Architectonics: Design of Molecular Architecture for Functional

Article Cite This: Acc. Chem. Res. 2018, 51, 414−426

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Architectonics: Design of Molecular Architecture for Functional Applications M. B. Avinash and Thimmaiah Govindaraju* Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, India

CONSPECTUS: The term architectonics has its roots in the architectural and philosophical (as early as 1600s) literature that refers to “the theory of structure” and “the structure of theory”, respectively. The concept of architectonics has been adapted to advance the field of molecular self-assembly and termed as molecular architectonics. In essence, the methodology of organizing molecular units in the required and controlled configurations to develop advanced functional systems for materials and biological applications comprises the field of molecular architectonics. This concept of designing noncovalent systems enables to focus on different functional aspects of designer molecules for biological and nonbiological applications and also strengthens our efforts toward the mastery over the art of controlled molecular self-assemblies. Programming complex molecular interactions and assemblies for specific functions has been one of the most challenging tasks in the modern era. Meticulously ordered molecular assemblies can impart remarkable developments in several areas spanning energy, health, and environment. For example, the well-defined nano-, micro-, and macroarchitectures of functional molecules with specific molecular ordering possess potential applications in flexible electronics, photovoltaics, photonic crystals, microreactors, sensors, drug delivery, biomedicine, and superhydrophobic coatings, among others. The functional molecular architectures having unparalleled properties are widely evident in various designs of Nature. By drawing inspirations from Nature, intended molecular architectures can be designed and developed to harvest various functions, as there is an inexhaustible resource and scope. In this Account, we present exquisite designer molecules developed by our group and others with an objective to master the art of molecular recognition and self-assembly for functional applications. We demonstrate the tailor-ability of molecular self-assemblies by employing biomolecules like amino acids and nucleobases as auxiliaries. Naphthalenediimide (NDI), perylenediimide (PDI), and few other molecular systems serve as functional modules. The effects of stereochemistry and minute structural modifications in the molecular designs on the supramolecular interactions, and construction of self-assembled zero-dimensional (OD), onedimensional (1D), and two-dimensional (2D) nano- and microarchitectures like particles, spheres, cups, bowls, fibers, belts, helical belts, supercoiled helices, sheets, fractals, and honeycomb-like arrays are discussed in extensive detail. Additionally, we present molecular systems that showcase the elegant designs of coassembly, templated assembly, hierarchical assembly, transient self-assembly, chiral denaturation, retentive helical memory, self-replication, supramolecular regulation, supramolecular speciation, supernon linearity, dynamic pathway complexity, supramolecular heterojunction, living supramolecular polymerization, and molecular machines. Finally, we describe the molecular engineering principles learnt over the years that have led to several applications, namely, organic electronics, self-cleaning, high-mechanical strength, and tissue engineering.

1. INTRODUCTION Molecular interactions and their self-assemblies form the basis for versatile structure and functions in biological and nonbiological systems.1−4 The chemistry of molecular self-assemblies consists of weak yet complex reciprocity of noncovalent interactions.5−8 The fields of self-assembly and supramolecular chemistry that started primarily on the fundamental principles of molecular recognition and host−guest chemistry have made significant progress in the last few decades.1−10 However, the controlled © 2018 American Chemical Society

organization of molecules into well-defined architectures and thereby coherent modulation of their properties are in its infancy.11,12 The process of custom-designing and engineering molecular self-assemblies is conceptualized as molecular architectonics (Figure 1).9−12 The term architectonics has been employed in the scientific literature with reference to structural Received: September 4, 2017 Published: January 24, 2018 414

DOI: 10.1021/acs.accounts.7b00434 Acc. Chem. Res. 2018, 51, 414−426

Article

Accounts of Chemical Research

Figure 1. Molecular architectonics for functional applications.

consolidated approach. This biomolecular characteristics inspired design strategy showcases a versatile approach to engineer the molecular organization for various functional applications as well as provide means to unravel some of the hidden secrets of complex biological systems.8,24,25

biology, DNA, assemblies on metal surfaces, and molecular electronics.13−17 In addition, Aono and Ariga (NIMS, Japan) have pioneered the field of nanoarchitectonics for the construction of nanoscale architectures.18−20 This Account is structured into three sections, namely, Molecular Architectonics, Functional Applications, and Conclusions and Outlook. The Molecular Architectonics section is further divided into three subsections entitled as Amino Acid Derivatives, Nucleobase Derivatives, and Miscellaneous. The first two subsections, namely, Amino Acid Derivatives and Nucleobase Derivatives, comprise exclusive examples from our group, and the Miscellaneous subsection discusses selected reports from literature. The molecular architectonics of functional modules that are developed in our and other groups have led to applications in organic electronics, high-mechanical strength, self-cleaning, and tissue engineering, which forms the content of Functional Applications. In the final section, general lessons distilled over years of investigations and understanding in formalizing the field of molecular architectonics and future directions for further advancements are presented.

2.1. Amino Acid Derivatives

Tryptophan comprises all possible characteristics of conventional auxiliaries, namely, hydrophobic, hydrophilic, aromatic, and metal binding functionality.22 Consequently, we tailored the NDI assembly by conjugating tryptophan (1) and tryptophanmethylester (2) into well-defined architectures like nanospheres, nanobelts, nanofibers, microparticles, and microfractals (Figure 2a−h). The weak π−π associations of NDI cores of 1 and 2 in acetonitrile, resulted in 0D nanospherical architectures (Figure 2a,h), while aqueous acetonitrile led to the formation of microparticles and nanofibers, respectively, due to induced π−π stacking (Figure 2b,g). Additional solvophilic interactions of 1 (−COOH) in aqueous acetonitrile resulted in random particulate structures, whereas the methylester functionality of 2 engendered 1D π−π stacking due to solvophobic interactions. Further, 2 that assembled into nanospheres in acetonitrile was found to undergo transformation to nanobelts at higher concentrations due to solvophobic force driven 1D π−π stacking (Figure 2c,f). The disodium salt of 1 formed fractals through coordination polymerization (Figure 2d,e). On the other hand, phenylalanine-methylester appended NDI (3) assembled into free-floating single-crystalline 2D nanosheets in aqueous acetonitrile (Figure 2i).23 Moreover, nanocups, mesocups, and bowllike complex architectures of 3 were obtained by employing chlorinated cosolvents, attributed to specific halogen-bonding interactions, as confirmed from the crystal structure (Figure 2j). The nanocups with 0.1−1.5 attoliter volume can be used as containers for miniaturized biological assays. In case of 1−3, the intermolecular face-to-face π−π stacking of NDI core was hindered due to stacking of electron-rich indole and phenyl groups with the NDI core that fostered charge transfer (CT) and exciplex formation, respectively (vide infra). Subsequent study showed that NDIs conjugated with glycine

2. MOLECULAR ARCHITECTONICS Arylenediimides (NDIs/PDIs) are among the fascinating class of molecules that have applications ranging from electronics to biomedicine and are thus of interest in our group as functional molecules.8,21,22 NDIs/PDIs possess high electron affinity, good charge carrier mobility, excellent thermal/oxidative stability, rainbow fluorescence, high fluorescence quantum yield, DNA intercalation, and antimicrobial and anticarcinogenic properties.8,21−23 Despite the remarkable properties, the performance of NDIs/PDIs in any particular application is largely limited by the design and mode of molecular organization. In this regard, we employed biomolecules like amino acids, nucleobases, and their derivatives as auxiliaries to tailor the assemblies of NDIs and PDIs.22 Remarkably, such auxiliaries furnish biocompatibility, stereospecificity, selective molecular recognition, metal binding, and hydrophobic, hydrophilic, and aromatic interactions in a single compact moiety. Moreover, all these forces are employed in a cooperative manner and thus qualify as a 415


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Figure 2. Self-assembled architectures of (a−d) 1, (e−h) 2, (i,j) 3, (k) 9, (l) 10, and (q) 26 and 27. (i) Insets: SAED and fluorescence image. Singlecrystal molecular packing of (m) alanine-, (n) phenylalanine-, and (o) tryptophan-functionalized NDIs. (p) Photograph of hydrogel, (q) AFM 3D image, and (r) coassembly of 26 and 27. Panels (a−h) and (m−o) adapted from refs 22 and 30, respectively, with permission of RSC. Panels (i,j) and (k,l) adapted from refs 23 and 28, respectively, with permission of Wiley-VCH. Panels (p−r) Adapted with permission from ref 36. Copyright 2016 American Chemical Society.

(4), glycinamide (5), and glycine-methylester (6) facilitate excimer-like fluorescence emissions due to intermolecular π−π stacking of NDI cores.26 Moreover, 4−6 were found to form 2D nanosheets with the aid of intermolecular hydrogen-bonding interactions. In asymmetrically functionalized NDIs, the transcription of molecular chirality from L-alanine-methylester imposed P-type (right-handed) supramolecular helical chirality to 7, while that of 8 (D-alanine-methylester) resulted in M-helix (left-handed).27 In an effort to understand the transcription of chirality from molecule to supramolecular level, we employed dipeptide auxiliaries.28 Homochiral (9 and 10) and heterochiral (11 and 12) dipeptide appended NDIs were composed of identical (L or D) and alternating (L and D or D and L) stereochemistries for α-phenylalanine units, respectively, while the achiral (13) auxiliary was composed of glycine units. CD studies showed that 9 and 11 facilitated M-helices, while 10 and 12 led to P-helices. However, the CD amplitudes of 11 and 12 were relatively low compared to homochiral counterparts (9 and 10) and their amplitudes were almost same as that of phenylmethylester appended NDIs. This suggested that the first stereocenter adjacent to NDI core determines the nature of supramolecular helicity and ability of the stereocenter to retain memorized stereochemical information in supramolecular chirogenesis in

spite of neighboring unit with opposite chirality, which is termed as retentive helical memory. The homochiral derivatives, namely, 9 and 10 resulted in 1D belts that pile up to form hierarchical structures with opposite helical signatures (Figure 2k,l). On the other hand, the heterochiral derivatives (11 and 12) resulted in mesospheres. In addition, we replaced linear dipeptide based auxiliaries with cyclic dipeptides (CDPs) (14−19).29 The homochiral CDPs exhibited characteristic CD signals due to excitonic coupling of transition dipole moments of NDI chromophores. However, the heterochiral CDPs and that involving glycine unit did not show any appreciable CD signals. These observations in principle support the mechanism of both spontaneous deracemization and chiral amplification pathways and suggest that organic/ inorganic catalytic surfaces might have played a key role in the evolution of homochiral biomolecules. The nature of molecular interactions in amino acid functionalized NDIs were further supported by their single crystals.30,31 Alanine functionalized NDIs exhibited cofacial stacking of the aromatic core and the characteristic blue-green emission of the crystal thus accounts for their excimer-like emission (Figure 2m).30 Phenylalanine functionalized NDIs showed slipped stacking, while stacking of NDI core with the phenyl group (side chain) clearly indicated the exciplex formation 416


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The greater steric repulsions of side chains of isoleucine 24 and phenylalanine 25 (1.8 and 2.25 times that of alanine, respectively) led to twisted nanoribbon and supercoiled nanohelical architectures. We designed a flexible π-electron-rich dipyrene tweezer-like molecular system 26 that suitably complex with electron-deficient aromatic guest 27 to obtain extended tweezer-inclusion-sandwich (TIS) CT assembly.36 The mechanical grinding of colorless powders of 26 and 27 resulted in red-colored powder, while their solutions upon ultrasonication yielded red-colored hydrogel due to nanofibrillar coassembly of 26 and 27 (Figure 2p−r). Further, this CT complex was found to be photoresponsive, as irradiation with UV light (λ = 365 nm) resulted in black coloration due to NDI radical anion formation, which reverts to red in 3 h under dark conditions. This photoinduced single electron transfer process was found to function reversibly over several cycles. In a distinct study of pH dependent self-assembly, histidine (pKa values of 4.1 for −COOH and 7.3 for imidazole) functionalized PDI 28 self-assembled into interconnected nanobelts at pH 2, thick nanofibers at pH 7, and thin nanofibers at pH 10.37 Contrary to thermodynamically controlled synthetic assemblies, 29 showed a kinetically driven extremely slow rate of helical organization over a day time.24 In addition, 29 exhibited irreversible molecular assembly behavior upon thermal treatment (termed as chiral denaturation) and the so-formed random aggregates could be made (helically) reversible only upon addition of thermally untreated aggregates, which act as seeds. This intriguing molecular assembly behavior of 29 provided us a rare opportunity to draw an unusual correlation with the secondary structure of proteins (Figure 3a). Systems like that of 29 are thought to bring about novel perspectives as well as provide intricate molecular mechanistic details, which could be instrumental in understanding protein conformational diseases caused due to protein misfolding. Further, we developed three-component modular systems (triads) comprising NDI, pyrene, and amino

(Figure 2n). Similarly, tryptophan functionalized NDIs revealed slipped stacking of the aromatic core with indole group (side chain), which accounted for CT interaction (Figure 2o). The relatively less bulky side chains of alanine facilitated cofacial helical columnar stacks with a twist of ∼69°, while the phenylalanine and tryptophan appended NDIs displayed supramolecular tilt helical organization with 2-fold helices by the virtue of 21 screw axes in the crystal lattice. Interestingly, the dipeptide of nonproteinogenic α-amino-isobutyric acid (20) resulted in 1D face-to-face (H-type) ordering, while the alanine-dipeptide (21) led to 2D edge-to-edge (J-type) chiral ordering due to β-bridgelike hydrogen-bond interactions between the peptide backbones.31 NDI is a highly π-acidic planar molecule with an estimated molecular quadrupole moment (Qzz) of +18.6 B (Buckinghams) that forms a unique pair with π-basic pyrene (Qzz = −13.8 B) due to their topological structural similarity and the complementary π-character.21,32,33 The alternate stacks of electron donor−acceptor based CT complexation is especially interesting due to high electrical conductivity and room-temperature ferroelectricity.34−36 However, the interaction energy for NDI−NDI (−27.17 kcal mol−1) stack is greater than those for NDI−pyrene (−23.35 kcal mol−1) and pyrene−pyrene (−16.45 kcal mol−1), and thereby self-sorting predominates over alternate stacking.11 We showed that NDI−pyrene dyads prefer alternate stacking (−53.62 kcal mol−1) over self-sorted assemblies (−43.62 kcal mol−1). Further, by minute molecular structural mutations on the side chain of amino acid (22−25) auxiliary, a wide variety of 1D and 2D architectures were obtained. The differences in the architectures of dyads were correlated to variable hydrophobicity and nonpolar surface area of the side chains of amino acid. The side chains of alanine, valine, isoleucine, and phenylalanine possess surface areas of 86, 135, 155, and 194 Å2, respectively. The less bulky side chains of alanine (22) and valine (23) engender planar 2D structures like nanosheets and comb-edged nanoflakes, respectively.

Figure 3. (a) Relevance of synthetic supramolecular helical assembly/reassembly of 29 with the (secondary structure) protein folding/refolding, (b) dynamic pathway complexity, (c) chiral denaturation, (d) supramolecular regulation, and (e) supramolecular speciation behaviors observed from molecular assemblies of 30−33. Adapted with permission from refs 24 and 25. Copyright 2013 and 2016 American Chemical Society. 417


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Watson−Crick (WC) hydrogen-bonding interactions. In addition, oligoadenine and oligoguanine resulted in P-type and M-type helical organization, respectively involving non-WC hydrogen-bonding interactions, while templating of oligocytosine was not fruitful, probably due to structural incompatibility (Figure 4b−d). In another report, we constructed adenineconjugated NDI (41) and oligothymidine (dTn) based hybrid ensemble to detect mercury ions in water (Figure 4e).41 WC hydrogen-bonding between 41 and dTn supported by NDI core and hydrophobic butyl group led to extended 2D functional coassembly. The specific interaction of mercury with thymine gives rise to distinct changes in chiro-optical and electrical conductivity properties, thus enabling rapid and sub-nanomolar detection (0.1 nM, 0.02 ppb), which is ∼100 times lower than the United States Environmental Protection Agency tolerance limit (Figure 4f,g).

acid (30−35) as an effective strategy to tailor molecular selfassembly and to emulate biological systems.25 We achieved three kinetically controlled molecular aggregation states of the triads (entitled as State I, State II, and State III) and also the dynamic pathway complexities associated with their transformations from one state to another by modulating the solvophobic forces (Figure 3b,c). Moreover, the triads of different aggregation states having distinct stereochemical information on amino acids were meticulously employed to engender emergent behaviors like “supramolecular regulation” and “supramolecular speciation” (Figure 3d,e). Further, a hitherto unknown emergent property in a self-assembled state under the majority-rules experiment termed as “super-nonlinearity” was discovered. These complex behaviors of synthetic systems are relevant in the context of prebiotic chemical evolution and emergent properties. 2.2. Nucleobase Derivatives

2.3. Miscellaneous

Nucleobases facilitate coding and encoding of genetic information through specific hydrogen-bonding patterns and this intriguing property inspired us to construct controllable molecular assemblies. Although, such a concept in the name of DNA nanotechnology has been an active area of research, it is rarely utilized for controlling assemblies of π-conjugated small molecules.38 In a minimalistic approach, a nucleobase-appended π-conjugated small molecular template was thought to be an attractive strategy.39 Consequently, templated assembly of adenine (36) and thymine (37) appended NDIs on the complementary peptide nucleic acid (PNA)-based molecular-clamps (38, 39) was investigated by NMR and morphological studies. It is interesting to note that both 36 and 37 form 1D architectures and in the presence of PNA molecular-clamps transform to 2D structures, which emphasizes the role of complementary templates. This concept was extended by designing adenine appended PDI 40 as a robust double zipper molecular template to construct hybrid DNA ensembles of random coiled deoxyoligonucleotides (Figure 4a).40 Achiral stacks of 40 in the presence of complementary oligothymine formed M-type helical organization owing to successful mutual-templating of complementary nucleobases of 40 and oligothymine via

Multipoint hydrogen-bonding modules play crucial roles in biological recognition processes and the secondary electrostatic interactions between adjacent hydrogen-bonds can have significant effect on the stability of the supramolecular complex.42 AAAA−DDDD quadrupole hydrogen-bonding array system with all the hydrogen-bond donors (D) on 42 and hydrogenbond acceptors (A) on 43 was designed, which resulted in association constant of over 3 × 1012 M−1 in dichloromethane. In another report, biocatalytic induction of supramolecular order was demonstrated by employing subtilisin for the hydrolysis of amphiphilic dipeptide 44a to 44b, which self-assembled to form nanofibers and in turn resulted in gels (Figure 5a).43 Stupp et al. designed a peptide amphiphile (45) with five segments each for specific functions: region I provides hydrophobicity, region II facilitates reversible cross-linking of the self-assembled structure, region III acts as flexible linker, region IV engenders mineralization, and region V aids in cell adhesion (Figure 5b).44 The nanofibers of 45 direct the mineralization of hydroxyapatite, and their crystallographic c-axes are aligned with the long axes of the fibers. In a recent report, self-assembly of 46 was found to enhance the covalent polymerization of 47 and 48 to

Figure 4. Hybrid ensemble formed from (a) 40 and deoxyoligonucleotide strands, (e) 41 and oligothymine/Hg2+. Hybrid ensembles of 40 with (b) oligothymine, (c) oligoadenine, and (d) oligoguanine strands. (f) Hg2+/CH3Hg+ detection device structure and the corresponding device response (g). Panels (a−d) adapted from ref 40 with permission of RSC. Panels (e−g) adapted with permissions from ref 41. Copyright 2014 American Chemical Society. 418


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Figure 5. Quadruple hydrogen-bonded complex of 42 and 43. (a) Subtilisin catalyzed fibrillation of 44b from 44a, (b) cylindrical micelle formed from 45. I, hydrophobic domain; II, reversible cross-linker; III, flexible linker; IV and V, facilitate mineralization and cell adhesion, respectively. (c) Simultaneous covalent and noncovalent polymerization of 46−48, (d) hexameric rosette structure leads to fibrils, (e) self-assembled trefoil knot of 49, (f) peptide nanotube of 50 templates silver nanowire formation. (g) Molecular elevator, (h) four-wheeled molecular motor, and (i) molecular machine drills holes in cell membrane. Panels (a), (d), (h), and (i) adapted from refs 43, 46, 51, and 52, respectively, with permission of NPG. Panels (b), (c), (e), (f) and (g) adapted from refs 44, 45, 47, 48, and 50, respectively, with permission of AAAS.

higher average molar weights (Figure 5c).45 The self-assembled structures of 46 in the hybrid cylindrical fibers could be reversibly removed by dissolution, thereby enabling novel delivery and repair functions. Interestingly, Sleiman et al. employed cyanuric acid to reprogram the assembly of unmodified polyadenine into stable and long fibers having hexameric rosette structure (Figure 5d).46 Sanders et al. reported the self-assembly of trefoil knot from a NDI-based aqueous disulfide (49) driven by the hydrophobic effect (Figure 5e).47 Gazit and Reches showed elegant selfassembly of diphenylalanine (50) into nanotubes and reduction of ionic silver within the nanotubes, which upon enzymatic degradation resulted in silver nanowires (Figure 5f).48 Ariga et al. designed a porphyrin−hydroquinone hybrid that combines the photonic functionality of porphyrins with reversible redox activity of hydroquinones (51 and 52).49 Stoddart et al. designed a trifurcated host−guest based nanoscale elevator that exerts

force of 200 pN (Figure 5g).50 Feringa et al. developed electrically driven directional motion of a four-wheeled molecular motor (Figure 5h).51 Recently, Tour et al. demonstrated molecular machines that drill holes in cell membranes upon ultraviolet irradiation (Figure 5i).52 Gazit et al. reported ordered assemblies of guanine and cytosine containing di-PNAs.53 The X-ray crystal structure showed the presence of both stacking interactions and Watson−Crick base pairing (Figure 6a). Additionally, di-PNA assemblies exhibited voltage-dependent electroluminescence and excitation-dependent fluorescence in the visible region (Figure 6b−g). In another report, authors demonstrated that nanotube lengths of 50 can be controlled by coassembling with 53 (Figure 6h−j).54 However, coassembly of 50 with triphenylalanine was shown to exhibit diverse architectures that include toroids (Figure 6k).55 Interestingly, when varying amounts of dodecanoic acid were mixed with peptide amphiphile (54−56); their coassembly due 419


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Figure 6. (a) Crystal structure of di-PNAs, (b) bright-field image, and (c−g) pseudocolors of excitation dependent emission in di-PNA. Adapted from ref 53 with permission of NPG. (h) Coassembly of 50 and 53. FESEM of (i) 50, (j) 50 and 53, and (k) 50 and triphenylalanine. TEM of coassembly of dodecanoic acid with (l,o) 54, (m,p) 55, and (n,q) 56. Ratio of peptide to dodecanoic acid in (l−n) 1:0.4 and (o−q) 1:1. Panels (h−j), (k), and (l−q) adapted with permission from refs 54, 55, and 56 respectively. Copyright 2016, 2016, and 2017, respectively, American Chemical Society.

hexamers and octamers. Meticulous investigation of the composition and kinetics of macrocyclization showed self-replicating diversification behavior that has parallels to speciation of biological systems. On the other hand, van Esch et al. reported the transient assembly of synthetic molecules into active materials under far from thermodynamic equilibrium (Figure 7e).61 The carboxylate groups on the inactive self-assembling building blocks (64a, 65a, 66a), upon transient methylation by the fuel dimethyl sulfate, yield methylesters (64b, 65b, 66b) that selfassemble into fibrous structures. Remarkably, lifetime, stiffness, and self-regeneration capabilities of these active materials were found to be dependent on the reaction kinetics and fuel levels, and their nonlinear fiber dynamics is reminiscent of microtubule behavior.

to anion−π interactions was found to result in cylindrical nanofibers, nanobelts, vesicles, and their mixtures (Figure 6l−q).56 Aida et al. reported linear heterojunctions formed by stepwise nanotubular coassembly of two molecular graphenes (Figure 7a).57 57 self-assembled to nanotubes and its bipyridyl groups coordinated to Cu2+, which acted as seeds for the assembly of 58 giving rise to linear heterojunctions. In another report, chain-growth polymerization was realized by templating conformationally constrained metastable monomers (59) on tailored initiators (60) via hydrogen-bonding (Figure 7b).58 The N-H amides of 59 engender intramolecular hydrogen-bonding, which is not possible in 60 due to N-methylated amide. However, 60 acted as template for its coassembly with 59 by reorganizing hydrogen-bonding interactions and the resulting free CO functionalities of templated 59 served as initiating end for further growth, which exemplify the living supramolecular polymerization with low polydispersity index. Sugiyasu et al. showed that 61 could be differentiated into nanofiber and nanosheet architectures through 1D and 2D living supramolecular polymerization (Figure 7c).59 Energy landscape was found to be strongly dependent on the molecular structure, as 1D self-assembly was driven by hydrogen-bonding and π−π stacking, whereas van der Waals forces among alkyl chains contributed toward their 2D assembly. Otto et al. reported 62 and 63 as having an aromatic core grafted with peptide and thiol functionalities, which upon oxidation form cyclic trimers and tetramers through disulfide bonds (Figure 7d).60 After a lag phase of several days, these cyclic products transform to cyclic

3. FUNCTIONAL APPLICATIONS 3.1. Organic Electronics

Electrical conductivity measurements by a two-probe method revealed that films of 20 (3.5 μS m−1) has 2-fold higher conductivity than 21 (1.6 μS m−1) due to face-to-face stacking.31 Scanning tunneling microscopy measurements on the 2D nanosheets of 7 showed nonlinear I−V (current−voltage) curve with a linear conductance of 2.22 nS.27 Remarkably, C-AFM studies showed 1.6 S cm−1 for 3 and such high conductivities are reported only in heavily doped conducting polymers/small molecules.23 Further, we investigated the bulk electronic mobilities of 3 by 420


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Figure 7. (a) Supramolecular heterojunction of 57 and 58, (b) polymerization of 59 on initiator 60, (c) energy landscape of 61 to 1D and 2D structures, (d) mechanism of self-replication of 62 and 63, and (e) chemically fuelled transient self-assembly. (f−h) Temporal assembly and disassembly of 64a,b. Panels (a), (b), and (e−h) adapted from refs 57, 58, and 61, respectively with permission of AAAS. Panels (c) and (d) adapted from refs 59 and 60, respectively, with permission of NPG.

negligible photocurrent due to CT complexation (Figure 8f). Giuseppone et al. reported self-assembly of 68 to nanowires under the action of light and electric field triggers (Figure 8g).63 These nanowires showed high conductivity (5 × 103 S m−1) and low interface resistance (2 × 10−4 Ωm). Stupp et al. reported CT crystals of pyromellitic diimide (69) and pyrene (70) derivatives, which showed room temperature ferroelectricity with Ps of ∼1 μC cm2 (Figure 8h,i).64

steady state space charge limited current (SCLC) measurements.12 The I−V curves showed linear dependence up to a certain voltage and a trap-free SCLC regime thereafter, resulting in mobility of 1 cm2 V−1 s−1 for 3 (Figure 8a,b). TIS-assembly structure of NDI and pyrene broke the center of symmetry of the supramolecular helical architectures, leading to spontaneous unidirectional alignment of the net molecular dipoles (Figure 8c).36 The resulting nanofibrous network was utilized to fabricate a solution processable thin-film ferroelectric capacitor with a saturation polarization (Ps) of ∼4 μC cm2 (Figure 8d,e).36 Additionally, photoinduced single electron transfer (PISET) reaction based photoresponsivity of the TIS coassembly enabled us to realize optically and electronically rewritable multistate memory. Aida et al. designed hexabenzocoronene (electron donor) and trinitrofluorenone (electron acceptor) based amphiphile 67 to form nanotubular architectures and mixed stack microfibers.62 The spatially segregated charge carriers in the nanotubular architecture facilitated photoconductive response with large on/off ratio greater than 104, whereas microfibers exhibited

3.2. Tissue Engineering

Development of scaffolds for cellular adhesion, proliferation and differentiation are posed by several challenges such as cellular signaling, biocompatibility, biodegradability, processability, scalability, stiffness, wettability, topography, conductivity, and oxidative stress.65 Stupp et al. designed V3A3E3 based peptide amphiphile that results in noodlelike strings having aligned nanofibers.66 Human mesenchymal stem cells (hMSCs) incorporated within the peptide strings were found to elongate along the string director axis (Figure 9a). Incorporation of carbon nanotubes resulted in black peptide strings having 421


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Figure 8. (a) SCLC device structure. A, Etched ITO coated glass; B, 5−10 μm of 3; C, aluminum electrode. (c) temperature (Δ) driven disassembly, electric field (E) induced net polarization (P) switching, and light responsive single-electron transformation reaction in coassembly of 26 and 27. (b) I−V plot of 3. (d) P−E loop and (e) photoresponsive ferroelectric switching device. Adapted with permission from refs 12 and 36. Copyright 2016 and 2016 ACS. (f) I−V plot of 67 with (orange) and without (green) photo irradiation. Adapted from ref 62 with permission of AAAS. (g) Schematic representation of triggered self-construction of nanowires of 68 in a nanotrench. Adapted from ref 63 with permission of NPG. P−E curves for 69 and 70 at (h) 7 K and (i) 300 K. Adapted from ref 64 with permission of NPG.

Figure 9. (a) Aligned cells in peptide string and (b) aligned nanofibers in black peptide string. (c) Calcium fluorescence of HL-1 cardiomyocytes in peptide string. Adapted from ref 66 with permission of NPG. (d) Sciatic nerve regeneration. Adapted from ref 67 with permission of Elsevier. (e) Silk. (f) Schematic representation and (g) FESEM of electrospun silk-melanin composite. (h) FESEM of myoblasts formed on silk−melanin mats. (i) Fluorescence staining of myoblasts cultured on silk−melanin mats. Adapted from ref 68 with permission of Wiley-VCH. (j) Schematic representation of covalently modified silk. Fluorescence image of hMSCs cultured on silk films covalently grafted with (k) YIGSR and (l) GYIGSR. Adapted with permission from ref 69. Copyright 2016 American Chemical Society.

electrical conductivities of 1−10 S cm−1 (Figure 9b). Further, HL-1 cardiomyoctes, a cell line with spontaneous electrical activity, proliferated extensively within the peptide strings (Figure 9c). In another report, RGDS based peptide

amphiphile was shown to facilitate sciatic nerve regeneration (Figure 9d).67 We developed a strategy to combine the properties of silk fibroin and melanin for skeletal muscle tissue engineering 422


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Accounts of Chemical Research application.68 Silk fibroin with its mechanical strength, biocompatibility, biodegradability, processability and scalability forms the core structure of our scaffold, while the naturally occurring polymeric pigment, melanin offers antioxidant and conducting properties. The electrospun fiber mats of silk−melanin composite showed strong antioxidant property by reducing the intracellular ROS levels and facilitated proliferation of mouse myoblast C2C12 cells and induced differentiation into aligned high aspect ratio myotubes (Figure 9e−i). On the other hand, silk fibroin scaffold covalently functionalized with short-peptide motif (YIGSR/GYIGSR) of integrin-binding extracellular protein (ECM) laminin mimics the functions of full length protein (Figure 9j).69 Covalently grafted silk with GYIGSR supported hMSCs proliferation and differentiation into neuron-like cells in the presence of a biochemical cue, on demand (Figure 9k,l).

macroscopic architectures revealed hydrogen-bonded 1D chains (71, 73) and 2D layers (72, 74) (Figure 10a−d). The mechanical properties measured by nanoindentation technique showed E of 5.4−20.5 GPa and hardness (H) of 240−1164 MPa, which is comparable or better than those of natural fibers.70,74 The presence of 2D hydrogen-bonded network and synergistic contributions from aromatic interactions played the crucial role in making 74, one of the stiffest and hardest organic crystal (Figure 10e). Moreover, 74 possesses very high yield strength (σy) of 388 MPa, and due to low density (∼1.3 g cm−3) its specific properties (ratios of E and σy to density) are comparable to that of structural metals. Notably, the molecular weights of CDPs (∼0.2 kDa) are nearly 3 orders of magnitude lower than those of natural structural proteins (50−300 kDa). Such reductionistic peptide engineering strategies could pave way for realistic industrial scale manufacturing through simplistic molecular materials designs. On the other hand, Gazit et al. had employed AFM-based indentation experiments to obtain the average point stiffness of 160 N m−1 and an estimated E of ∼19 GPa for nanotubes of 50 (Figure 10f).75 53 self-assembled into spheres with pointstiffness of 885 N m−1 and E of 275 GPa, and the exact reasons for the exceptional stiffness is unclear (Figure 10g).76 Joshi et al. probed the mechanical properties of cyclic peptide 75 that selfassembled into microfibers having E of 11.3 ± 3.3 GPa and H of 387 ± 136 MPa (Figure 10h).77 These efforts could invariably pave the way for the development of stiff and tough biocompatible composite materials. 3.3.2. Self-Cleaning. Lotus-leaf inspired superhydrophobic (contact angle ≥ 150°) surfaces have been mimicked by using lithography, sublimation, plasma techniques, self-assembled monolayers, and electrochemical methods.78 All these methods

3.3. Miscellaneous

3.3.1. High Mechanical Strength. Mechanical strength of amyloid fibers and silks is attributed primarily to hydrogenbonding (β-sheet) interactions.70 Theoretically estimated elastic modulus (E) of ∼10 GPa for hydrogen-bonded assemblies is effectively achieved in spider dragline silk.70,71 We envisioned a reductionistic approach to employ cyclic dipeptides (CDPs), which offers several advantages like (i) rigid structural and self-complementary motifs, (ii) versatile supramolecular synthons, (iii) tailorable chemical groups via their α-substituents that render additional functionalities, (iv) variable stereochemistry, (v) biocompatibility, (vi) solution processability, and (vii) scalability.71−73 We employed CDPs of alanine (71 and 72) to exploit multiple hydrogen-bonding interactions, while that of unnatural phenylglycine (73 and 74) to introduce orthogonal aromatic interactions.71 Self-assembled single-crystalline

Figure 10. Self-assembled architectures and single-crystal hydrogen-bonded molecular packing of (a) 71, (b) 72, (c) 73, and (d) 74. (e) Plot of E versus strength for various materials. Adapted from ref 71 with permission of NPG. (f) AFM, (g) SEM, and (h) TEM images of 50, 53, and 75, respectively. Panels (f) and (h) adapted from refs 75 and 77, respectively. Copyright 2005 and 2015 American Chemical Society. Panel (g) adapted from ref 76 with permission of Wiley-VCH. 423


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functional applications. We described several strategies developed by our group and others for functional molecular assemblies and applications in organic electronics, self-cleaning, high-mechanical strength, and tissue engineering. Mastering the art of programmed molecular assemblies having specific functions will be crucial for harvesting efficient performances in almost all technological fields. Thus, it is imperative that one embarks on more and more molecular designs and engineering strategies to achieve well-defined architectures of functional molecular self-assemblies. Natural systems that have innumerable molecular designs with sophisticated functions can serve as the basis for researchers to explore, replicate, and emulate the design and/or function. Once we understand the working principles of natural systems and establish their function in primitive synthetic modular systems, it can be advanced to greater heights in terms of complexity and efficiency. Therefore, we are certain that sustained efforts in molecular architectonics are bound to bring about significant advancements in the field of engineering molecular interactions and assemblies for applications in energy, health, and environment. In addition, molecular architectonics is believed to enable creation of lifelike systems with complex properties.

involve fabrication of rough surfaces and subsequent low-surfaceenergy coatings. However, breath-figure technique (BFT) attracted our interest owing to its simple solution processability, its robustness, and its excellent tunability of array size over 3 orders of magnitude. The evaporation of volatile solution facilitates condensation of water droplets on the cold surface and subsequent solidification of the solute under favorable conditions produces highly ordered arrays of well-defined cavities (50 nm to 20 μm) called breath-figure arrays. We fabricated highly ordered breath-figure arrays of 76 from dichoromethane solution (Figure 11a−c).78 These microarrays were then sputtered

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Thimmaiah Govindaraju: 0000-0002-9423-4275 Notes

The authors declare no competing financial interest. Biographies M. B. Avinash received his Integrated MSc (Hons.) in Applied Chemistry from Kuvempu University (India). He then obtained his PhD from JNCASR under the supervision of Prof. T. Govindaraju. Currently, he is working as a Research Associate in the same group. His research interests include (bio)molecular engineering and bioinspired design strategies to develop advanced functional materials and biological applications. T. Govindaraju is an Associate Professor at New Chemistry Unit, JNCASR, Bengaluru, India. He received his MSc from Bangalore University and PhD from National Chemical Laboratory and University of Pune, India. He pursued his postdoctoral research at the University of WisconsinMadison, and as Alexander von Humboldt fellow at the Max Planck Institute of Molecular Physiology, Dortmund, Germany. His research interests are at the interface of chemistry, biology, and materials, including organic synthesis, peptide chemistry, neuro- degenerative diseases, molecular probes, molecular architectonics, and nanoarchitectonics.

Figure 11. (a−c) Honeycomb-like hierarchical microarray of 76. (d) Contact angle, (e) tilt angle, and (f−h) self-cleanability of microarray surface of 76. Adapted from ref 78 with permission of Wiley-VCH. (i) Fluorescent image of 78. Adapted from ref 80 with permission of RSC.

with nanostructured gold and coated with a self-assembled monolayer of 1H,1H,2H,2H-perfluorodecanethiol, which successfully mimics the self-cleaning property of lotus-leaf (contact angle 156° and tilt angle 3°; Figure 11d−h). Further, fluorescent dyes and electroactive materials were homogeneously incorporated within the self-assembled microarrays of 76 to yield highly fluorescent hydrophobic molecular materials, which may enable applications in organic electronics. Besides 76, few other small organic molecules, namely, 77 and 78, are also known to form breath-figure arrays (Figure 11i).79,80 However, nonhierarchical arrays of 78 that lack nanostructured roughness hinder the fabrication of superhydrophobic surfaces.

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DEDICATION Dedicated to Prof. K. N. Ganesh on the occasion of his 65th birthday. ACKNOWLEDGMENTS Authors thank Prof. C. N. R. Rao for constant support and encouragement, JNCASR, IYBA and special Nanobiotechnology grant, DBT, SERB, DST-SwarnaJayanti Fellowship, Government of India, Sheikh Saqr Laboratory (SSL)-ICMSJNCASR for financial support to T.G. DRDO for RA fellowship

4. CONCLUSIONS AND OUTLOOK In this Account, we presented molecular architectonics, a state of the art in engineering molecular organization for various 424


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Conductivity and Attoliter Containers. Adv. Funct. Mater. 2011, 21, 3875−3882. (24) Avinash, M. B.; Govindaraju, T. Extremely Slow Dynamics of an Abiotic Helical Assembly: Unusual Relevance to the Secondary Structure of Proteins. J. Phys. Chem. Lett. 2013, 4, 583−588. (25) Avinash, M. B.; Sandeepa, K. V.; Govindaraju, T. Emergent Behaviors in Kinetically Controlled Dynamic Self-Assembly of Synthetic Molecular Systems. ACS Omega 2016, 1, 378−387. (26) Pandeeswar, M.; Govindaraju, T. Bioinspired Nanoarchitectonics of Naphthalene Diimide to Access 2D Sheets of Tunable Size, Shape, and Optoelectronic Properties. J. Inorg. Organomet. Polym. Mater. 2015, 25, 293−300. (27) Pandeeswar, M.; Govindaraju, T. Green-fluorescent naphthalene diimide: conducting layered hierarchical 2D nanosheets and reversible probe for detection of aromatic solvents. RSC Adv. 2013, 3, 11459− 11462. (28) Pandeeswar, M.; Avinash, M. B.; Govindaraju, T. Chiral Transcription and Retentive Helical Memory: Probing Peptide Auxiliaries Appended with Naphthalenediimides for Their OneDimensional Molecular Organization. Chem. - Eur. J. 2012, 18, 4818−4822. (29) Manchineella, S.; Prathyusha, V.; Priyakumar, U. D.; Govindaraju, T. Solvent-Induced Helical Assembly and Reversible Chiroptical Switching of Chiral Cyclic-Dipeptide-Functionalized Naphthalenediimides. Chem. - Eur. J. 2013, 19, 16615−16624. (30) Pandeeswar, M.; Khare, H.; Ramakumar, S.; Govindaraju, T. Biomimetic molecular organization of naphthalene diimide in the solid state: tunable (chiro-) optical, viscoelastic and nanoscale properties. RSC Adv. 2014, 4, 20154−20163. (31) Pandeeswar, M.; Khare, H.; Ramakumar, S.; Govindaraju, T. Crystallographic insight-guided nanoarchitectonics and conductivity modulation of an n-type organic semiconductor through peptide conjugation. Chem. Commun. 2015, 51, 8315−8318. (32) Sakai, N.; Mareda, J.; Vauthey, E.; Matile, S. Core-substituted naphthalenediimides. Chem. Commun. 2010, 46, 4225−4237. (33) Avinash, M. B.; Sandeepa, K. V.; Govindaraju, T. Molecular assembly of amino acid interlinked, topologically symmetric, πcomplementary donor−acceptor−donor triads. Beilstein J. Org. Chem. 2013, 9, 1565−1571. (34) Horiuchi, S.; Tokura, Y. Organic ferroelectrics. Nat. Mater. 2008, 7, 357−366. (35) Tayi, A. S.; Kaeser, A.; Matsumoto, M.; Aida, T.; Stupp, S. I. Supramolecular ferroelectrics. Nat. Chem. 2015, 7, 281−294. (36) Pandeeswar, M.; Senanayak, S. P.; Narayan, K. S.; Govindaraju, T. Multi-Stimuli-Responsive Charge-Transfer Hydrogel for RoomTemperature Organic Ferroelectric Thin-Film Devices. J. Am. Chem. Soc. 2016, 138, 8259−8268. (37) Pandeeswar, M.; Govindaraju, T. Engineering molecular selfassembly of perylene diimide through pH-responsive chiroptical switching. Mol. Syst. Des. Eng. 2016, 1, 202−207. (38) Seeman, N. C. An Overview of Structural DNA Nanotechnology. Mol. Biotechnol. 2007, 37, 246. (39) Narayanaswamy, N.; Avinash, M. B.; Govindaraju, T. Exploring hydrogen-bonding and weak aromatic interactions induced assembly of adenine and thymine functionalised naphthalenediimides. New J. Chem. 2013, 37, 1302−1306. (40) Narayanaswamy, N.; Suresh, G.; Priyakumar, U. D.; Govindaraju, T. Double zipper helical assembly of deoxyoligonucleotides: mutual templating and chiral imprinting to form hybrid DNA ensembles. Chem. Commun. 2015, 51, 5493−5496. (41) Dwivedi, A. K.; Pandeeswar, M.; Govindaraju, T. Assembly Modulation of PDI Derivative as a Supramolecular Fluorescence Switching Probe for Detection of Cationic Surfactant and Metal Ions in Aqueous Media. ACS Appl. Mater. Interfaces 2014, 6, 21369−21379. (42) Blight, B. A.; Hunter, C. A.; Leigh, D. A.; McNab, H.; Thomson, P. I. T. An AAAA−DDDD quadruple hydrogen-bond array. Nat. Chem. 2011, 3, 244−248. (43) Hirst, A. R.; Roy, S.; Arora, M.; Das, A. K.; Hodson, N.; Murray, P.; Marshall, S.; Javid, N.; Sefcik, J.; Boekhoven, J.; van Esch, J. H.;

to M.B.A and coauthors of all the papers cited in this article for their valuable contribution.

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Architectonics: Design of Molecular Architecture for Functional

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