Design Of New Reagents Research Articles

Oxa-azabenzobenzocyclooctynes (O-ABCs): heterobiarylcyclooctynes bearing an endocyclic heteroatom.

We report the synthesis of heterobiarylcyclooctynes bearing an endocyclic heteroatom, oxa-azabenzobenzocyclooctynes (O-ABCs). The integration of design strategies for accelerating strain-promoted azide-alkyne cycloadditions results in reactivity with organic azides that surpasses all cyclooctyne reagents reported to date. O-ABCs and related compounds provide insights into the effects of structural modifications on reactivity that can aid in the design of new reagents for click and bioorthogonal chemistry.

Reactivity of biarylazacyclooctynones in copper-free click chemistry.

The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called “copper-free click chemistry”, is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC’s aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC’s aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC’s central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry.

Ligand design and metal-ion recognition. Comparison of the interaction of cobalt(II) and nickel(II) with 16- to 19-membered mixed-donor macrocycles

The interaction of cobalt(II) and nickel(II) with a range of 16- to 19-membered ring macrocycles incorporating nitrogen, oxygen and/or sulfur heteroatoms is reported. These ligands constitute an extensive array of related macrocyclic structures in which the positions of the donor atoms, their spacing, and the macrocyclic ring size all vary in a systematic manner. Emphasis has been given to the examination of structure–function relationships in the complexation behaviour. Physical measurements confirm the 1 : 1 metal to macrocyclic ligand stoichiometry of the respective complexes. Stability constants for the metal complexes have been determined potentiometrically in 95% methanol (I= 0.1 mol dm–3, NEt4ClO4). An X-ray crystallographic study of [NiL18(H2O)][NO3]2(L18= 5,6,7,8,10,11,12,13,19,20-decahydrodibenzo[f,I][1,8,11,4,15]oxadithiadiazacycloheptadecine) confirms that the nickel ion is six-co-ordinate with the complex cation exhibiting a distorted-octahedral geometry defined by all five donor atoms of the ON2S2 macrocycle and a water molecule; the macrocyclic backbone incorporating the N–O–N donor fragment is arranged meridionally. Molecular mechanics modelling of selected nickel(II) complexes has also been undertaken. As well as their considerable intrinsic interest, the results provide a potentially useful background upon which the design of new reagents for metal-ion discrimination may be based.