Synthesis and Mechanochemical Activity of Peptide-Based Cu(I) Bis(N-heterocyclic carbene) Complexes

Abstract

With the class of shock-absorbing proteins, nature created some of the most robust materials combining both mechanical strength and elasticity. Their excellent ability to dissipate energy to prevent surrounding cells from damage is an interesting property that regularly is exploited for applications in biomimetic materials. Similar to biomaterials, where mechanical stimuli are transmitted into a (bio)chemical response, mechanophoric catalysts transform mechanical energy into a chemical reaction. Force transmission is realized commonly by polymeric handles directing the applied force to the mechanophoric bond, which in turn leads to stress-induced activation of the catalyst. Therefore, shock-absorbing proteins able to take up and store mechanical energy elastically for subsequent force transduction to the labile bond seem to be perfect candidates to fulfill this task. Here, we report on the synthesis of two different latent mechanophoric copper(I) bis(N-heterocyclic carbene) complexes bearing either two carboxyl groups or two amino groups which allow conjugation reactions with either the N- or the C-terminus of amino acids or peptides. The chosen catalysts can be activated, for instance, by applying external mechanical force via ultrasound, removing one N-heterocyclic carbene (NHC) ligand. Post-modification of the mechanophoric catalysts via peptide coupling (Gly, Val) and first reactions showed that the mechanoresponsive behavior was still present after the coupling. Subsequent polycondensation of both catalysts lead to a polyamide including the Cu(I) moiety. Mechanochemical activation by ultrasound showed conversions in the copper(I)-catalyzed alkyne-azide "click" reaction (CuAAC) up to 9.9% proving the potential application for the time and spatial controlled CuAAC.

Keywords: copper(I); mechanocatalysts; mechanochemistry; peptide coupling; “click” chemistry.

Figure 1

Energy dissipation mechanisms in proteins. (a) “Molecular spring” behavior and (b) stepwise unfolding of single protein domains under stress. (c) Top: Molecular structure of the low molecular weight catalysts bearing an amino acid (glycine or l-valine). Bottom: Exploitation of the “molecular spring” behavior for an efficient force transmission to facilitate the cleavage of the Cu–carbene bond.

Scheme 1

Pathway for the synthesis of both mechanophoric catalysts 4 and 8 bearing either (a) two carboxyl or (b) two amino groups.

Figure 2

¹H NMR spectra of (a) the NHC precursor 2, (b) the methyl ester protected complex 3, and (c) the deprotected complex 4 bearing two carboxyl groups.

Figure 3

¹H NMR spectra of (a) the NHC precursor 6, (b) the Boc-protected complex 7, and (c) the deprotected complex 8 bearing two amino groups.

Scheme 2

Performed peptide coupling reactions using the mechanophoric catalysts. (a) Coupling of methyl ester protected glycine (9) and (b) of methyl ester protected l-valine (10) to [Cu(C₁₀COOH-NHC)₂]Br (4). (c) The coupling of both the bifunctional carboxy (4) and bifunctional amino catalysts (8) generating a polymeric mechanocatalyst (13). rt: Room temperature.

Figure 4

¹H NMR spectra of (a) glycine-modified complex 11, (b) l-valine-modified complex 12, and (c) of the polymeric catalyst 13.

Figure 5

The peptide coupling between the two bifunctional catalysts 4 and 8 can be followed via GPC. It is expected that the reaction follows a step-growth mechanism due to its polycondensation character. This is proven by GPC where the formation of the dimer is observed early during the reaction. The formation of higher molecular weight species is only observed, if most of the monomer is consumed (75 h).

Figure 6

Activation of the latent catalyst is achieved by ultrasonication which cleaves one of the two shielding NHC ligands. This allows the alkyne to coordinate to the Cu(I) and the “click” reaction can take place. As a model reaction, the “click” reaction between benzyl azide (14) and phenylacetylene (15) was chosen.

Figure 7

Percentage of conversion of phenylacetylene (15) and benzyl azide (14) to the “clicked” product 16 as calculated from ¹H NMR spectroscopy with a standard deviation of ±1%. Samples were taken after the cycles 0, 3, 5, 10, 14, and 17.