Tandem β-Elimination/Hetero-Michael Addition Rearrangement of an N-Alkylated Pyridinium Oxime to an O-Alkylated Pyridine Oxime Ether: An Experimental and Computational Study

Abstract

A novel OH(-)-promoted tandem reaction involving C(β)-N(+)(pyridinium) cleavage and ether C(β)-O(oxime) bond formation in aqueous media has been presented. The study fully elucidates the fascinating reaction behavior of N-benzoylethylpyridinium-4-oxime chloride in aqueous media under mild reaction conditions. The reaction journey begins with the exclusive β-elimination and formation of pyridine-4-oxime and phenyl vinyl ketone and ends with the formation of O-alkylated pyridine oxime ether. A combination of experimental and computational studies enabled the introduction of a new type of rearrangement process that involves a unique tandem reaction sequence. We showed that (E)-O-benzoylethylpyridine-4-oxime is formed in aqueous solution by a base-induced tandem β-elimination/hetero-Michael addition rearrangement of (E)-N-benzoylethylpyridinium-4-oximate, the novel synthetic route to this engaging target class of compounds. The complete mechanistic picture of this rearrangement process was presented and discussed in terms of the E1cb reaction scheme within the rate-limiting β-elimination step.

The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes

“…We manually placed dopamine 1 within the cluster, resulting in the initial stationary-point ( SP ) complexes (Figure 3 ). The system was modeled at the (CPCM)/M06–2X/6–311++G(2df,2pd)//(CPCM)/M06–2X/6–31+G(d) level of theory employing the M06–2X functional designed by Zhao and Truhlar to accurately reproduce thermodynamic and kinetic parameters (Zhao and Truhlar, 2008 , 2011 ; Bell and Head-Gordon, 2011 ; Cheong et al, 2011 ; Picek et al, 2015 ; Saftić et al, 2015 ), being particularly successful in treating non-bonding interactions. To account for the polarization effects caused by the rest of the enzyme, we included a conductor-like polarizable continuum model (CPCM) (Cossi et al, 2003 ) with a dielectric constant of ε = 4, taking the rest of the parameters for pure water, as employed in many studies by Siegbahn, Himo and their co-workers in elucidating the catalytic mechanism of a large variety of enzymes (Himo, 2006 ; Siegbahn and Borowski, 2006 ; Siegbahn and Himo, 2011 ).…”

5‐Triazolyluracils and Their N1‐Sulfonyl Derivatives: Intriguing Reactivity Differences in the Sulfonation of Triazole N1′‐Substituted and N1′‐Unsubstituted Uracil Molecules

“…UV (MeOH): (2df,2pd)//(SMD)/M06-2X/6-31+G(d) models employed here, which turned out to be very accurate in estimating both pK a and reaction thermodynamic values in solution. [25] All of the transition state structures were verified to have the appropriate imaginary frequency, from which the corresponding reactants and products were determined using the Intrinsic Reaction Coordinate (IRC) procedure. [26] pK a values were calculated in a relative fashion using AH + B [27] for the N-H deprotonation in 5 and 7, N,N,NЈ,NЈ-tetramethylguanidine (pK a = 13.65) [27] for DBUH + and pyridineH + , H 3 PO 4 (pK a = 8.48) [28] and H 2 PO 4 -(pK a = 10.58) [28] for the first and second deprotonation of H 2 CO 3 , respectively.…”

Novel Insights into the Thioesterolytic Activity of N-Substituted Pyridinium-4-oximes

“…The ability of oximes to act as esterolytic agents had already been recognized in the late 1950s and various terms like oximolysis, esterolysis, thiocholine ester hydrolysis and cholinesterase pseudo-activity have been adopted to describe the phenomenon [2][3][4][5][6][7][8][9][10]. This reflects their biological role, making them especially effective reagents involved in the reactivation of acetylcholinesterase (AcChE) initially inhibited by organophosphorus poisons (pesticides, nerve gases) [1] or catalysts, which mimic the catalytic mode of hydrolases, as well as excellent Michael donors in nucleophilic additions [11]. The biological importance and pharmacological application of pyridinuim oximes arises from their abilities to reactivate AcChE, the essential enzyme involved in neurotransmission, inhibited by organophosphorus poisons.…”

“…AcCh + is more susceptible to neutral and base-catalyzed hydrolysis than ethyl acetate but less susceptible to acid-catalyzed hydrolysis [8], while majority of thioesters undergoes both acid and base-catalyzed hydrolysis [10]. Kinetic studies indicated that there are two distinct types of thioesters-one which possesses an activated carbonyl group due to the presence of electron-withdrawing substituents on the α-carbon and second type which lacks an activated carbonyl-unactivated thioesters such as AcSCh + [11]. Unactivated thioesters display three distinct regions in the pH-rate profile-HO − -ion catalysis above pH 7, neutral (uncatalyzed) hydrolysis between pH 2-7 and H + -ion catalysis below pH 2 [11].…”