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Anthony J Kirby

Publications and source records attributed to Anthony J Kirby.

10 recordsLinked to original sources
PubMed2006

Efficient intramolecular general acid catalysis of nucleophilic attack on a phosphodiester.

The hydrolysis of methyl 8-dimethylamino-1-naphthyl phosphate 4 and its reactions with a representative range of nucleophiles are catalyzed by the dimethylammonium group at acidic pH with rate accelerations of the order of 106. The reaction persists up to pH 7 because the strong intramolecular hydrogen bond, which is the key to efficient general acid catalysis, is present also in the reactant. The sensitivity to the basicity of the nucleophile (Brønsted beta(nuc) = 0.29) lies between values measured previously for mono- and triesters. The comparisons suggest that general acid catalyzed reactions of phosphate mono- or diesters with strongly basic oxyanion nucleophiles (like those derived from a serine oxygen or a bound water molecule in an enzyme active site) will be fastest when their negative charges are neutralized by protonation. Reactions with NH2OH and its N-methylated derivatives show an apparent alpha-effect, but NH2OMe reacts no faster than a primary amine of similar basicity. It is suggested that the reaction involving NH2OH as an oxygen nucleophile proceeds through the pre-equilibrium formation of the tautomer H3N+-O- as the active nucleophile: ab initio calculations support this idea.

Catalysis↗
PubMed2006

Toward bifunctional antibody catalysis.

Antibodies that catalyze the deprotonation of unactivated benzisoxazoles to give the corresponding salicylonitriles were prepared using as antigen a 2-aminobenzimidazolium derivative coupled to a carrier protein via its benzene ring. The hapten was designed to induce an antibody binding site with both a base and an acid, in position to initiate proton transfer and stabilize developing negative charge at the phenoxide leaving group, respectively. Consistent with this design, the catalysts exhibit bell-shaped pH-rate profiles, while chemical modification identified several functional groups that could participate in bifunctional catalysis. One of the antibodies, 13G5, is particularly notable in catalyzing the elimination of 6-glutaramidebenzisoxazole with a > 10(5)-fold rate acceleration over background and an effective molarity of > 10(4) M for its catalytic base. These properties compare favorably to the efficiencies achieved by the best previously characterized antibodies with substantially more reactive substrates.

Antibodies, Catalytic↗
PubMed2005

Intramolecular general acid catalysis of phosphate transfer. nucleophilic attack by oxyanions on the PO3 2- group.

Phosphate transfer from the 8-dimethylammonium-naphthyl-1-phosphate monoanion 4m to water and to a range of nucleophiles shows general acid catalysis by the neighboring NH(+) group, through the strong intramolecular hydrogen bond. Reactivity is insensitive to the charge on the nucleophile, so that fluoride and oxyanions displace dimethylaminonaphthol from the PO3(2-) group as effectively as do amines of the same basicity. Reactivity is (predictably) relatively insensitive to the basicity of the nucleophile and to the alpha-effect. A strong intramolecular hydrogen bond is present in the product, but also in the reactant, as evidenced by major perturbations in the pK(a)'s of the phosphate and dimethylamino groups, to 3.94 and 9.31, respectively, and by ab initio calculations. Rate accelerations are of the order of 10(6)-fold despite this stabilization: the strength of the hydrogen bond is evidently significantly enhanced in the transition state. The evidence suggests that it also depends remarkably strongly on the degree of ionization of the reacting phosphate group and will be significantly reduced for the neutral PO(OH)2 group. Thus, the hydrolysis of the substrate cation 4+ shows a correspondingly greater, >10(8)-fold acceleration.

Journal Article↗
PubMed2004

Thorpe-Ingold effects in cyclizations to five-membered and six-membered rings containing planar segments. The rearrangement of N(1)-alkyl-substituted dihydroorotic acids to hydantoinacetic acids in base.

While the gem-dimethyl effect (GDME) is quantitatively similar for cyclizations to cyclopentane and cyclohexane rings and their homomorphs, in systems containing planar segments the GDME is stronger for the formation of five-membered rings. Planar pentagons have smaller angles than planar hexagons and their formation is helped by the decrease in the potential internal bond angle caused by substituents, as suggested by Thorpe and Ingold for small rings. The phenomenon is illustrated with crystal structure data on five-membered hydantoins and six-membered dihydrouracils containing four-atom planar segments. Such a Thorpe-Ingold effect explains the rearrangement in base of N-alkyl substituted dihydroorotic acids 1 to hydantoinacetic acids 3. The reaction involves initial hydrolysis to N-(N-alkylcarbamoyl)aspartic acids 2 and their subsequent cyclization. The unsubstituted N-carbamoylaspartic acid 2a is stable in 1 M KOH, the N(1)-methyl and ethyl compounds 2b and 2c are in equilibrium with the hydantoinacetic acids 3, while the cyclization of the N(1)-isopropyl and cyclohexyl derivatives 2d and 2e is irreversible. Experimental data on equilibria and pK(a)s for ionization of the carboxy and NH groups allow equilibria and rates involving the N-unsubstituted compounds to be estimated and compared with those for the N-alkyl derivatives. The strongest effect is observed on the equilibrium [3(2-)]/2[(2-)], where substitution of H by methyl increases K 600-fold. In vitro the kinetic regioselectivity for acid catalyzed cyclization of N-carbamoylaspartic to hydantoinacetic acid against dihydroorotic acid is only 10:1. This, together with the weaker acidity of the remote carboxyl group, favours cyclization to dihydroorotic acid under biological conditions.

Journal Article↗
PubMed2004

Nucleophilic attack by oxyanions on a phosphate monoester dianion: the positive effect of a cationic general Acid.

The two negative charges on a phosphate monoester RO-PO32- at neutral pH provide a considerable electrostatic barrier toward reactions with nucleophilic reagents with a negative charge on the attacking atom. Electrostatic repulsion disappears when the hydrolysis of an aryl phosphate monoester is catalyzed by a neighboring cationic general acid. The hydrolysis of 8-dimethylammonium-1-phosphate (1) is catalyzed by oxyanions, fluoride anion, and hydroxylamines at similar rates.

Journal Article↗
PubMed2003

Gemini surfactants: new synthetic vectors for gene transfection.

The superior surfactant properties of cationic gemini surfactants are applied to the complex problem of introducing genes into cells. Of almost 250 new compounds tested, of some 20 different structural types, a majority showed very good transfection activity in vitro. The surfactant is shown to bind and compact DNA efficiently, and structural studies and calculations provide a working picture of the "lipoplex" formed. The lipoplex can penetrate the outer membranes of many cell types, to appear in the cytoplasm encapsulated within endosomes. Escape from the endosome--a key step for transfection--may be controlled by changes in the aggregation behavior of the lipoplex as the pH falls. The evidence suggests that DNA may be released from the lipoplex before entry into the nucleus, where the new gene can be expressed with high efficiency.

Genetic Therapy↗
PubMed2003

Kinetics and mechanism of the cyclization of omega-(p-nitrophenyl)-hydantoic acid amides: steric hindrance to proton transfer causes a 10(4)-fold change in rate.

The pH-rate profiles for the cyclization of primary 2,3-dimethyl and 2,2,3-trimethyl-hydantoinamides (2-UAm and 3-UAm respectively) differ strikingly from those for the cyclizations of the corresponding N-methylated amides 2-MUAm and 3-MUAm; which are dominated by the water reaction, spanning some 6 pH units. For the cyclization of UAm the plateau extends over no more than two pH units. The difference is due to the slower base-catalyzed cyclization of the N-methylamides. The solvent kinetic isotope effect for this hydroxide-catalyzed reaction is close to 1.2, consistent with a slow protonation by water of the amino-group of the negatively charged tetrahedral intermediate. General base catalysis was observed with bases of pKBH up to 8. The Brønsted beta are compatible with a hydrogen bonding mechanism for the GBC. In the gem-dimethyl compounds 3 the leaving group is flanked by substituents on both sides. The N-methyl group in 3-MUAm hinders frontal access of the proton, causing a 14000 fold decrease in rate. This is only 3800 fold in the compound with one methyl group at position 2.

Journal Article↗
PubMed2002

3,5,7-trimethyl-1-azatricyclo[3.3.1.1(3,7)]decan-2-ylidene, an aminocarbene without pi conjugation.

3,5,7-trimethyl-1 -azatricyclo[3.3.1.1(3,7)]decan-2-ylidene, an aminocarbene without pi conjugation, has been generated from the corresponding tosylhydrazone salt. Addition of the carbene to alkenes is stereospecifically cis, thus showing that the reacting state is singlet. Competition studies reveal that the carbene is somewhat nucleophilic, implying a measure of overlap between the lone pair on nitrogen and the empty orbital on carbon. In turn, such overlap implies a pyramidal structure for the divalent carbon.

Journal Article↗