Investigating the effect of hydrogen bonding environments in amide cleavage reactions at zinc(ii) complexes with intramolecular amide oxygen co-ordination

Abstract

Amide oxygen co-ordination to a zinc(II) ion around a hydrogen bonding microenvironment is a common structural/functional feature of metalloproteases. We report two strategies to position hydrogen bonding groups in the proximity of a zinc(II)-bound amide oxygen, and we investigate their effect on the stability of the amide group. Polydentate tripodal ligands (6-R¹-2-pyridylmethyl)-R² (R¹ = NHCO^tBu, R² = N(CH₂-py-6-X)₂ X = H L¹, X = NH₂, H L², X = NH₂L³) form [(L)Zn]²⁺ cations (L = L¹, 1; L², 2; L³, 3) with intramolecular amide oxygen co-ordination (1–3), and intramolecular N–H⋯OC(amide) hydrogen bonding (2, 3) rigidly fixed by the ligand framework. 1–3 undergo cleavage of the tert-butyl amide upon addition of Me₄NOH·5H₂O (1 equiv.) in methanol at 50(1) °C. Under these conditions the half-life, t_1/2, of the amide bond is 0.4 h for 1, 9 h for 2 and 320 h for 3. Mononuclear zinc(II) complexes of (6-NHCO^tBu-2-pyridylmethyl)-R² (R² = N(CH₂CH₂)₂S) L⁴ and chelating N2 ligands without hydrogen bonding groups (1,10-phenanthroline L⁵, 2-(aminomethyl)pyridine L⁶) as control compounds, and with an amino hydrogen bonding group (6-amino-2-(aminomethyl)pyridine L⁷) have been synthesised. Amide cleavage is in this case faster at the zinc(II) complex with the amino hydrogen bonding group. Thus, hydrogen bonding environments can both accelerate and slow down amide bond cleavage reactions at zinc(II) sites. Importantly, the magnitude of the effect exerted by the hydrogen bonding environments was found to be significant; 800-fold rate difference. This result highlights the importance of hydrogen bonding environments around metal centres in amide cleavage reactions, which may be relevant to the chemistry of natural metalloproteases and applicable to the design of more efficient artificial protein cleaving agents.