Hydrogen Bonding Effects on Reactivity

Hydrogen bonds play a crucial role in the catalytic activity of biological systems. In this thesis, the effect of hydrogen bonds on the reactivity of phosphate triesters is studied, particularly towards hydrolysis and the attack of hydroxylamine.
The synthesis of methyl 8-hydroxy-1, 9-anthryl cyclic phosphate 46 and its reaction with water and nucleophiles are investigated. These reactions are accelerated by the presence of the hydroxyl group through hydrogen bonding, with a rate acceleration of about 30 and 173 fold (~9 and 13 kJ mol-1, respectively) in comparison to the hydrolysis of methyl 1,9-anthryl cyclic phosphate and methyl 1,8-naphthyl cyclic phosphate. It is concluded that the presence of hydroxyl group plays a significant catalytic role in increasing the rate of P-O cleavage through hydrogen bond catalysis in a system where both the hydrogen bond donor and reacting group are held in a fixed relationship.
The catalytic role of hydrogen bond are also evaluated on the reaction of acyclic phosphate triesters with hydroxylamine. The hydrolysis of diethyl 8-hydroxy-1-naphthyl phosphate was studied. The rate of hydrolysis was enhanced almost 500 fold compared with diethyl 1-naphthyl phosphate and diethyl 2′-hydroxy-2-biphenyl phosphate. The rotational freedom of biphenyl rings leads to less effective hydrogen bond interaction between the hydroxyl group and leaving group oxygen.
An attempt was made to study the effect of multiple hydrogen bonds on phenyl triesters. Diethyl 1,2- and 1,3-dihydroxy phenyl phosphate were synthesised and their hydrolysis studied in the presence of hydroxylamine. The rate of the reaction was a similar to that of diethyl 1-hydroxy phenyl phosphate. The reaction of these triesters is catalysed by the ionised hydroxyl group with a mechanism involving intramolecular nucleophilic catalysis instead of hydrogen bond enhanced departure of the aryloxy group. The reaction is stereospecific for displacement of alkoxide anion. It is concluded that the hydroxyl group in these structures is more effective as a nucleophile than hydrogen bond donor when an exo-alkyl group is present. The rate of reaction of diethyl phenyl phosphate was too slow to measure accurately under these conditions, and so any hydrogen bond enhanced cleavage may be too inefficient to be observed in the presence of the cyclisation pathway. Attempts to create models with multiple hydrogen bond donors acting on the leaving group using an anthracene scaffold are carried out, but were not successful in creating the desired targets