laboratory chemistry’

Abstract

An accurate crystal structure determination has evidenced a planar conformation for 3-acetylamino-5-methyl-1,2,4-oxadiazole (5), in agreement with quantum-mechanical calculations in the gas phase. In the crystal, a series of strong intermolecular N7H7....O9 hydrogen bonds links the amido groups of different molecules, causing the formation of infinite parallel ordered chains. The effect of the DMSO solvent on the energy and charge distribution of compound 5 and on its relevant 5– anion, involved in a fully degenerate rearrangement (FDR), has been deepened by quantum-mechanical DFT calculations. The calculated energy barrier for the FDR increases in going from in vacuo to DMSO, in agreement with previsions based on the Hughes and Ingold rules concerning the nucleophilic substitution of an anionic reagent (the deprotonated amido group in the side-chain) on a neutral substrate (the 1,2,4-oxadiazole ring)

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

“…The synthesis and crystal structure of 3-acetylamino-5-methyl-1,2,4-oxadiazole, NV848 , has been previously reported in the literature [ 60 , 61 , 62 ].…”

“…2,3,4,5,6-Pentafluoro- N -(5-(perfluorophenyl)-1,2,4-oxadiazol-3-yl)benzamide ( NV914 ) was prepared by acylation of the amine 2 [ 60 , 61 , 62 ] with perfluorobenzoyl chloride, as reported in Scheme 2 .…”

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

“…The synthesis and crystal structure of 3-acetylamino-5-methyl-1,2,4-oxadiazole, NV848 , has been previously reported in the literature [ 60 , 61 , 62 ].…”

“…2,3,4,5,6-Pentafluoro- N -(5-(perfluorophenyl)-1,2,4-oxadiazol-3-yl)benzamide ( NV914 ) was prepared by acylation of the amine 2 [ 60 , 61 , 62 ] with perfluorobenzoyl chloride, as reported in Scheme 2 .…”

Unexpected Substituent Effects in the Iso-Heterocyclic Boulton–Katritzky Rearrangement of 3-Aroylamino-5-methyl-1,2,4-oxadiazoles: A Mechanistic Study

“…To explain these effects, it is worth recalling here the "insilico" work by Mugnoli et al on the fully degenerated rearrangement of the anion of 3-acetylamino-5-methyl-1,2,4ozadiazole. 34 On that occasion, it was shown that the atomic subset constituted by atoms O1−N2−C3•••O9 (Figure 8) overall decreases its electron density on passing from the reactant to the transition state, whereas at the same time, the two methyl groups (in particular, the one of the acetylamino moiety) increase their electron density. Hence, the sensitivity constant ρ 3 is forced to assume a positive value.…”

“…The photochemical behavior (irradiation at 254 nm) of the same substrates in methanol was ascribed to both the nature of the rearranging chromophore and the multiplicity of the involved excited state . Furthermore, the fully degenerated base-catalyzed ( t- BuOK) rearrangement of 3-acetylamino-5-methyl-1,2,4-oxadiazole in dimethyl sulfoxide solution (Scheme ) was investigated both experimentally by means of dynamic NMR techniques and a computational approach, which furnished interesting results on the course of the fully degenerate rearrangement of the anion of 3-acetylamino-5-methyl-1,2,4-oxadiazole. , On the grounds of the previous studies on the topic, in the present work, we investigated the kinetics of the iso-heterocyclic rearrangement depicted in Scheme for five differently substituted substrates ( 1a–e , chosen to span from the strong electron-donating p -methoxy group to the strong electron-withdrawing p -nitro group) under a variety of acidic or alkaline conditions to gain a deeper mechanistic understanding of the reaction course.…”

The Boulton–Katritzky Reaction: A Kinetic Study of the Effect of 5‐Nitrogen Substituents on the Rearrangement of Some (Z)‐Phenylhydrazones of 3‐Benzoyl‐1,2,4‐oxadiazoles

“…For this reason, we have investigated in depth the BKR (mostly examining the reactivity of ( Z )‐arylhydrazones of 5‐substituted 3‐benzoyl‐1,2,4‐oxadiazoles 3 and 5 , see Scheme ) collecting experimental kinetic data6 as well as in‐silico information6g to gain an accurate mechanistic picture of this process. We have ascertained that BKR are S N i processes involving a quasi‐aromatic bicyclic transition state with 10 π‐electrons,6g–6i and that their occurrence is strongly affected by the different stability (aromaticity) of starting and final products 13…”

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

“…The synthesis and crystal structure of 3-acetylamino-5-methyl-1,2,4-oxadiazole, NV848 , has been previously reported in the literature [ 60 , 61 , 62 ].…”

“…2,3,4,5,6-Pentafluoro- N -(5-(perfluorophenyl)-1,2,4-oxadiazol-3-yl)benzamide ( NV914 ) was prepared by acylation of the amine 2 [ 60 , 61 , 62 ] with perfluorobenzoyl chloride, as reported in Scheme 2 .…”

Unexpected Substituent Effects in the Iso-Heterocyclic Boulton–Katritzky Rearrangement of 3-Aroylamino-5-methyl-1,2,4-oxadiazoles: A Mechanistic Study

“…To explain these effects, it is worth recalling here the "insilico" work by Mugnoli et al on the fully degenerated rearrangement of the anion of 3-acetylamino-5-methyl-1,2,4ozadiazole. 34 On that occasion, it was shown that the atomic subset constituted by atoms O1−N2−C3•••O9 (Figure 8) overall decreases its electron density on passing from the reactant to the transition state, whereas at the same time, the two methyl groups (in particular, the one of the acetylamino moiety) increase their electron density. Hence, the sensitivity constant ρ 3 is forced to assume a positive value.…”

“…The photochemical behavior (irradiation at 254 nm) of the same substrates in methanol was ascribed to both the nature of the rearranging chromophore and the multiplicity of the involved excited state . Furthermore, the fully degenerated base-catalyzed ( t- BuOK) rearrangement of 3-acetylamino-5-methyl-1,2,4-oxadiazole in dimethyl sulfoxide solution (Scheme ) was investigated both experimentally by means of dynamic NMR techniques and a computational approach, which furnished interesting results on the course of the fully degenerate rearrangement of the anion of 3-acetylamino-5-methyl-1,2,4-oxadiazole. , On the grounds of the previous studies on the topic, in the present work, we investigated the kinetics of the iso-heterocyclic rearrangement depicted in Scheme for five differently substituted substrates ( 1a–e , chosen to span from the strong electron-donating p -methoxy group to the strong electron-withdrawing p -nitro group) under a variety of acidic or alkaline conditions to gain a deeper mechanistic understanding of the reaction course.…”

The Boulton–Katritzky Reaction: A Kinetic Study of the Effect of 5‐Nitrogen Substituents on the Rearrangement of Some (Z)‐Phenylhydrazones of 3‐Benzoyl‐1,2,4‐oxadiazoles

“…For this reason, we have investigated in depth the BKR (mostly examining the reactivity of ( Z )‐arylhydrazones of 5‐substituted 3‐benzoyl‐1,2,4‐oxadiazoles 3 and 5 , see Scheme ) collecting experimental kinetic data6 as well as in‐silico information6g to gain an accurate mechanistic picture of this process. We have ascertained that BKR are S N i processes involving a quasi‐aromatic bicyclic transition state with 10 π‐electrons,6g–6i and that their occurrence is strongly affected by the different stability (aromaticity) of starting and final products 13…”

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

“…The synthesis and crystal structure of 3-acetylamino-5-methyl-1,2,4-oxadiazole, NV848 , has been previously reported in the literature [ 60 , 61 , 62 ].…”

“…2,3,4,5,6-Pentafluoro- N -(5-(perfluorophenyl)-1,2,4-oxadiazol-3-yl)benzamide ( NV914 ) was prepared by acylation of the amine 2 [ 60 , 61 , 62 ] with perfluorobenzoyl chloride, as reported in Scheme 2 .…”

Unexpected Substituent Effects in the Iso-Heterocyclic Boulton–Katritzky Rearrangement of 3-Aroylamino-5-methyl-1,2,4-oxadiazoles: A Mechanistic Study

“…To explain these effects, it is worth recalling here the "insilico" work by Mugnoli et al on the fully degenerated rearrangement of the anion of 3-acetylamino-5-methyl-1,2,4ozadiazole. 34 On that occasion, it was shown that the atomic subset constituted by atoms O1−N2−C3•••O9 (Figure 8) overall decreases its electron density on passing from the reactant to the transition state, whereas at the same time, the two methyl groups (in particular, the one of the acetylamino moiety) increase their electron density. Hence, the sensitivity constant ρ 3 is forced to assume a positive value.…”

“…The photochemical behavior (irradiation at 254 nm) of the same substrates in methanol was ascribed to both the nature of the rearranging chromophore and the multiplicity of the involved excited state . Furthermore, the fully degenerated base-catalyzed ( t- BuOK) rearrangement of 3-acetylamino-5-methyl-1,2,4-oxadiazole in dimethyl sulfoxide solution (Scheme ) was investigated both experimentally by means of dynamic NMR techniques and a computational approach, which furnished interesting results on the course of the fully degenerate rearrangement of the anion of 3-acetylamino-5-methyl-1,2,4-oxadiazole. , On the grounds of the previous studies on the topic, in the present work, we investigated the kinetics of the iso-heterocyclic rearrangement depicted in Scheme for five differently substituted substrates ( 1a–e , chosen to span from the strong electron-donating p -methoxy group to the strong electron-withdrawing p -nitro group) under a variety of acidic or alkaline conditions to gain a deeper mechanistic understanding of the reaction course.…”

The Boulton–Katritzky Reaction: A Kinetic Study of the Effect of 5‐Nitrogen Substituents on the Rearrangement of Some (Z)‐Phenylhydrazones of 3‐Benzoyl‐1,2,4‐oxadiazoles

“…For this reason, we have investigated in depth the BKR (mostly examining the reactivity of ( Z )‐arylhydrazones of 5‐substituted 3‐benzoyl‐1,2,4‐oxadiazoles 3 and 5 , see Scheme ) collecting experimental kinetic data6 as well as in‐silico information6g to gain an accurate mechanistic picture of this process. We have ascertained that BKR are S N i processes involving a quasi‐aromatic bicyclic transition state with 10 π‐electrons,6g–6i and that their occurrence is strongly affected by the different stability (aromaticity) of starting and final products 13…”