Self-Assembly Can Direct Dynamic Covalent Bond Formation toward Diversity or Specificity

Abstract

With the advent of reversible covalent chemistry the study of the interplay between covalent bond formation and noncovalent interactions has become increasingly relevant. Here we report that the interplay between reversible disulfide chemistry and self-assembly can give rise either to molecular diversity, i.e., the emergence of a unprecedentedly large range of macrocycles or to molecular specificity, i.e., the autocatalytic emergence of a single species. The two phenomena are the result of two different modes of self-assembly, demonstrating that control over self-assembly pathways can enable control over covalent bond formation.

Scheme 1. Dynamic Combinatorial Chemistry of Building Block 1

Figure 1

UPLC analyses of DCLs made from 6.0 mM building block 1 in a 9:1 mixture of aqueous borate buffer (50 mM, pH 8.2) and DMF (A) without agitation and (B) stirred at 1200 rpm.

Figure 2

(A) LMC percentage (left axis) and maximal detected LMC size (n, right axis) of DCLs prepared from 1 (6.0 mM) in 50 mM borate buffer (pH = 8.2) with different amounts of DMF as a cosolvent. (B) Fluorescence emission maximum (left axis, λ_exc = 553 nm) and LMC content (right axis) of solutions containing 230 nM Nile Red and a DCL prepared from 1 (50 mM borate buffer, pH = 8.2, without cosolvent), at different building block concentrations. Lines are drawn to guide the eye.

Figure 3

UPLC chromatogram of the isolated hexamer dissolved in MeCN:H₂O 2:1 (0.1 V/V % TFA) after (A) 0 days, (B) 7 days and (C) 12 days. (D) Temporal evolution of a DCL prepared by dissolving the hexamer of 1 in MeOH (0.44 mM).

Figure 4

(A) Change of the product distribution with time in a DCL prepared of building block 1, showing the characteristic sigmoidal growth of the hexamer. (B) Change of the relative concentration of the hexamer of 1 in a DCL prepared from 1 (6.0 mM) in a 9:1 mixture of aqueous borate buffer (50 mM, pH = 8.2) and DMF without seeding (squares) and upon seeding with 5.0% (circles) and with 10% (triangles) preformed hexamer seed at t = 0 min.

Figure 5

Cryogenic (A–D) and negative stain (E,F) TEM images of a stirred DCL made from preoxidized (80%, NaBO₃) building block 1 (6.0 mM) in various stages of the self-replication process at (A) 3%; t = 0 h (B) 4%; t = 2 h, (C) 16%; t = 3.5 h, (D) 18%; t = 20 h, (E) 65%; t = 43 h, (F) 100% hexamer content; t = 72 h.

Figure 6

AFM images of a stirred DCL made from preoxidized (80%, NaBO₃) building block 1 (6.0 mM) at (A) 54% (B) 100% conversion to hexamer (5 months old sample).

Figure 7

UPLC traces of DCLs prepared from (A) 2, quickly oxidized with NaBO₃ and left unagitated (B) 2, stirred for 3 days (C) 3, unagitated after 7 days (D) 3, stirred for 7 days.

Scheme 2. Simplified Potential Energy Landscape of Dynamic Combinatorial Libraries of Building Block 1 in Water