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.
The development of 2-isocyanopyridines as novel convertible isocyanides for multicomponent chemistry is reported. Comparison of 12 representatives of this class revealed 2-bromo-6-isocyanopyridine as the optimal reagent in terms of stability and synthetic efficiency. It combines sufficient nucleophilicity with good leaving group capacity of the resulting amide moiety under both basic and acidic conditions. To demonstrate the practical utility of this reagent, an efficient two-step synthesis of the potent opioid carfentanil is presented.
Reaction of substituted o‐aminobenzyl chlorides with isocyanides in the presence of a weak base (NaHCO3) at room temperature afforded the diversely functionalized 2‐aminoindoles in good to excellent yields. A formal [4+1] cycloaddition of the in situ generated aza‐ortho‐xylylenes with isocyanides accounted for the reaction outcome.
Chondroitin sulfate (CS) and hyaluronic acid (HA) methacrylate (MA) hydrogels are under investigation for biomedical applications. Here, the hydrolytic (in)stability of the MA esters in these polysaccharides and hydrogels is investigated. Hydrogels made with glycidyl methacrylate-derivatized CS (CSGMA) or methacrylic anhydride (CSMA) degraded after 2− 25 days in a cross-linking density-dependent manner (pH 7.4, 37 °C). HA methacrylate (HAMA) hydrogels were stable over 50 days under the same conditions. CS(G)MA hydrogel degradation rates increased with pH, due to hydroxide-driven ester hydrolysis. Desulfated chondroitin MA hydrogels also degrade, indicating that sulfate groups are not responsible for CS(G)MA's hydrolytic sensitivity (pH 7.0−8.0, 37 °C). This sensitivity is likely because CS(G)MA's N-acetyl-galactosamines do not form hydrogen bonds with adjacent glucuronic acid oxygens, whereas HAMA's Nacetyl-glucosamines do. This bond absence allows CS(G)MA higher chain flexibility and hydration and could increase ester hydrolysis sensitivity in CS(G)MA networks. This report helps in biodegradable hydrogel development based on endogenous polysaccharides for clinical applications.
Urea removal from dialysate is the
major obstacle in realization
of a miniature dialysis device, based on continuous dialysate regeneration
in a closed loop, used for the treatment of patients suffering from
end-stage kidney disease. For the development of a polymeric urea
sorbent, capable of removing urea from dialysate with high binding
capacities and fast reaction kinetics, a systematic kinetic study
was performed on the reactivity of urea with a library of low-molecular-weight
carbonyl compounds in phosphate-buffered saline (pH 7.4) at 323 K.
It was found that dialdehydes do not react with urea under these conditions
but need to be activated under acidic conditions and require aldehyde
groups in close proximity to each other to allow a reaction with urea.
Among the 31 (hydrated) carbonyl compounds tested, triformylmethane,
ninhydrin, and phenylglyoxaldehyde were the most reactive ones with
urea. This is attributed to the low dehydration energies of these
compounds, as calculated by Gibbs free energy differences between
the hydrated and dehydrated carbonyl compounds, which are favorable
for the reaction with urea. Therefore, future urea sorbents should
contain such functional groups at the highest possible density.
For
realization of a wearable artificial kidney based on regeneration
of a small volume of dialysate, efficient urea removal from dialysate
is a major challenge. Here a potentially suitable polymeric sorbent
based on phenylglyoxaldehyde (PGA), able to covalently bind urea under
physiological conditions, is described. Sorbent beads containing PGA
groups were obtained by suspension polymerization of either styrene
or vinylphenylethan-1-one (VPE), followed by modification of the aromatic
groups of poly(styrene) and poly(VPE) into PGA. It was found that
PGA-functionalized sorbent beads had maximum urea binding capacities
of 1.4–2.2 mmol/g and removed ∼0.6 mmol urea/g in 8
h at 37 °C under static conditions from urea-enriched phosphate-buffered
saline, conditions representative of dialysate regeneration. This
means that the daily urea production of a dialysis patient can be
removed with a few hundred grams of this sorbent which, is an important
step forward in the development of a wearable artificial kidney.
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