Hydrolytic Stability of Hydrazones and Oximes

Abstract

Hydrazones and oximes are common conjugates, but are labile to hydrolysis. The hydrolytic stability of isostructural hydrazones and an oxime have been determined at pD 5.0-9.0. The hydrolysis of each adduct was catalyzed by acid. Rate constants for oxime hydrolysis were nearly 10 3 -fold lower than those for simple hydrazones; a trialkylhydrazonium ion (formed after condensation) was even more stable than the oxime. The data suggest a general mechanism for conjugate hydrolysis. Keywordsconjugates; hydrazones; hydrolysis; oximes; reaction mechanisms Molecules containing carbon-nitrogen double bonds are prevalent in both chemical and biological contexts. The foundations for our current understanding of carbon-nitrogen doublebond formation and hydrolysis were laid by seminal early work on hydrazone hydrolysis and formation,[1] and by contributions from mechanistic studies on enzymes that utilize pyridoxal phosphate.[2] In particular, the meticulous kinetic analyses of Jencks resulted in the delineation of a carbinolamine intermediate in carbon-nitrogen double-bond formation and hydrolysis, and elucidation of the general mechanism of carbonyl-group addition reactions.[3,4] These principles were summarized in a landmark review. [5] Hydrazones and oximes (C 1 =N 1 −X 2 ) possess greater intrinsic hydrolytic stability than do imines. The textbook explanation for this greater stability invokes the participation of X 2 in electron delocalization (Figure 1).[6] The contribution of resonance form II in alkylhydrazones and oximes, and resonance form IV in acylhydrazones increases the negative-charge density

Smart Design of Stable Extracellular Matrix Mimetic Hydrogel: Synthesis, Characterization, and In Vitro and In Vivo Evaluation for Tissue Engineering

“…The fundamental hydrolysis mechanism of hydrazone, oxime or imine, involves the protonation of N 1 followed by nucleophilic attack of water ( II , Figure 1 ). [ 26 ] However, in hydrazones and oximes the neighboring heteroatom (X) gets protonated fi rst VI , (due to signifi cantly higher pKa of X as compared to N 1 ) making it less susceptible towards nucleophilic attack by water. [ 26 ] Thus, the key for designing molecules with resilient hydrazone bond, the molecule should possess ability to prevent protonation of N 1 , which could be achieved Table 1 shows the gel characteristics of these materials after 24 h. The loss tangent (tan δ ), that gives a measure of energy loss in the material upon deformation, was shown to be < 1 in all cases.…”

“…[ 26 ] However, in hydrazones and oximes the neighboring heteroatom (X) gets protonated fi rst VI , (due to signifi cantly higher pKa of X as compared to N 1 ) making it less susceptible towards nucleophilic attack by water. [ 26 ] Thus, the key for designing molecules with resilient hydrazone bond, the molecule should possess ability to prevent protonation of N 1 , which could be achieved Table 1 shows the gel characteristics of these materials after 24 h. The loss tangent (tan δ ), that gives a measure of energy loss in the material upon deformation, was shown to be < 1 in all cases. [ 29 ] This demonstrates predominantly elastic rather than viscous behavior of the hydrogels (Table 1 ) which is typical for ideal gels with few loops, dangling ends or physical entanglements.…”

Metallo‐Controlled Dynamic Molecular Tweezers: Design, Synthesis, and Self‐Assembly by Metal‐Ion Coordination

“…Second, a palladium-catalyzed reaction between benzophenone imine as a source of nitrogen and 11 gave the corresponding bisimine product, identified by LC/MS, which was subsequently selectively deprotected by virtue of the more labile character of imine vs. hydrazone. [35] A solid-state structure of 7, which was obtained by X-ray crystallographic analysis of single crystals obtained by slow diffusion of diisopropyl ether into a chloroform solution of 7, is reported in the Supporting Information. 4 was prepared by high-yield monofunctionalization through pH-controlled reaction of primary amine with 1,4,5,8-naphthalenetetracarboxylic dianhydride to afford monoimide 12.…”

Synthesis and X-Ray Structural Characterization of 1-(5-Bromobenzofuran-2-Yl)-2-Mesitylethanoneoxime and 1-(5-Bromobenzofuran-2-Yl)-2-Mesitylethanone-O-(2- Phenylacetyl)oxime

“…They exist as two geometric stereo isomers: a syn isomer and an anti isomer. Aldoximes, except for aromatic aldoximes, which exist only as anti isomers, and ketoximes can be separated almost completely and obtained as a syn isomer and an anti isomer 3 .…”