Rate-determining proton transfer in intramolecular catalysis of amide hydrolysis by the carboxylic acid group

Aldersley, M. F.; Kirby, Anthony J.; Lancaster, P. W.

doi:10.1039/c39720000570

Cited by 9 publications

(8 citation statements)

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“…Under acidic pH, as observed for 22 , both compounds formed the cyanohydrin adducts 27 and 31 respectively, but no hydrolysis of these adducts were observed even after 3–5 days (Supporting Information Figure S32). On the other hand, when the reactions were repeated at pH 7.5–8.0, cyanohydrin adduct 27 , which has a 1,5‐relationship, was not only found to hydrolyze to the corresponding α‐hydroxy amide 29 (2 days, Figure ) but further converted cleanly to the corresponding α‐hydroxy acid (Supporting Information Figures S33–S35), which is consistent with anchimeric assisted hydrolysis of the amide as reported by Kirby . However, cyanohydrin adduct 31 , which has a 1,6‐relationship, was found to persist (Figure ) over days with no further hydrolysis (Figures S36–S37); at pH 13, the formation of the cyanohydrin adduct itself was not observed (Supporting Information Figure S38).…”

Section: Resultssupporting

confidence: 83%

Anchimeric‐Assisted Spontaneous Hydrolysis of Cyanohydrins Under Ambient Conditions: Implications for Cyanide‐Initiated Selective Transformations

Reddy

Liotta

Krishnamurthy

2017

Chemistry A European J

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Nitrile/cyanide hydrolysis is of importance from the perspective of organic chemistry, especially, prebiotic chemistry. Herein we report that cyanohydrins, generated by the reaction of cyanide with β-keto acids and γ-keto-alcohols, spontaneously hydrolyze under ambient conditions (aqueous medium, RT, and a range of pH). The spontaneous hydrolysis is affected by an intramolecular proton transfer and an intramolecular 5-exo-dig attack, but with a twist. In the case of β-keto acids, the hydrolysis is mediated by the neighboring carboxylic acid group only at pH values less than 7, whereas in the case of γ-keto-alcohols the hydrolysis is mediated by the neighboring hydroxyl group only at pH values greater than 7. The results, in combination with previous works, have implications for selective transformations of cyanide-initiated prebiotic systems chemistry.

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Section: Resultssupporting

confidence: 83%

Anchimeric‐Assisted Spontaneous Hydrolysis of Cyanohydrins Under Ambient Conditions: Implications for Cyanide‐Initiated Selective Transformations

Reddy

Liotta

Krishnamurthy

2017

Chemistry A European J

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“…In more concentrated acid, where the starting amide is largely protonated, eq 7 reduces to eq 11. kKx{H+)(H2Q)"72 73 A2(H+)/A3 71 72 , _ fcA,A3(FI20)"73 Aobsd--"--A2 71 (11) (12) Equation 12 suggests that in stronger acid, as A becomes protonated, the reaction rate will become independent of the acidity of the solution (if 73/71 does not change significantly).…”

Section: Discussionmentioning

confidence: 99%

Rate-determining processes in the hydrolysis of maleanilinic acids in acidic solutions

Kluger¹,

Lam²

1976

J. Am. Chem. Soc.

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“…56 However, in the case of the maleamic acid substitution being an isopropyl group, the proton transfer process was found to become the rate-determining step, leading to strong general-acid catalysis. 57 (70% Dox release at pH 6.0 vs. 10% release at pH 7.0 at 5 h). This selectivity is higher than the previously discussed spiro diorthoester linker with the pH 6/7 cleavage ratio being around 4 at 5 h. This advantage reaffirms why the old maleamic acid linker strategy is still being actively studied in the field.…”

Section: Maleic Acid-derived Linkersmentioning

confidence: 99%

“…The rate‐limiting step for the hydrolysis was confirmed to be the breakdown of 30 56 . However, in the case of the maleamic acid substitution being an isopropyl group, the proton transfer process was found to become the rate‐determining step, leading to strong general‐acid catalysis 57 . There have not been thorough studies as to whether the reaction is under kinetic or thermodynamic control.…”

Section: Ph‐sensitive Linkersmentioning

confidence: 99%

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Yang

Pan

Choudhury

et al. 2020

Medicinal Research Reviews

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Smart drugs, such as antibody-drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites. K E Y W O R D S antibody-drug conjugates, click and release, drug delivery, linker chemistry, targeted delivery, triggered release 1 | INTRODUCTION In the world of drug discovery and development, the concept of "smart drugs" broadly refers to those that can selectively affect disease-relevant target(s). However, to a certain degree, essentially all drugs are already selective toward the desired target(s) whether they are enzyme inhibitors, receptor ligands, ion channel blockers, inhibitors of protein-protein interaction, or even genotoxins used for cancer chemotherapy, among others. They would not have made through the various milestones of drug discovery and developmental processes if they were not sufficiently selective for the intended target(s). However, once administered into the human body, the highly complex living system often leads to many unexpected off-target effects. Thus, various additional approaches have been studied and

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Rate-determining proton transfer in intramolecular catalysis of amide hydrolysis by the carboxylic acid group

Cited by 9 publications

References 0 publications

Anchimeric‐Assisted Spontaneous Hydrolysis of Cyanohydrins Under Ambient Conditions: Implications for Cyanide‐Initiated Selective Transformations

Anchimeric‐Assisted Spontaneous Hydrolysis of Cyanohydrins Under Ambient Conditions: Implications for Cyanide‐Initiated Selective Transformations

Rate-determining processes in the hydrolysis of maleanilinic acids in acidic solutions

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

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