Visible-light-mediated Diels-Alder reactions under single-chain polymer confinement: investigating the role of the crosslinking moiety on catalyst activity.

Macromolecular scaffolds are rapidly emerging in catalysis owing to the ability to control catalyst placement at precise locations. This spatial proximity allows for enhanced catalyst activity that may not be observed using small molecules. Herein, we describe a triphenylpyrylium (TPT)-based visible-light active single-chain polymer nanoparticle (SCNP) that facilitates the radical cation [4 + 2]-cycloaddition. We find that the catalytic activity is highly dependent on the styrylarene comonomer used, wherein it can act as a redox mediator under confinement, increasing the catalytic turnover (TON) by up to 30 times in comparison to free TPT in solution. Mechanistic studies indicate that TPT excited states are quenched by the acene, with the resultant radical cation formed from naphthalene-based SCNPs able to proceed in oxidizing the dienophile in the elementary step of the reaction, while leading to near quantitative yields of the cycloadduct. The TPT-SCNP demonstrates enhanced photocatalyst efficiency compared to molecular TPT, and is able to be recycled and reused in three iterations of the reaction prior to decreased performance from photobleaching. Our results overall suggest that the confined nature of the SCNP and spatial proximity of acene-based pendants enforces their participation as cocatalytic redox mediators that impart enhanced photoredox catalysis under confinement.

Nickel-Catalyzed Alkene Difunctionalization as a Method for Polymerization.

Alkene dicarbofunctionalization is a rapidly emerging tool for complex molecule synthesis that installs two carbon fragments regioselectively across an alkene. This method has the potential to engineer stereodefined polymers, yet the application of difunctionalization reactions to polymer synthesis remains unexplored. Herein, we describe the first example of a Ni-catalyzed difunctionalization of alkenes with arylboronic esters and aryl bromides innate to the alkene. The polymerization reaction proceeds regioselectively with the addition of the aryl bromide to the terminal alkenyl carbon and arylboronic ester to the internal benzylic carbon. The resultant poly[arylene-α-(aryl)ethylene]s comprise aryl groups installed at regular intervals along the polymer backbone through chain propagation in two directions. Polymers with molecular weights generally ranging from 30 to 175 kDa were obtained after successful fractionation from oligomeric species. Thermal analysis of the poly[arylene α-(aryl)ethylene]s revealed stability up to ∼399 °C, with a Tg of 90 °C, both of which are similar in value to poly(styrene)s and poly(phenylene methylene)s.

Photochemically Mediated Polymerization of Molecular Furan and Pyridine: Synthesis of Nanothreads at Reduced Pressures.

Nanothreads are emerging one-dimensional sp3-hybridized materials with high predicted tensile strength and a tunable band gap. They can be synthesized by compressing aromatic or nonaromatic small molecules to pressures ranging from 15-30 GPa. Recently, new avenues are being sought that reduce the pressure required to afford nanothreads; the focus has been placed on the polymerization of molecules with reduced aromaticity, favorable stacking, and/or the use of higher reaction temperatures. Herein, we report the photochemically mediated polymerization of pyridine and furan aromatic precursors, which achieves nanothread formation at reduced pressures. In the case of pyridine, it was found that a combination of slow compression/decompression with broadband UV light exposure yielded a crystalline product featuring a six-fold diffraction pattern with similar interplanar spacings to previously synthesized pyridine-derived nanothreads at a reduced pressure. When furan is compressed to 8 GPa and exposed to broadband UV light, a crystalline solid is recovered that similarly demonstrates X-ray diffraction with an interplanar spacing akin to that of the high-pressure synthesized furan-derived nanothreads. Our method realizes a 1.9-fold reduction in the maximum pressure required to afford furan-derived nanothreads and a 1.4-fold reduction in pressure required for pyridine-derived nanothreads. Density functional theory and multiconfigurational wavefunction-based computations were used to understand the photochemical activation of furan and subsequent cascade thermal cycloadditions. The reduction of the onset pressure is caused by an initial [4+4] cycloaddition followed by increasingly facile thermal [4+2]-cycloadditions during polymerization.

Ligand-induced shifts in conformational ensembles that describe transcriptional activation.

Nuclear receptors function as ligand-regulated transcription factors whose ability to regulate diverse physiological processes is closely linked with conformational changes induced upon ligand binding. Understanding how conformational populations of nuclear receptors are shifted by various ligands could illuminate strategies for the design of synthetic modulators to regulate specific transcriptional programs. Here, we investigate ligand-induced conformational changes using a reconstructed, ancestral nuclear receptor. By making substitutions at a key position, we engineer receptor variants with altered ligand specificities. We combine cellular and biophysical experiments to characterize transcriptional activity, as well as elucidate mechanisms underlying altered transcription in receptor variants. We then use atomistic molecular dynamics (MD) simulations with enhanced sampling to generate ensembles of wildtype and engineered receptors in combination with multiple ligands, followed by conformational analysis and correlation of MD-based predictions with functional ligand profiles. We determine that conformational ensembles accurately describe ligand responses based on observed population shifts. These studies provide a platform which will allow structural characterization of physiologically-relevant conformational ensembles, as well as provide the ability to design and predict transcriptional responses in novel ligands.

Perfect and Defective 13C-Furan-Derived Nanothreads from Modest-Pressure Synthesis Analyzed by 13C NMR.

The molecular structure of nanothreads produced by the slow compression of 13C4-furan was studied by advanced solid-state NMR. Spectral editing showed that >95% of carbon atoms were bonded to one hydrogen (C-H) and that there were 2-4% CH2, 0.6% C═O, and <0.3% CH3 groups. Alkenes accounted for 18% of the CH moieties, while trapped, unreacted furan made up 7%. Two-dimensional (2D) 13C-13C and 1H-13C NMR identified 12% of all carbon in asymmetric O-CH═CH-CH-CH- and 24% in symmetric O-CH-CH═CH-CH- rings. While the former represented defects or chain ends, some of the latter appeared to form repeating thread segments. Around 10% of carbon atoms were found in highly ordered, fully saturated nanothread segments. Unusually slow 13C spin-exchange with sites outside the perfect thread segments documented a length of at least 14 bonds; the small width of the perfect-thread signals also implied a fairly long, regular structure. Carbons in the perfect threads underwent relatively slow spin-lattice relaxation, indicating slow spin exchange with other threads and smaller amplitude motions. Through partial inversion recovery, the signals of the perfect threads were observed and analyzed selectively. Previously considered syn-threads with four different C-H bond orientations were ruled out by centerband-only detection of exchange NMR, which was, on the contrary, consistent with anti-threads. The observed 13C chemical shifts were matched well by quantum-chemical calculations for anti-threads but not for more complex structures like syn/anti-threads. These observations represent the first direct determination of the atomic-level structure of fully saturated nanothreads.

Scalable Synthesis of Crystalline One-Dimensional Carbon Nanothreads through Modest-Pressure Polymerization of Furan.

Carbon nanothreads, which are one-dimensional sp3-rich polymers, combine high tensile strength with flexibility owing to subnanometer widths and diamond-like cores. These extended carbon solids are constructed through pressure-induced polymerization of sp2 molecules such as benzene. Whereas a few examples of carbon nanothreads have been reported, the need for high onset pressures (≥17 GPa) to synthesize them precludes scalability and limits scope. Herein, we report the scalable synthesis of carbon nanothreads based on molecular furan, which can be achieved through ambient temperature pressure-induced polymerization with an onset reaction pressure of only 10 GPa due to its lessened aromaticity relative to other molecular precursors. When slowly compressed to 15 GPa and gradually decompressed to 1.5 GPa, a sharp 6-fold diffraction pattern is observed in situ, indicating a well-ordered crystalline material formed from liquid furan. Single-crystal X-ray diffraction (XRD) of the reaction product exhibits three distinct d-spacings from 4.75 to 4.9 Å, whose size, angular spacing, and degree of anisotropy are consistent with our atomistic simulations for crystals of furan nanothreads. Further evidence for polymerization was obtained by powder XRD, Raman/IR spectroscopy, and mass spectrometry. Comparison of the IR spectra with computed vibrational modes provides provisional identification of spectral features characteristic of specific nanothread structures, namely syn, anti, and syn/anti configurations. Mass spectrometry suggests that molecular weights of at least 6 kDa are possible. Furan therefore presents a strategic entry toward scalable carbon nanothreads.

'Sacrificial' supramolecular assembly and pressure-induced polymerization: toward sequence-defined functionalized nanothreads.

Limited supramolecular strategies have been utilized to synthesize sequence-defined polymers, despite the prominence of noncovalent interactions in materials design. Herein, we illustrate the utility of 'sacrificial' aryl-perfluoroaryl supramolecular synthons to synthesize sp3-hybridized nanothreads from sp2-enriched reactants. Our strategy features A-B reactant pairs in the form of a phenol:pentafluorophenol co-crystal that is preorganized for an electronically-biased and sequence-defined polymerization. The polymerization, initiated at 12 GPa, affords an alternating copolymer featuring exogenous -OH functionalities. The external substitution is confirmed through IR spectroscopy. Importantly, the inclusion of the functional unit provides the first experimental glimpse at reaction mechanism: keto-enol tautomerization that can only occur during cycloaddition is observed through IR spectroscopy. Our approach realizes the first example of a functionalized nanothread and attains sequence definition through sacrificial supramolecular preorganization and presents a further approach for de novo design of complex nanothreads.

Sub-10 nm Resolution Patterning of Pockets for Enzyme Immobilization with Independent Density and Quasi-3D Topography Control.

The ability to precisely control the localization of enzymes on a surface is critical for several applications including biosensing, bionanoreactors, and single molecule studies. Despite recent advances, fabrication of enzyme patterns with resolution at the single enzyme level is limited by the lack of lithography methods that combine high resolution, compatibility with soft, polymeric structures, ease of fabrication, and high throughput. Here, a method to generate enzyme nanopatterns (using thermolysin as a model system) on a polymer surface is demonstrated using thermochemical scanning probe lithography (tc-SPL). Electrostatic immobilization of negatively charged sulfonated enzymes occurs selectively at positively charged amine nanopatterns produced by thermal deprotection of amines along the side-chain of a methacrylate-based copolymer film via tc-SPL. This process occurs simultaneously with local thermal quasi-3D topographical patterning of the same polymer, offering lateral sub-10 nm resolution, and vertical 1 nm resolution, as well as high throughput (5.2 × 104 µm2/h). The obtained single-enzyme resolution patterns are characterized by atomic force microscopy (AFM) and fluorescence microscopy. The enzyme density, the surface passivation, and the quasi-3D arbitrary geometry of these patterned pockets are directly controlled during the tc-SPL process in a single step without the need of markers or masks. Other unique features of this patterning approach include the combined single-enzyme resolution over mm2 areas and the possibility of fabricating enzymes nanogradients.

Poly(arylenevinylene)s through Ring-Opening Metathesis Polymerization of an Unsymmetrical Donor-Acceptor Cyclophane.

Reported are well-defined donor-acceptor alternating copolymers prepared using ring-opening metathesis polymerization (ROMP). Unsymmetrical cyclophanedienes comprising electron-donating (4-methoxy-1-(2-ethylhexyl)oxy)benzene (MEH) and electron-accepting benzothiadiazole (BT) rings were synthesized from the corresponding [3.3]dithiaparacyclophanes. ROMP of the strained unsymmetrical and "electronically-ambiguous" cyclophanedienes proceeded in a controlled manner in the presence of either Hoveyda-Grubbs II or Grubbs II initiator in wake of both steric and electronic encumbrance. The resulting polymers, comprising alternating BT and MEH-PPV units, are achieved in molecular weights exceeding 20k with D values ranging from 1.1-1.4. The living nature of the polymerization is verified through the formation of rod-coil and rod-rod block copolymers. Our strategy to develop previously unrealized polymers from functional building blocks featuring a locked-in D-A unit is significant in a field striving to achieve well-defined and sequence-specific materials.

Synthesis and folding behaviour of poly(p-phenylene vinylene)-based ß-sheet polychromophores.

This contribution describes the design and synthesis of ß-sheet-mimicking synthetic polymers comprising distinct poly(p-phenylene vinylene) (PPV) and poly(norbornene) (PNB) backbones with multiple turns. The rod-coil-coil-rod tetrablock copolymers, synthesized using ring-opening metathesis polymerization (ROMP) and featuring orthogonal face-to-face π-π stacking and phenyl/perfluorophenyl interactions, show persistent folding both in bulk and at the single molecule level, irrespective of the number of ß-turns. Single molecule polarization studies reveal that the copolymers are more anisotropic than the corresponding homopolymers. Examination of the spectral signatures of the single molecules shows a dominant emissive chromophore in the linked materials compared to the homopolymer. The lack of significant spectral changes of the folded materials along with the existence of a dominant emission spectrum supports the proposed structure of well-aligned, minimally-interacting chromophores. Utilization of this reliably folding, phenyl/perfluorophenyl functionality could provide an extremely useful tool in future functional materials design.

Molecular Recognition in the Colloidal World.

Colloidal self-assembly is a bottom-up technique to fabricate functional nanomaterials, with paramount interest stemming from programmable assembly of smaller building blocks into dynamic crystalline domains and photonic materials. Multiple established colloidal platforms feature diverse shapes and bonding interactions, while achieving specific orientations along with short- and long-range order. A major impediment to their universal use as building blocks for predesigned architectures is the inability to precisely dictate and control particle functionalization and concomitant reversible self-assembly. Progress in colloidal self-assembly necessitates the development of strategies that endow bonding specificity and directionality within assemblies. Methodologies that emulate molecular and polymeric three-dimensional (3D) architectures feature elements of covalent bonding, while high-fidelity molecular recognition events have been installed to realize responsive reconfigurable assemblies. The emergence of anisotropic 'colloidal molecules', coupled with the ability to site-specifically decorate particle surfaces with supramolecular recognition motifs, has facilitated the formation of superstructures via directional interactions and shape recognition. In this Account, we describe supramolecular assembly routes to drive colloidal particles into precisely assembled architectures or crystalline lattices via directional noncovalent molecular interactions. The design principles are based upon the fabrication of colloidal particles bearing surface-exposed functional groups that can undergo programmable conjugation to install recognition motifs with high fidelity. Modular and versatile by design, our strategy allows for the introduction and integration of molecular recognition principles into the colloidal world. We define noncovalent molecular interactions as site-specific forces that are predictable (i.e., feature selective and controllable complementary bonding partners) and can engage in tunable high-fidelity interactions. Examples include metal coordination and host-guest interactions as well as hydrogen bonding and DNA hybridization. On the colloidal scale, these interactions can be used to drive the reversible formation of open structures. Key to the design is the ability to covalently conjugate supramolecular motifs onto the particle surface and/or noncovalently associate with small molecules that can mediate and direct assembly. Efforts exploiting the binding strength inherent to DNA hybridization for the preparation of reversible open-packed structures are then detailed. We describe strategies that led to the introduction of dual-responsive DNA-mediated orthogonal assembly as well as colloidal clusters that afford distinct DNA-ligated close-packed lattices. Further focus is placed on two essential and related efforts: the engineering of complex superstructures that undergo phase transitions and colloidal crystals featuring a high density of functional anchors that aid in crystallization. The design principles discussed in this Account highlight the synergy stemming from coupling well-established noncovalent interactions common on the molecular and polymeric length scales with colloidal platforms to engineer reconfigurable functional architectures by design. Directional strategies and methods such as those illustrated herein feature molecular control and dynamic assembly that afford both open-packed 1D and 2D lattices and are amenable to 3D colloidal frameworks. Multiple methods to direct colloidal assembly have been reported, yet few are capable of crystallizing 2D and 3D architectures of interest for optical data storage, electronics, and photonics. Indeed, early implications are that [supra]molecular control over colloidal assembly can fabricate rationally structured designer materials from simple fundamental building blocks.

Supramolecular Multiblock Copolymers Featuring Complex Secondary Structures.

This contribution introduces main-chain supramolecular ABC and ABB'A block copolymers sustained by orthogonal metal coordination and hydrogen bonding between telechelic polymers that feature distinct secondary structure motifs. Controlled polymerization techniques in combination with supramolecular assembly are used to engineer heterotelechelic π-sheets that undergo high-fidelity association with both helical and coil-forming synthetic polymers. Our design features multiple advances to achieve our targeted structures, in particular, those emulating sheet-like structural aspects using poly(p-phenylenevinylene)s (PPVs). To engineer heterotelechelic PPVs in a sheet-like design, we engineer an iterative one-pot cross metathesis-ring-opening metathesis polymerization (CM-ROMP) strategy that affords functionalized Grubbs-II initiators that subsequently polymerize a paracyclophanediene. Supramolecular assembly of two heterotelechelic PPVs is used to realize a parallel π-sheet, wherein further orthogonal assembly with helical motifs is possible. We also construct an antiparallel π-sheet, wherein terminal PPV blocks are adjacent to a flexible coil-like poly(norbornene) (PNB). The PNB is designed, through supramolecular chain collapse, to expose benzene and perfluorobenzene motifs that promote a hairpin turn via charge-transfer-aided folding. We demonstrate that targeted helix-(π-sheet)-helix and helix-(π-sheet)-coil assemblies occur without compromising intrinsic helicity, while both parallel and antiparallel ß-sheet-like structures are realized. Our main-chain orthogonal assembly approach allows the engineering of multiblock copolymer scaffolds featuring diverse secondary structures via the directional assembly of telechelic building blocks. The targeted assemblies, a mix of sequence-defined helix-sheet-coil and helix-sheet-helix architectures, are Nature-inspired synthetic mimics that expose α/ß and α+ß protein classes via de novo design and cooperative assembly strategies.

Light-Mediated Reversible Assembly of Polymeric Colloids.

This contribution highlights the functionalization of colloidal particles featuring high-symmetry patches with telechelic block copolymers and subsequent reversible self-assembly of the resulting particles into longer chain and branched structures using host-guest complexation. The 3-(trimethoxysilyl)propyl methacrylate (TPM)-based anisotropic particles, obtained through a cluster-encapsulation process, consist of poly(styrene) patches and are site-specifically functionalized with block copolymers bearing pendant viologen or azobenzene motifs. Key to the design is the engineering of heterotelechelic α-hydroxy-ω-formyl-poly(norbornene)s via ring-opening metathesis polymerization (ROMP). The block copolymers feature both main chain anchor points to the particle surface, as well as orthogonal reactive sites for cyanine dye conjugation. The polymeric particles undergo directed and reversible supramolecular assembly in the presence of the host cucurbit[8]uril.

Supramolecular Diblock Copolymers Featuring Well-defined Telechelic Building Blocks.

We report supramolecular AB diblock copolymers comprised of well-defined telechelic building blocks. Helical motifs, formed via reversible addition-fragmentation chain-transfer (RAFT) or anionic polymerization, are assembled with coil-forming and sheet-featuring blocks obtained via atom-transfer radical polymerization (ATRP) or ring-opening metathesis polymerization (ROMP). Interpolymer hydrogen bonding or metal-coordination achieves dynamic diblock architectures featuring hybrid topologies of coils, helices, and/or π-stacked sheets that, on a basic level, mimic protein structural motifs in fully synthetic systems. The intrinsic properties of each block (e.g., circular dichroism and fluorescence) remain unaffected in the wake of self-assembly. This strategy to develop complex synthetic polymer scaffolds from functional building blocks is significant in a field striving to produce architectures reminiscent of biosynthesis, yet fully synthetic in nature. This is the first plug-and-play approach to fabricate hybrid π-sheet/helix, π-sheet/coil, and helix/coil architectures via directional self-assembly.

Redox-Responsive Viologen-Mediated Self-Assembly of CB[7]-Modified Patchy Particles.

Sulfonated surface patches of poly(styrene)-based colloidal particles (CPs) were functionalized with cucurbit[7]uril (CB[7]). The macrocycles served as recognition units for diphenyl viologen (DPV(2+)), a rigid bridging ligand. The addition of DPV(2+) to aqueous suspensions of the particles triggered the self-assembly of short linear and branched chainlike structures. The self-assembly mechanism is based on hydrophobic/ion-charge interactions that are established between DPV(2+) and surface-adsorbed CB[7]. DPV(2+) guides the self-assembly of the CPs by forming a ternary DPV(2+)⊂(CB[7])2 complex in which the two CB[7] macrocycles are attached to two different particles. Viologen-driven particle assembly was found to be both directional and reversible. Whereas sodium chloride triggers irreversible particle disassembly, the one-electron reduction of DPV(2+) with sodium dithionite causes disassembly that can be reversed via air oxidation. Thus, this bottom-up synthetic supramolecular approach allowed for the reversible formation and directional alignment of a 2D colloidal material.

Metal-Organic Coordination versus Hydrogen Bonding: Highly Efficient Templated Photocycloadditions of Trisubstituted Isomeric Olefins in the Solid State.

Trisubstituted olefins are reactants in template-directed, solid-state [2+2] photocycloaddition reactions. Whereas hydrogen-bond-based templates afford crystalline assemblies with olefins that are photostable, AgI coordination results in carbon-carbon double bonds that react stereoselectively and result in quantitative yield.

Fabrication of supramolecular semiconductor block copolymers by ring-opening metathesis polymerization.

ω-Telechelic poly(p-phenylene vinylene) species (PPVs) are prepared by living ring-opening metathesis polymerization of a [2.2]paracyclophane-1,9-diene in the presence of Hoveyda-Grubbs 2nd generation initiator, with terminating agents based on N(1) ,N(3) -bis(6-butyramidopyridin-2-yl)-5-hydroxyisophthalamide (Hamilton wedge), cyanuric acid, Pd(II) -SCS-pincer, or pyridine moieties installing the supramolecular motifs. The resultant telechelic polymers are self-assembled into supramolecular block copolymers (BCPs) via metal coordination or hydrogen bonding and analyzed by (1) H NMR spectroscopy. The optical properties are examined, whereby individual PPVs exhibit similar properties regardless of the nature of the end group. Upon self-assembly, different behaviors emerge: the hydrogen-bonding BCP behaves similarly to the parent PPVs whereas the metallosupramolecular BCP demonstrates a hypsochromic shift and a more intense emission owing to the suppression of aggregation. These results demonstrate that directional self-assembly can be a facile method to construct BCPs with semiconducting networks, while combating solubility and aggregation.

Engineering orthogonality in supramolecular polymers: from simple scaffolds to complex materials.

Owing to the mastery exhibited by Nature in integrating both covalent and noncovalent interactions in a highly efficient manner, the quest to construct polymeric systems that rival not only the precision and fidelity but also the structure of natural systems has remained a daunting challenge. Supramolecular chemists have long endeavored to control the interplay between covalent and noncovalent bond formation, so as to examine and fully comprehend how function is predicated on self-assembly. The ability to reliably control polymer self-assembly is essential to generate "smart" materials and has the potential to tailor polymer properties (i.e., viscosity, electronic properties) through fine-tuning the noncovalent interactions that comprise the polymer architecture. In this context, supramolecular polymers have a distinct advantage over fully covalent systems in that they are dynamically modular, since noncovalent recognition motifs can be engineered to either impart a desired functionality within the overall architecture or provide a designed bias for the self-assembly process. In this Account, we describe engineering principles being developed and pursued by our group that exploit the orthogonal nature of noncovalent interactions, such as hydrogen bonding, metal coordination, and Coulombic interactions, to direct the self-assembly of functionalized macromolecules, resulting in the formation of supramolecular polymers. To begin, we describe our efforts to fabricate a modular poly(norbornene)-based scaffold via ring-opening metathesis polymerization (ROMP), wherein pendant molecular recognition elements based upon nucleobase-mimicking elements (e.g., thymine, diaminotriazine) or SCS-Pd(II) pincer were integrated within covalent monofunctional or symmetrically functionalized polymers. The simple polymer backbones exhibited reliable self-assembly with complementary polymers or small molecules. Within these systems, we applied successful protecting group strategies and template polymerizations to enhance the control afforded by ROMP. Main-chain-functionalized alternating block polymers based upon SCS-Pd(II) pincer-pyridine motifs were achieved through the combined exploitation of bimetallic initiators and supramolecularly functionalized terminators. Our initial design principles led to the successful fabrication of both main-chain- and side-chain-functionalized poly(norbornenes) via ROMP. Utilizing all of these techniques in concert led to engineering orthogonality while achieving complexity through the installation of multiple supramolecular motifs within the side chain, main chain, or both in our polymer systems. The exploitation and modification of design principles based upon functional ROMP initiators and terminators has resulted in the first synthesis of main-chain heterotelechelic polymers that self-assemble into A/B/C supramolecular triblock polymers composed of orthogonal cyanuric acid-Hamilton wedge and SCS-Pd(II) pincer-pyridine motifs. Furthermore, supramolecular A/B/A triblock copolymers were realized through the amalgamation of functionalized monomers, ROMP initiators, and terminators. To date, this ROMP-fabricated system represents the only known method to afford polymer main chains and side chains studded with orthogonal motifs. We end by discussing the impetus to attain functional materials via orthogonal self-assembly. Collectively, our studies suggest that combining covalent and noncovalent bonds in a well-defined and precise manner is an essential design element to achieve complex architectures. The results discussed in this Account illustrate the finesse associated with engineering orthogonal interactions within supramolecular systems and are considered essential steps toward developing complex biomimetic materials with high precision and fidelity.