Arylboronic Acid-Catalyzed Hydrolyses of Salicylaldehyde Imines

Boronic acids accelerate hydrolyses of the Schiff's bases derived from salicylaldehyde and primary amines. The accelerations of Schiff's base hydrolyses are due to the formation of a complex between the boronic acid and the imine followed by the break-down of the complex to products. The formation of a reversible complex between arylboronic acids and imines allows the rate of hydrolysis to display typical Michaelis-Menten enzyme-substrate kinetics, including situations where the imine is completely saturated with the boronic acid.;This thesis focuses on the ability of different arylboronic/benzeneboronic acids(BBAs) to catalyze the hydrolysis of different imines, most of them being salicylaldehyde imines made using primary amines or amino acids, an example being salicylidene-threonine.;In order to better understand the mechanism involved in the imine hydrolysis by arylboronic acids, I studied structure-activity relationships(SAR) for different substituted BBAs and of different imine substrates undergoing hydrolyses. Herein, I present the most important aspects of these SAR studies on both the catalysts(BBAs) and on their imine substrates. I hypothesized that electron withdrawing groups would enable BBAs to be more easily ionized, thus becoming better hydrogen bond donors and making it easier to have higher affinities for the imine substrates.;SAR experiments conducted with different fluoro-substituted benzeneboronic acids showed that all fluoro-BBAs have higher catalytic efficiencies of imine hydrolysis than the un-substituted boronic acid except for the catalysts with two fluorine atoms substituted in the ortho-position with respect to the boron atom. The latter presumably induced steric hindrance. SAR on BBAs enabled me to discover novel catalysts for the hydrolysis of salicylidene-3-hydroxyaniline imine. The best ones are with 2,3,5-trifluoroBBA and 2,3,4,5-tetrafluoroBBA and their kcat/KM values go over 1000 fold higher than with the unsubstituted BBA.;Furthermore, SAR of different imine substrates highlights the most important structural determinants of the enhanced catalytic efficiency. The most important contribution to the efficiency of imine hydrolysis are shown to be the hydrogen bonding donors or acceptors (hydroxy or amino groups) in the imine substrates which are demonstrated to activate the catalytic turn-over (kcat) of the arylboronic acid catalyst.;The pH dependencies for BBA catalyzed hydrolysis of salicylaldehyde-3-hydroxyaniline shows that rate constants are maximal at lower pH values and decrease with increasing pH. The kinetics shows single proton ionizations, demonstrating that there is no other ionization event related to the imine itself which could affect catalytic efficiency. Moreover, the kcat, K M and kcat/KM dependencies with pH shows that kcat is independent of pH. This indicates the absence of hydroxide or hydronium ion involvement in the hydrolysis.;The plots of Log10 (KM), Log10 (kcat), Log10 (kcat/KM), vs. Hammett sigma substituent constants indicate that kcat, KM and kcat/KM all dependent on electron withdrawing substituent groups present in the benzeneboronic acids.;The hydrogen bonding network provided by the hydroxyl or amino groups in the imine substrates during the hydrolysis could assist the BBA catalysts in binding tighter to the substrate, which in turn, are reflected in higher catalytic efficiencies. The presence of hydroxyl and amino groups in imine substrates of 2,3,4,5-tetrafluoroBBA resulted in 5- to over 100-fold increases in kcat/KM values. Thus the 2,3,4,5-tetrafluoroBBA-catalyzed kcat/KM value for salicylidene-threonine is 33 M -1sec-1 and for salicylidene-lysine is 17 M -1sec-1 whereas for salicylidene-valine, without an amino acid side chain hydroxyl or amino group, it is only 8 M-1sec -1.;The relative stabilities of the complexes between BBAs and imines are predicted through docking experiments with the software SCULPT provided by MDL. NMR spectroscopy experiments are performed to confirm the structures.;This thesis highlights the importance of the hydroxyl group substituted to the benzene ring in aniline or benzylamine based imines in inducing better catalytic efficiencies for their hydrolyses by fluoro-substituted BBAs. Examples are shown in the kcat/KM values for the hydrolysis of salicylidene-3-hydroxyaniline with 2,3,5-trifluoroBBA (232 M-1sec -1), and 2,3,4,5-tetrafluoroBBA (175 M-1sec -1).