Anthony J. Kirby

The Most Twisted Amide: Structure and Reactions

The title amide 1 behaves more like a ketone-up to a point! The crystal structure of this (90°) twisted amide shows a pyramidal nitrogen atom next to a planar carbonyl group.

Mechanism and stereoelectronic effects in the lysozyme reaction

Lysozyme occupies a special place in the history of enzymology as the first enzyme to have its three-dimensional crystal structure elucidated by Phillips and co-workers in 1965. The crystallography, and much biochemical work, revealed three factors likely to be important for the mechanism of action: catalysis by the carboxyl group of Glu-35, catalysis by the ionized carboxyl group of Asp-52, and the conformation of the bound polysaccharide substrate. The work of the last 20 years has defined likely roles for the catalytic groups, but discussion of the conformational question came to a head only very recently with the suggestion that the fundamental stereoelectronic requirements of the glycoside-cleavage reaction might be decisive. Recent work on all three interlinked factors are reviewed.

Intramolecular Catalysis of Phosphodiester Hydrolysis by Two Imidazoles

Two imidazole groups act together to catalyze the hydrolysis of the phosphodiester bis(2-(1-methyl-1H-imidazolyl)phenyl) phosphate (BMIPP). A full investigation involving searching computational and electrospray ionization (ESI-MS-/MS) and ultra mass spectrometry (LTQ-FT) experiments made possible a choice between two kinetically equivalent mechanisms. The preferred pathway, involving intramolecular nucleophilic catalysis by imidazole, assisted by intramolecular general acid catalysis by the imidazolium group, offers the first simple model for the mechanism used by the extensive phospholipase D superfamily.

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.

Synthesis of 8-substituted 1-naphthylamine derivatives. exceptional reactivity of the substituents.

Abstract 8-Lithio-1-N, N-dimethylaminonaphthalene has been prepared, and converted in good yield to the 8-CHO, COCH3, n-Bu2B and OH derivatives. The peri-relationship confers special reactivity on both 1 and 8 substituents: the aldehyde (5) is largely ring-closed in acid, the borane (9) is inert to oxidation because of the B → N interaction, and the 8-methoxymethyl NMe3+ derivative is formed only with difficulty, and readily demethylated.

Phosphorylimidazole derivatives: potentially biosignaling molecules.

The phosphorylation of imidazole by two activated phosphate diesters and a triester gives phosphorylimidazole derivatives that are stable enough in aqueous solution to be observed and identified by ESI-MS/MS and NMR. Half-lives ranging from hours to days (in the case of the monoethyl ester) show that it is possible to design molecules with variable half-lives with potential to be used for biological intervention experiments as possible inhibitors of biosignaling processes or as haptens for the generation of antibodies.

Bond length and reactivity: the gauche effect. A combined crystallographic and theoretical investigation of the effects of β-substituents on C–OX bond length

The ‘variable oxygen probe’ is applied to systems with the general structure Y–C–C–OX (Y = F, H, SiR3), using both crystal structure correlations (including 25 new structures) and ab initio calculations (SCF[DZP]), for 20 structures, Y–CH2–CH2–OX: Y = H, F and SiH3(gauche and trans); X = CH3, CHO (E and Z) and NO2. The calculations reproduce conformational preferences well (all our 2-fluoroethyl derivatives crystallise with F gauche to OX). Both crystal and calculated structures give linear bond-length/pKHOX correlations. From the crystal structures: definitive correlations are derived for primary and secondary alcohol derivatives; no significant difference is observed between axial and equatorial cyclohexyl systems; β-fluorine has a small bond-shortening effect on the C–OX bond, which is greatest for the best leaving groups OX; and data for two systems with β-silicon are consistent with a bond-lengthening effect. The inductive effect of β-fluorine, observed as its effect on the C–OX bond length, shows no significant dependence on geometry.Calculated bond lengths give similar results, but show the different sensitivities to varying OX expected from frontier orbital considerations (σY–C–σ*C–OX for Y = Si > H > F). The length of the C–OX bond in Y–CH2–CH2–OX is a linear function of the electronegativity of Y. 1,3-Interaction energies calculated (at the MP2[DZP] level) for the isodesmic reaction Y–CH2–CH2–OX + CH3–CH3→ CH3–CH2–OX + Y–CH2–CH3 give a measure of the destablising effect of β-fluorine and the stabilising effect of β-silicon in these systems. In three different systems which react with participation of adjacent σ-bonds, the lengthening of the C–OX bond, observed in the ground state using the variable oxygen probe, is not accompanied by significant involvement of the adjacent orbitals. It is suggested that C–OX bond breaking, and the further structural reorganisation, are not closely coupled in such reactions.

New light on phosphate transfer from triesters.

The reactivity of triesters is discussed in the general context of phosphate transfer, as usually studied for the reactions of mono- and diesters. Systematic work has typically concentrated on the Linear Free Energy Relationships measuring the dependence of reactivity on the nucleophile and the leaving group, but new results indicate that it can depend equally strongly on the two non-leaving (sometimes known as spectator) groups. This conclusion is supported by first results from theoretical calculations: which also predict that a two-step mechanism can be favored over a concerted S(N)2(P) mechanism even for reactions involving leaving groups as good as p-nitrophenolate. This article is part of a Special Issue entitled: Chemistry and mechanism of phosphatases, diesterases and triesterases.

Novel spermine-based cationic gemini surfactants for gene delivery

Two types of spermine-based gemini surfactants have been synthesised; structure-activity studies have shown one type to be far superior in gene transection than the other.

Intramolecular General Base Catalysis in the Hydrolysis of a Phosphate Diester. Calculational Guidance to a Choice of Mechanism

Notwithstanding its half-life of 70 years at 25 °C, the spontaneous hydrolysis of the anion of di-2-pyridyl phosphate (DPP) is thousands of times faster (ca. 3000 at 100 °C, over 10000-fold at 25 °C) than expected for a diester with leaving groups of pK(a) 9.09. The kinetic parameters do not permit a conclusive choice between five possible mechanisms considered, but the combination of kinetics and calculational evidence supports a single-step, concerted, S(N)2(P) mechanism involving the attack of solvent water on phosphorus assisted by intramolecular catalysis by a (weakly basic) pyridine nitrogen acting as a general base. Catalysis is relatively efficient for this mechanism, with an estimated effective molarity (EM) of the general base of >15 M, consistent with the absence of catalysis by typical buffers. Further new results confirm that varying the nonleaving group has minimal effect on the rate of spontaneous diester hydrolysis, in striking contrast to the major effect on the corresponding reaction of triesters: though protonation of one nitrogen of DPP(-) increases the rate of hydrolysis by 6 orders of magnitude, in line with expectation.