Effect of Substituents on the Reactivity of Ninhydrin with Urea

Abstract

Ninhydrin, i. e. the stable hydrate of the reactive species indanetrione, is a well-known compound used for the quantification of ammonia and amino acids. However, substituent effects on the reactivity of ninhydrin with nucleophiles are not described. In this work, the kinetics of the reaction of C4-and C5-substituted ninhydrins with urea was studied and monitored by 13 C-NMR. Surprisingly, the obtained results show that electron donating groups (EDGs) as well as electron withdrawing groups (EWGs) decrease the rate of the reaction. EDGs decrease the electrophilicity of indanetrione, resulting in slower overall kinetics than unsubstituted ninhydrin. The calculated Gibbs free energy differences for the dehydration of unsubstituted and substituted ninhydrins and the subsequent reaction with urea showed that the dehydration of the compounds is more sensitive to electronic effects than the subsequent reaction with urea. Therefore, although EWGs increase the electrophilicity of indanetrione, this is more than counterbalanced by an adverse shift of the hydration equilibrium towards the unreactive hydrate (i. e. ninhydrin), resulting in slower kinetics as well.[a] J. Scheme 1. The mechanism of reaction of ninhydrin with amino acids. R.d.s. = rate-determining step. 1 e = ninhydrin, Table 1 entry e.

Reactivity of (Vicinal) Carbonyl Compounds with Urea

“…To understand why certain carbonyl compounds and hydrates such as ninhydrin and PGA react with urea, whereas carbonyl compounds and hydrates such as hexafluoroacetone (entry 15) and 2,2-dihydroxy-4,4,5,5-tetramethylcyclopentane-1,3-dione (entry 2) do not, we calculated the changes in Gibbs free energy (Δ G ) for these reactions using a computational model that we used in our previous study on the reaction of ninhydrin derivatives with urea. 22 Most of the carbonyl compounds that we tested are predominately present in their hydrated forms. Consequently, the first step in the reaction mechanism is the dehydration of the hydrate and thus the formation of the carbonyl (as shown in Scheme 5 for ninhydrin).…”

“…24 Based on these reports, we systematically analyzed the kinetics of the reaction of several aromatic carbonyl compounds and nonaromatic analogues thereof with urea in aqueous solution representative for dialysate and determined the second-order rate constant. It is expected that the kinetics of the reaction of carbonyl compounds with urea decreases upon incorporation of the carbonyl groups in a polymeric sorbent due to substituent effects 22 and decreased accessibility of polymeric groups as compared with molecules in solution. Still, this fundamental knowledge can be used for the future design of urea sorbents with fast kinetics and high binding capacities.…”

A Ninhydrin‐Type Urea Sorbent for the Development of a Wearable Artificial Kidney

“…The reaction of 5‐substituted‐ninhydrin with urea is shown in Scheme 1A . In addition, we investigated the effect of electron donating and electron withdrawing substituents on the reactivity of ninhydrin toward urea, and found that an electron donating group such as a methyl‐ or a tert‐butyl‐ group on the 5‐position shows the highest reactivity of the ninhydrin derivates with urea 23. Therefore, we concluded that a sorbent with an electron‐donating carbon–carbon backbone, functionalized with ninhydrin groups on the 5‐position would structure‐wise be optimal.…”

“…A) The reaction of 5‐substituted ninhydrin with urea23 and B) synthesis of ninhydrin sorbents via Smakman's route19,24 and C) the route described in this work. R = side products.…”

Interaction of Ninhydrin With N-Hydroxyurea and N-Alkoxyureas in Acetic Acid

“…It is therefore important to create the reaction strategies that give access to such biologically active synthones. As it is known, [1][2][3][4] ninhydrin (indane-1,2,3trione hydrate) reacts with urea and N,N'-dimethylureas yielding 3a,8a-dihydroxy-1,3,3a,8a-tetrahydroindeno [1,2d]imidazole-2,8-diones (1a,b) (Scheme 1).…”