Sequence-Defined Macrocycles for Understanding and Controlling the Build-up of Hierarchical Order in Self-Assembled 2D Arrays

Abstract

Anfinsen's dogma that sequence dictates structure is fundamental to understanding the activity and assembly of proteins. This idea has been applied to all manner of oligomers but not to the behavior of cyclic oligomers, aka macrocycles. We do this here by providing the first proofs that sequence controls the hierarchical assembly of nonbiological macrocycles, in this case, at graphite surfaces. To design macrocycles with one (AAA), two (AAB), or three (ABC) different carbazole units, we needed to subvert the synthetic preferences for one-pot macrocyclizations. We developed a new stepwise synthesis with sequence-defined targets made in 11, 17, and 22 steps with 25, 10, and 5% yields, respectively. The linear build up of primary sequence (1°) also enabled a thermal Huisgen cycloaddition to proceed regioselectively for the first time using geometric control. The resulting macrocycles are planar (2° structure) and form H-bonded dimers (3°) at surfaces. Primary sequences encoded into the suite of tricarb macrocycles were shown by scanning-tunneling microscopy (STM) to impact the next levels of supramolecular ordering (4°) and 2D crystalline polymorphs (5°) at solution-graphite interfaces. STM imaging of an AAB macrocycle revealed the formation of a new gap phase that was inaccessible using only C₃-symmetric macrocycles. STM imaging of two additional sequence-controlled macrocycles (AAD, ABE) allowed us to identify the factors driving the formation of this new polymorph. This demonstration of how sequence controls the hierarchical patterning of macrocycles raises the importance of stepwise syntheses relative to one-pot macrocyclizations to offer new approaches for greater understanding and control of hierarchical assembly.

Figure 1.

(a) Primary (1°) structure of a tricarb macrocycle in which A, B, and C are three carbazole monomers linked by triazole (Tz) units. (b) The tricarb macrocycle adopts a planar secondary (2°) structure. (c) The tertiary (3°) structure adopted on graphite surfaces involves macrocycle dimers stabilized by lateral H-bonding between CH donors and N atom acceptors, forming a H-bonding array at the intermacrocycle seam. (d) Propagation of side-on interactions between macrocycles leads to the generation of quaternary (4°) superstructures on graphite surfaces; 6-membered rosettes are preferred. (e) Patterning of rosettes across the surface results in the formation of crystalline 2D polymorphs.

Figure 2.

Syntheses of a three-component macrocycle by means of either (a) a statistical one-pot method in which the desired macrocycle (*) is produced along with a statistical distribution of nine additional macrocycles or (b) a stepwise method in which the desired macrocycle is made over more steps in a targeted manner.

Figure 3.

(a) Primary (1°) sequence of the tricarb macrocycles synthesized in this work: AAA, BBB, CCC, AAC, AAD, ABE. (b) Formulas and color-coded letters of the sequence elements used in tricarb macrocycles. (c) Chemical structures of all the synthesized tricarb macrocycles overlaid onto their cartoon representations.

Figure 4.

Aromatic region of the ¹H NMR spectra of the key intermediates along the stepwise pathway (500 MHz, 298 K, CDCl₃).

Figure 5.

(a) Aromatic regions of the ¹H NMR spectra (1 mM/500 MHz/CDCl₃/298 K) of TC-6618, TC-18, and TC-6 show identical chemical shifts. (b) ¹³C NMR spectra (1 mM/125 MHz/CDCl₃/298 K) of TC-6618, TC-18, and TC-6 can only be distinguished by the unique peaks from the alkyl-chain substituents. ¹³C NMR peaks arising from octadecyl chains are marked in red and peaks arising from hexyl chains are marked in blue.

Figure 6.

Aromatic region of the ¹H NMR spectrum of TC-610MeCy (0.5 mM/600 MHz/CDCl₃/298 K).

Figure 7.

(a) General mechanism in which (top) 1,5 and (bottom) 1,4 regioisomers can form in thermal Huisgen’s azide-alkyne cycloaddition. (b) Molecular mechanics modeling (MMFF94) showing the orientation of the terminal azido and alkynyl functionalities within a tricarbazole crescent and the reaction conditions for the formation of TC-10 under thermal conditions.

Figure 8.

Models of the (a) flower and (c) honeycomb phases formed by (b) TC-18. High-resolution STM images of TC-18 at the TCB/graphite interface showing the (d) flower phase (5 μM, I_t = 0.3 nA, V_sample = −0.8 V), (e) mixed phases (75 μM, I_t = 0.03 nA, V_sample = −0.4 V), and (f) honeycomb phase (100 μM, I_t = 0.03 nA, V_sample = −0.4 V; unit cell: a = b = 2.9 ± 0.1 nm).

Figure 9.

High-resolution STM images of (a) TC-6618 at the TCB/graphite interface showing (b) gap phase (25 μM, I_t = 0.15 nA, V_sample = −1 V), (c) honeycomb (unit cell: a = b = 2.9 ± 0.1 nm; 100 μM, I_t = 0.55 nA, V_sample = −1 V), and (d) nonordered packing states (300 μM, I_t = 0.5 nA, V_sample = −0.8 V).

Figure 10.

(a) High-resolution STM imaging of the gap phase formed by (b) TC-6618. (c) Model of the gap phase showing the zigzag (green), honeycomb (purple), and the line defect transition between the two structures (black dot).

Figure 11.

(a) Macrocycle TC-610MeCy. High-resolution STM images of TC-610MeCy at the TCB/graphite interface showing (b) honeycomb ordering (unit cell: a = b = 2.9 ± 0.1 nm 300 μM, I_t = 0.13 nA, V_sample = −0.8 V), (c) the coexistence of honeycomb and nonordered phases (300 μM, I_t = 0.6 nA, V_sample = −0.5 V), and (d) the nonordered packing state (300 μM, I_t = 1.1 nA, V_sample = −0.6 V).

Figure 12.

(a) Macrocycle TC-66HEG. (b) STM images of TC-66HEG at the TCB/graphite interface with honeycomb ordering (10 μM, I_t = 0.15 nA, V_sample = −0.7 V). (c) Models of the octadecyl chains (green) of TC-6618 surface adsorbed to form the gap and (d) HEG chains (red) of TC-66HEG directed away into solution leading to the formation of the honeycomb phase.

Scheme 1.

Synthetic Sequence Leading to the One-Pot Preparation of C₃-Symmetric Macrocycles (TC-6, TC-10, TC-18) from the Azide-alkyne Building Block 7 Bearing the Appropriate Alkyl Chain

Scheme 2.. General Stepwise Synthesis of Sequence-Defined Tricarb Macrocycles^a

^aStep I: TMS-protected carbazoles (7a-TMS, 7b-TMS, or 7e-TMS) are coupled with amine-substituted carbazoles (8a or 8b) and, after deprotection, give the corresponding crescent dimer. Step II: The crescent dimer is coupled with an additional TMS-protected carbazole building block (7b-TMS to 7d-TMS). Step III: Following installation of the azide and deprotection of the alkyne, the crescent trimer can be closed to produce the tricarb macrocycle. Reactions 1 and 3: CuSO₄/NaAsc/TBTA/2:1:1 THF/EtOH/H₂O/55 °C/Ar. Reactions 2 and 5: K₂CO₃/1:1 MeOH/THF. Reaction 4: TsOH/NaNO₂/NaN₃/THF/0 °C.