N–H⋯X interactions stabilize intra-residue C5 hydrogen bonded conformations in heterocyclic α-amino acid derivatives

Nature makes extensive and elaborate use of hydrogen bonding to assemble and stabilize biomolecular structures. The shapes of peptides and proteins rely significantly on N–H⋯O C interactions, which are the linchpins of turns, sheets and helices. The C5 H-bond, in which a single residue provides both donor and acceptor, is generally considered too weak to force the backbone to adopt extended structures. Exploiting the synergy between gas phase (experimental and quantum chemistry) and solution spectroscopies to decipher IR spectroscopic data, this work demonstrates that the extended C5-based conformation in 4-membered ring heterocyclic α-amino acid derivatives is significantly stabilized by the formation of an N–H⋯X H-bond. In this synergic system the strength of the C5 interaction remains constant while the N–H⋯X H-bond strength, and thereby the support provided by it, varies with the heteroatom.

In 4-membered ring heterocyclic α-amino acid derivatives, extended conformations based on intraresidue C5 H-bonds can be stabilized by N–H⋯X H-bonds, making the combined C5–C6γ structures prominent in both gas phase and in weakly polar solutions.     

Arene–perfluoroarene interactions confer enhanced mechanical properties to synthetic nanotubes

Supramolecular nanotubes prepared through macrocycle assembly offer unique properties that stem from their long-range order, structural predictability, and tunable microenvironments. However, assemblies that rely on weak non-covalent interactions often have limited aspect ratios and poor mechanical integrity, which diminish their utility. Here pentagonal imine-linked macrocycles are prepared by condensing a pyridine-containing diamine and either terephthalaldehyde or 2,3,5,6-tetrafluoroterephthalaldehyde. Atomic force microscopy and synchrotron in solvo X-ray diffraction demonstrate that protonation of the pyridine groups drives assembly into high-aspect ratio nanotube assemblies. A 1 : 1 mixture of each macrocycle yielded nanotubes with enhanced crystallinity upon protonation. UV-Vis and fluorescence spectroscopy indicate that nanotubes containing both arene and perfluoroarene subunits display spectroscopic signatures of arene–perfluoroarene interactions. Touch-spun polymeric fibers containing assembled nanotubes prepared from the perhydro- or perfluorinated macrocycles exhibited Young''s moduli of 1.09 and 0.49 GPa, respectively. Fibers containing nanotube assemblies reinforced by arene–perfluoroarene interactions yielded a 93% increase in the Young''s modulus over the perhydro derivative, up to 2.1 GPa. These findings demonstrate that tuning the chemical composition of the monomeric macrocycles can have profound effects on the mechanical strength of the resulting assemblies. More broadly, these results will inspire future studies into tuning orthogonal non-covalent interactions between macrocycles to yield nanotubes with emergent functions and technological potential.

Arene–perfluoroarene interactions resulted in enhanced crystallinity between analogous perhydro- and perfluoro macrocycles in a supramolecular nanotube assembly.     

Organic room-temperature phosphorescence from halogen-bonded organic frameworks: hidden electronic effects in rigidified chromophores

Development of purely organic materials displaying room-temperature phosphorescence (RTP) will expand the toolbox of inorganic phosphors for imaging, sensing or display applications. While molecular solids were found to suppress non-radiative energy dissipation and make the RTP process kinetically favourable, such an effect should be enhanced by the presence of multivalent directional non-covalent interactions. Here we report phosphorescence of a series of fast triplet-forming tetraethyl naphthalene-1,4,5,8-tetracarboxylates. Various numbers of bromo substituents were introduced to modulate intermolecular halogen-bonding interactions. Bright RTP with quantum yields up to 20% was observed when the molecule is surrounded by a Br⋯O halogen-bonded network. Spectroscopic and computational analyses revealed that judicious heavy-atom positioning suppresses non-radiative relaxation and enhances intersystem crossing at the same time. The latter effect was found to be facilitated by the orbital angular momentum change, in addition to the conventional heavy-atom effect. Our results suggest the potential of multivalent non-covalent interactions for excited-state conformation and electronic control.

The number and position of halogen substituents in purely organic π–π* chromophores critically affect the efficiency of phosphorescence.     

Cell–cell interactions via non-covalent click chemistry

Metabolic glycoengineering with unnatural sugars became a valuable tool for introducing recognition markers on the cell membranes via bioorthogonal chemistry. By using this strategy, we functionalized the surface of tumor and T cells using complementary artificial markers based on both β-cyclodextrins (β-CDs) and adamantyl trimers, respectively. Once tied on cell surfaces, the artificial markers induced cell–cell adhesion through non-covalent click chemistry. These unnatural interactions between A459 lung tumor cells and Jurkat T cells triggered the activation of natural killer (NK) cells thanks to the increased production of interleukin-2 (IL-2) in the vicinity of cancer cells, leading ultimately to their cytolysis. The ready-to-use surface markers designed in this study can be easily inserted on the membrane of a wide range of cells previously submitted to metabolic glycoengineering, thereby offering a simple way to investigate and manipulate intercellular interactions.

We designed complementary artificial markers that were introduced on the surface of cells previously modified by metabolic glycoengineering. These recognition markers enable unnatural cell–cell adhesion through non-covalent click chemistry.     

Exciton interactions in helical crystals of a hydrogen-bonded eumelanin monomer

Eumelanin, a naturally occurring group of heterogeneous polymers/aggregates providing photoprotection to living organisms, consist of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) building blocks. Despite their prevalence in the animal world, the structure and therefore the mechanism behind the photoprotective broadband absorption and non-radiative decay of eumelanin remain largely unknown. As a small step towards solving the incessant mystery, DHI is crystallized in a non-protic solvent environment to obtain DHI crystals having a helical packing motif. The present approach reflects the solitary directional effect of hydrogen bonds between the DHI chromophores for generating the crystalline assembly and filters out any involvement of the surrounding solvent environment. The DHI single crystals having an atypical chiral packing motif (P2₁2₁2₁ Sohncke space group) incorporate enantiomeric zig-zag helical stacks arranged in a herringbone fashion with respect to each other. Each of the zig-zag helical stacks originates from a bifurcated hydrogen bonding interaction between the hydroxyl substituents in adjacent DHI chromophores which act as the backbone structure for the helical assembly. Fragment-based excited state analysis performed on the DHI crystalline assembly demonstrates exciton delocalization along the DHI units that connect each enantiomeric helical stack while, within each stack, the excitons remain localized. Fascinatingly, over the time evolution for generation of single-crystals of the DHI-monomer, mesoscopic double-helical crystals are formed, possibly attributed to the presence of covalently connected DHI trimers in chloroform solution. The oligomeric DHI (in line with the chemical disorder model) along with the characteristic crystalline packing observed for DHI provides insights into the broadband absorption feature exhibited by the chromophore.

Single crystals of DHI monomer, a eumelanin precursor, adopt an atypical chiral packing arrangement incorporating enantiomeric zig-zag helical stacks while its covalently connected DHI trimer forms double-helical crystals in the mesoscopic scale.

Eumelanin, which represents a broad class of natural pigments found in the animal kingdom, acts as a biological shield for protecting the skin cells against harsh UV radiation.¹ Eumelanin, a black coloured pigment, obtained from the oxidative polymerization of 5,6-dihydroxyindoles (DHIs) and 5,6-dihydroxyindole carboxylic acid (DHICA) is one of the extensively explored archetypes of the melanin family (Fig. 1a).² Eumelanin has synergistic merits of possessing broadband UV absorption and proficient dissipation of the excessive electronic energy via non-radiative deactivation of the excited states, thereby resulting in the photoprotective nature of the pigment.³ Apart from the photoprotective behaviour, melanin possesses exceptional antioxidant activity via its free radical scavenging traits.^4–7 However, much less has been understood about the fundamental photophysics and structural features of eumelanin due to the enormous heterogeneity in the molecular framework^8,9 coupled with poor solubility in common solvents.¹⁰ Recent years have witnessed a growing interest towards unravelling the excited state processes occurring in the eumelanin pigment upon interaction with light.^11,12 A better correlation between the structure–property relationship and photoexcited state processes in eumelanin can guide the development of inspired functional materials for potential application in biomedical and dermo-cosmetic fields.^1,13–15Open in a separate windowFig. 1(a) Chemical diagrams of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole carboxylic acid (DHICA). (b) Various unconventional hydrogen bonding interactions identified in DHI crystals.In the natural world, the chromophoric architecture of eumelanin can symbolize an organized and efficient organic system for photoprotection that nature developed through evolution. The outcome of the research done so far indicates the presence of continuous π-stacks of oligomers in eumelanin which induce different levels of aggregation to construct the eumelanin framework.¹⁶ Furthermore, eumelanin has been reported to exhibit weak fluorescence which indicates the presence of competing non-radiative channels that provide efficient de-excitation pathways for repopulating the ground states.^17–20 The broadband absorption of eumelanin has theoretically and experimentally been evaluated, in part, to be a result of π-stacking interactions between the oligomers of DHI/DHICA in multiple oxidation states.^21–24 While dealing with biomacromolecules, non-covalent interactions such as hydrogen bonding and π–π stacking take the centre stage in controlling the supramolecular architecture, especially in the 3-dimensional structures of proteins and DNA. Modulating the balance between each of these noncovalent interactions over another will produce significant changes not only in the structure but also in the functional properties.Hydrogen bonding is simultaneously both ubiquitous and diverse and therefore its significance in biochemical systems comes as no surprise particularly due to the surrounding aqueous environment. Apart from the classical hydrogen bonding interactions, an array of hydrogen bond-like weak interactions which include a delocalized π-system acting as the acceptor group to the X–H hydrogen donor (X = O, N, C) is identified to provide additional contributions for stabilizing the biomolecular structure and controlling intrinsic functions (Fig. 1b).^25,26 Investigations aimed at identification (using X-ray crystallography) followed by energetic quantification of the major stabilizing interactions such as those with the aromatic π-rings in biological complexes are of paramount importance for developments in diverse areas including drug design. There has been extensive research conducted on eumelanin building blocks showcasing their ability to form hydrogen bonds through the –OH and –NH functional groups.^27,28 Most reports almost exclusively focus on the hydrogen bonding with the solvent environment surrounding the eumelanin monomer units.²⁹ Findings from these theoretical studies have demonstrated the role of several deactivation pathways in the presence of a protic solvent, namely –OH and –NH bond elongation and 5-/6-membered ring puckerings.¹⁸Chemical and spectral evidence from the eumelanin polymeric structures identified so far points to five main levels of chemical disorder leading to the supramolecular structure, which includes (i) disorder from the simultaneous presence of different building blocks; (ii) molecular size disorder; (iii) disorder from the position of coupling; (iv) electronic/redox disorder of the constituent units and (v) supramolecular disorder.³⁰ Given the complex structure of melanin, a bottom-up approach using the building blocks or basic constituent molecules of eumelanin is a pertinent strategy for the mechanistic study of the photoproperties of eumelanin. This can be followed by understanding the more intricate structures of melanin formed from the constituents with less complex approaches. Due to the abundant presence of water in the natural media, the corresponding solute–solvent interactions can have profound significance in driving the fast polymerization and the consequent heterogeneity of natural melanin. The tedious task of extracting melanin from natural sources and the lack of solubility of the polymeric melanin material in organic/aqueous solvents have called for basic model systems to understand the complex eumelanin architecture. In this regard, we have adopted a facile approach to decode the perpetual puzzle by single crystal X-ray crystallographic and spectroscopic analyses of DHI crystalline aggregates derived from a non-aqueous environment (chloroform). Due to the highly autooxidative³¹ nature of eumelanin precursors even in the slight presence of protic solvents, the simple model implemented here precludes the contribution of solute–solvent hydrogen bonding interaction towards the formation and resultant structure of DHI crystalline aggregates. In chloroform, each DHI molecule experiences weak interactions solely from the neighbouring DHI chromophores thereby leading to helical aggregation.Our efforts towards recognizing and monitoring the photogenerated excitons and charge-transfer dynamics in crystalline and contorted polyaromatic assemblies^32–36 prompted us to explore the structure–optical property relationship in the eumelanin precursor molecule DHI. Unlike the commonly understood π-stacking in eumelanin derivatives, the single crystals of DHI arrange in a helical zig-zag fashion with a completely edge-to-face aggregate structure driven by both conventional and unconventional hydrogen bonds (Fig. 1b). The structural heterogeneity imposed by the different hydrogen bonds has led to varied levels of exciton delocalization between the neighbouring chromophores in the crystalline DHI aggregates. Along with the diffracting single crystals of monomeric DHI, covalently connected trimeric units of DHI are also identified in chloroform solution, which form double-helical crystals in the mesoscopic scale. Such double-helical architectures are omnipresent in nature as exemplified by the DNA structure.DHI was synthesized by following a previously reported procedure having l-dopa as the starting material (Scheme S1, Appendix C1–C4 and C7, ESI^†).³⁷ Slow evaporation from dry chloroform solution of DHI produced colourless diamond shaped single crystals of DHI (Fig. S1a^†). Interestingly, the DHI molecule with no chiral centre atypically crystallized in the Sohncke space group, P2₁2₁2₁ (Table S1^†). Single-crystal X-ray structure analysis revealed the presence of conventional and unconventional hydrogen bonds directing the crystalline self-assembly of DHI chromophores about a zig-zag helical backbone. Fig. 2 presents the four different types of non-covalent dimers (D1–4) distinguished within the DHI crystal. The zig-zag helical stacks proceed along the crystallographic a-axis (Fig. S2^†) and are fabricated by bifurcated O–H⋯O hydrogen bonds (d_O1⋯H = 2.25 Å, d_O2⋯H = 2.34 Å, <O1–H–O2 = 67.89°) between the two hydroxyl substituents in the DHI chromophore (D3 in Fig. 2). Such bifurcated hydrogen bonded assemblies are prevalent in the secondary and tertiary structures of proteins.³⁸ Interestingly, in the DHI crystal, enantiomeric helical stacks (Fig. S2^†) that are arranged with respect to different screw axes are observed, wherein each stack aligns in a herringbone fashion to the other zig-zag helix (as represented by the dimers D1, D2 and D4). The stacks are interconnected majorly through the unconventional hydrogen bonds such as C–H⋯π (d_C–H⋯π = 2.66–2.99 Å), O–H⋯π (d_O–H⋯π = 2.59 Å), C–H⋯N (d_C–H⋯N = 2.72 Å), C–H⋯O (d_C–H⋯O = 2.66 Å) and the classical N–H⋯O (d_N–H⋯O = 2.72 Å) hydrogen bonds. The absence of π–π stacking interaction is validated by the Hirshfeld surface analysis wherein the formation of the DHI crystalline assembly is majorly stabilized by the C⋯H (40.5%), H⋯H (29.7%), N⋯H (4.3%) and O⋯H (25.4%) noncovalent interactions (Fig. S3 and Table S2^†).Open in a separate windowFig. 2Different orientations of DHI (D1–4) and the directing hydrogen bonds observed in the single crystal.Detailed examination of the interchromophoric interactions supporting the zig-zag helical stacks in DHI crystals using Bader''s quantum theory of atoms in molecules (QTAIM) analysis revealed the presence of supramolecular synthons in the crystal system (Fig. S4^†). This is evidenced by the (3,+1) ring critical points in each of the representative dimers. For a molecular self-assembly to occur efficiently, recognition between the intermolecular functionalities is important, which often culminates in the formation of smaller repetitive units or supramolecular synthons.³⁹ The recognition information which is then carried by these units forms the kernel of self-aggregation or crystallization processes. In the case of DHI crystals, all the dimer assemblies D1–D4 display synthon formation with the D1 and D3 synthons showing greater energetic stabilities. The dimer unit representing the helical backbone, D3, forms two supramolecular synthons orchestrated by the bifurcated O–H⋯O hydrogen bonds and a weak C–H⋯O interaction (Fig. S4^†). The five- and six-membered rings so formed fabricate the helical zig-zag backbone of the DHI crystal. Similarly, the dimer D1 also forms two synthons through a classical N–H⋯O interaction along with the weak C–H⋯π and O–H⋯π interactions. D2 and D4 dimers are stabilized by one synthon each, materialized by C–H⋯π and C–H⋯N interactions in D2 and N–H⋯O and C–H⋯O interactions in D4.The synthon formation and the concomitant electron delocalization involving the π-rings in dimers D1 and D2 have resulted in the aromatic stabilization of the π-rings upon comparison with the monomer DHI. The nucleus independent chemical shift (NICS(1)) values evaluated for D1–4 and monomer DHI in the ground state indicate the aromatic stabilization of the π-surface leading to the favourable alternate stacking of the enantiomeric zig-zag helices facilitated by the unconventional hydrogen bonds. The negative NICS(1) values for the six- and five-membered (6C, 5C) rings of molecule A (Fig. S5 and Table S3^†) increased to −27.22 ppm (6C) and −29.13 ppm (5C) when compared to the monomer DHI (6C: −26.14 ppm, 5C: −28.03 ppm). Similarly, in D2, the π-surface of molecule B that is involved in the weak interaction undergoes aromatic stabilization (6C: −29.43 ppm, 5C: −31.48 ppm). Truncated symmetry adapted perturbation theory (SAPT(0)) analysis⁴⁰ performed on the DHI dimers shows higher stabilization for D1 (E^SAPT_int = −9.70 kcal mol⁻¹) and D3 (E^SAPT_int = −6.57 kcal mol⁻¹) dimers, which could be attributed to the two supporting supramolecular synthons in both the dimers (Table S4^†). The total stabilization of D1 and D3 orientations is facilitated by the higher contributions of electrostatic energy (E⁽¹⁾_elc = −6.17 to −6.14 kcal mol⁻¹) and induction energy (E⁽¹⁾_elc = −1.60 to −1.38 kcal mol⁻¹) towards the total SAPT energy. The dominant role of the stronger classical hydrogen bonds in the fabrication of D1 and D3 synthons when compared to the other DHI orientations (having equal contribution from the weak unconventional interactions) explains the observed energy distribution in the SAPT(0) analysis.The crystalline architecture of the DHI precursor molecule identified herein could provide a sound model for understanding the inherent nature of the excited energy states leading to the characteristic photo-function of the eumelanin pigment. Several experimental and theoretical investigations on eumelanin aggregates revealed the occurrence of excitation energy transfer within the aggregates.^41,42 The extent of energy delocalization within the four dimer orientations in the DHI crystal structure is determined using the fragment-based excited state analysis developed by Plasser, executed in the TheoDORE package.^43–45 The expanse of excitation delocalization amongst the fragment units is described by the value of participation ratio (PR). The contribution towards the exciton delocalization from the fragments is defined by the mean position or the POS value, wherein the indicated number shows the involvement of one or more units. The charge-transfer or Frenkel character of the excited states is defined by the CT number which assumes values closer to one for pure CT states and closer to zero for pure Frenkel states. In dimers D1 and D2, the first singlet excited state of highest oscillator strength (S2) shows Frenkel exciton character with effective delocalization of the excitons between the individual constituting units during the excitation process (Tables S5 and S6^†). The low CT values of the S2 states in D1 (PR = 1.79, POS = 1.33, CT = 0.08) and D2 (PR = 1.98, POS = 1.45, CT = 0.02) along with a PR close to a value of two indicated the delocalization of the Frenkel excitons on the two monomers. Hence, there exists a possible excitation energy delocalization along the adjacent enantiomeric stacks in the DHI crystal. However, for D3 with the bifurcated hydrogen bonding interaction between the monomeric units, both S1 and S2 states have significant oscillator strength. The Frenkel excitons in S1 and S2 states remain localized on only one fragment of D3 (Table S7^†), while in D4, there exists a partial delocalization of the Frenkel excitons in the S1 state (Table S8^†). Thus, it is understood that within each enantiomeric stack the initial Frenkel excitons remain localized on one fragment. The natural transition orbitals (NTOs) of dimers D1–4 give an idea about the nature of the dominant orbital transitions for the allowed electronic excitations. The allowed electronic excitation in all the dimers could only be well represented by taking two distinct orbital transitions with significant coefficients into consideration. The absence of a single dominant orbital transition in the dimers proposed the need for fragment-based hole–electron analysis for the better understanding of the electronic energy delocalization. The hole–electron isosurface analysis provides a pictorial representation of the corresponding delocalized and localized nature of the initial Frenkel excitons in the four DHI orientations (Fig. 3). The delocalization of the hole and electron density on both the fragments puts forward the possibility of effective energy transfer in dimers D1, D2 and D4.⁴⁶ In dimer D3, a very weak delocalization of the electron–hole densities was observed suggesting a localized exciton formation.Open in a separate windowFig. 3Hole–electron isosurface plots of the DHI orientations in the crystal. (a) D1, (b) D2, (c) D3 and (d) D4.Several factors including slight exposure to air,⁴⁷ humidity and/or light have been observed to cause the autooxidative polymerization of DHI, wherein lowered temperatures decrease the kinetics of this solid-state polymerization. Although, a major fraction of the solid oligomer mixture remains as the DHI monomer (≥80%), oligomeric units up to DHI-hexamers have been identified with varying solubilities in different solvents. MALDI-MS spectra (Appendix C5, ESI^†) sequentially collected for the oligomer mixture in CHCl₃ and DMSO indicated the major presence of DHI trimers (in CHCl₃; m/z = 442.138) and DHI-hexamers (in DMSO; m/z = 882.382) along with the smaller counterparts. Interestingly, over the time course for nucleation and the subsequent growth mechanism of the single crystals of monomeric DHI in chloroform, oligomerization of DHI is found to occur concurrently to form the covalently connected DHI trimer (DHI-T). Along with the diffracting single crystals of DHI, small right-handed double-helical crystals (non-diffracting, Fig. S1b–f and S6^†) are observed for the first time, which could be attributed to the self-assembled morphology of DHI-T (Fig. 4a). Observed only in chloroform, we speculate that the prolonged exposure of the chlorinated solvent plays a significant role in the chemical transformation of the DHI monomer to the covalent trimer, possibly through a radical initiated reaction.⁴⁸ The ¹H-NMR spectrum obtained for the bulk crystalline sample dissolved in CDCl₃ along with the observed MALDI-MS data of the DHI trimer evidenced the formation of DHI-T, although in very low yields when compared to the monomer (Appendix C5 and C6^†).Open in a separate windowFig. 4(a) Optical microscopy images of the right-handed double-helical crystals of the DHI trimer. (b) Normalized absorbance and excitation spectra showing DHI-T formation in chloroform solution and the Kubelka–Munk transformed diffuse reflectance spectrum of the DHI bulk crystal. (c) Optimized structure of DHI-T at the CAM-B3LYP/6-311g+(d,p) level of theory.With the understanding that DHI readily aggregates/crystallizes in chloroform, the directionality of the hydrogen bonding interactions (to the π-ring) within the definite spatial arrangements of D1 and D2 orientations hints towards the mode/position of coupling for the associated generation of DHI-T (Appendix C9^†). The molecular structure of the DHI trimer that best fits the observed characterization data (Fig. S7a and Appendix C8, ESI^†) is in line with the chemical disorder model having semiquinone and catechol units connected covalently as an extension of the D1 and D2 noncovalent interactions. Geometry optimization of the predicted structure of the DHI-T performed using the CAM-B3LYP/6-311g+(d,p) level of theory in Gaussian 16 suite shows a twisted conformation having the possibility of forming intramolecular hydrogen bonds from the –OH and –NH functionalities (Fig. 4 and S7b^†). Separation of DHI-T from DHI is a real challenge since exposure of DHI to the adsorbent in column chromatography accelerates the oxidative polymerization of DHI, resulting in a black, insoluble material difficult to characterize. Also, the presence of higher oligomer units of DHI (hexamers etc.) was not identified in the multiple data sets collected for the DHI sample dissolved in CHCl₃.Solvent-dependent steady-state UV-vis absorption and fluorescence emission measurements of DHI were performed and the line shapes of the absorption spectra of monomeric DHI in different solvents match consistently (Fig. S8^†). Two major absorption bands at λ_a1 ∼ 270 nm and λ_a2 ∼ 300 nm form the characteristic absorption spectrum of the DHI monomer. The fluorescence emission of monomeric DHI exhibits a single broad spectral feature peaking at λ_em ∼ 330 nm in a majority of the solvents. The relative fluorescence quantum yields are found to be exceptionally low in chloroform, dichloromethane, THF and water (Table S9^†) indicating the presence of non-radiative decay channels for dissipating the excitation energy. In chloroform, the emergence of a red-shifted tail in the absorption spectrum of the DHI-monomer is observed over time possibly signifying the onset of DHI-T formation. The fluorescence emission in CHCl₃ also shows a new band peaking at λ_em ∼ 460 nm along with the emission band at λ_em ∼ 335 nm (Fig. S9^†). A broad red-shifted band arising at 370 nm in the excitation spectrum of DHI solution collected in chloroform at λ_em ∼ 460 nm (Fig. 4b) evidenced the presence of the DHI trimer. A similar decrease in fluorescence quantum yield in chloroform and the concomitant emergence of new bands in the fluorescence emission profiles have been noted previously in tryptophan and other indole species synthesized for eumelanin investigation.^49,50 In such cases, the photoionization of excited indole leads to the ejection of a solvated electron which attacks the chloroform molecule, releasing a chloride ion, and further undergoes reactions to yield photoproducts.Spectroscopic investigation of the crystalline DHI (containing both monomer single crystals and covalent trimer crystals) sample showed broad, red-shifted absorption bands spanning from 210 to 560 nm (Fig. 4b and S10^†). The solid-state absorption spectrum shows two prominent bands at λ_a1 ∼ 280 nm and λ_a2 ∼ 305 nm which could be attributed to the red-shifted absorption bands of the crystalline DHI monomer (compared to the monomer absorption bands in the solution state). The observed red-shift in the absorption band of the DHI crystal arises from the nonplanar packing motif and the ensuing intermolecular interactions in the solid state. The presence of a broad shoulder band centred at λ_a3 ∼ 375 nm in the absorption spectrum could be assigned to the double-helical crystal of the covalent DHI trimer. The crystalline state fluorescence emission spectrum of DHI spans from 390 to 490 nm (Fig. S10^†). The excitation energies and the allowed vertical transitions of the monomer and DHI-T have been computed at the CAM-B3LYP/6-311g+(d,p) level of theory. Unlike the precursor DHI monomer which undergoes higher energy electronic transitions (at 270 nm and 300 nm), the favorable transition in the covalent trimer is red-shifted with the S₀ → S₁ electronic excitation occurring at ∼434 nm. Hence, the spectroscopic and theoretical investigation of bulk crystalline DHI indicates that the broad absorption profile of the eumelanin precursor could be ascribed to the combined effects of the non-planar chromophore stacking and the presence of covalent DHI trimers that exist as double-helical aggregates. The photoprotective nature of eumelanin arises from the signature broadband absorption of eumelanin which spans throughout the UV and visible region tailing around 800 nm as explained by the chemical disorder model. In line with this understanding, the spectroscopic data of the DHI crystal also exhibit broadband absorption which expands up to 600 nm unlike the DHI monomer. Moreover, the low relative fluorescence quantum yields of DHI suggest the presence of non-radiative decay pathways within the DHI units. The oligomeric trimer which in itself shows structural heterogeneity aggregates as double helical structures and shows a red-shifted absorption band which is comparable to the computed TDDFT vertical excitation energies. Thus, our report on the characterization of DHI and the oligomeric trimer could possibly be beneficial in advancing melanin structure characterization and elucidating the photoprotective function of eumelanin.The solid-state CD spectrum of crystalline DHI (in KBr, Fig. S11a^†) showed the signatures for the presence of helical packing^51–55 (possibly from the zig-zag helical motif along with the double helical arrangement). However, the basis of the CD couplet of significant intensity spanning from ∼250 to 600 nm (including ranges outside of the absorption maxima) could not be exclusively assigned to chiral absorption from the chromophoric packing.⁵⁶ In the case of macromolecular systems having long-range organization, differential scattering of incident left and right circularly polarized light can provide significant contributions to the observed circular dichroism.^57–59 The occurrence of broad CD bands outside the absorption bands of the macromolecule can signify the possible role of differential scattering in the circular dichroism.⁶⁰ Although, for the DHI sample, the characteristic CD spectrum has been found to be concurrent for the different data sets collected using freshly prepared crystalline samples on different days (Fig. S11a^†), the ratios of the intensities of the positive and negative bands have been observed to vary. Such a heterogeneity in the ellipticity values of the positive and negative bands could be attributed to the possible presence of different enantiomeric assemblies that exhibit varying abilities to undergo chiral absorption and differential scattering.⁵⁷ The possibility of having linear dichroism (LD) artifacts in the CD data was evaluated for the DHI sample (Fig. S11b^†).⁶¹ The LD artifact fell within the error bar of the order of 10⁻³–10⁻⁴ mdeg and hence, the contribution of LD to the strong CD signal of DHI could be ignored.^62,63 Also, the idea of having a chiral nucleation centre, probably from any conformationally chiral DHI oligomer units, leading to the double-helical aggregation and the consequent mesoscopic chirality could not be ignored while assessing the origin of the observed CD spectrum. The existing uncertainties in solving the source of the double-helical aggregation of the DHI chromophores and identifying the intermolecular forces acting behind the same remain a challenge that requires detailed examination in future studies.     

Depolymerization of supramolecular polymers by a covalent reaction; transforming an intercalator into a sequestrator

Controlling the reciprocity between chemical reactivity and supramolecular structure is a topic of great interest in the emergence of molecular complexity. In this work, we investigate the effect of a covalent reaction as a trigger to depolymerize a supramolecular assembly. We focus on the impact of an in situ thiol–ene reaction on the (co)polymerization of three derivatives of benzene-1,3,5-tricarboxamide (BTA) monomers functionalized with cysteine, hexylcysteine, and alkyl side chains: Cys-BTA, HexCys-BTA, and a-BTA. Long supramolecular polymers of Cys-BTA can be depolymerized into short dimeric aggregates of HexCys-BTAvia the in situ thiol–ene reaction. Analysis of the system by time-resolved spectroscopy and light scattering unravels the fast dynamicity of the structures and the mechanism of depolymerization. Moreover, by intercalating the reactive Cys-BTA monomer into an unreactive inert polymer, the in situ thiol–ene reaction transforms the intercalator into a sequestrator and induces the depolymerization of the unreactive polymer. This work shows that the implementation of reactivity into supramolecular assemblies enables temporal control of depolymerization processes, which can bring us one step closer to understanding the interplay between non-covalent and covalent chemistry.

We report on the controlled depolymerization of supramolecular 1D polymers into well-defined dimers triggered by a covalent reaction on the side chains of the monomer.     

Molecular insights into chirality transfer from double axially chiral phosphoric acid in a synergistic enantioselective intramolecular amination

In the most general practice of asymmetric catalysis, a chiral catalyst, typically bearing a center or an axis of chirality, is employed as the chiral source for imparting enantiocontrol over the developing product. Given the current interest toward optically pure compounds, various forms of chiral induction enabled by diverse chiral sources as well as the use of multiple catalysts under one-pot conditions have been in focus. In one such promising development, an achiral N-sulfonamide protected 1,6-amino allyl alcohol (NaphSO₂NHCH₂C(Ph)₂CH₂CH CHCH₂OH) was subjected to Tsuji–Trost activation and an intramolecular amination to form important chiral pyrrolidine frameworks. A dual catalytic system comprising Pd(PPh₃)₄ and DAPCy (β-cyclohexyl substituted double axially chiral phosphoric acid derived from two homocoupled BINOL backbones with a dynamic central chiral axis) under mild conditions was reported to offer quantitative conversion with an ee of 95%. Here, we provide molecular insights into the origin of chiral induction by DAPCy, as obtained through a comprehensive density functional theory (SMD_(toluene)/B3LYP-D3/6-31G**,Pd(SDD)) investigation. Two key steps in the mechanism are identified to involve a cooperative mode of activation of the Pd-bound allyl alcohol in the form of a Pd-π-allyl moiety at one end of the substrate, followed by an intramolecular nucleophilic addition of N-sulfonamide from the other end to yield a pyrrolidine derivative bearing an α-vinyl stereogenic center. (S,R,S)-DAPCy is found to steer the dehydroxylation to yield a Pd-π-allyl intermediate with a suitably poised si prochiral face for the nucleophilic addition. In the enantiocontrolled (as well as the turn-over determining step) nucleophilic addition, the chiral catalyst is identified to serve as a chiral phosphate counterion. The chiral induction is facilitated by a series of N–H⋯O, C–H⋯O, C–H⋯π, lone pair (lp)⋯π, O–H⋯O, O–H⋯π, and π⋯π noncovalent interactions, which is noted as more effective in the lower energy C–N bond formation transition state through the si prochiral face of the Pd-π-allyl moiety. These insights into the novel dynamic axially double chiral catalyst could be valuable toward exploiting such modes of stereoinduction.

The origin of enantiocontrol in an intramolecular amination involving Pd(PPh₃)₄ and a double axially chiral phosphoric acid (DAPCy) dual catalytic system is traced to a more effective series of noncovalent interactions in the lower energy C–N bond formation transition state.     

Selective adsorptive separation of cyclohexane over benzene using thienothiophene cages

The selective separation of benzene (Bz) and cyclohexane (Cy) is one of the most challenging chemical separations in the petrochemical and oil industries. In this work, we report an environmentally friendly and energy saving approach to separate Cy over Bz using thienothiophene cages (ThT-cages) with adaptive porosity. Interestingly, cyclohexane was readily captured selectively from an equimolar benzene/cyclohexane mixture with a purity of 94%. This high selectivity arises from the C–H⋯S, C–H⋯π and C–H⋯N interactions between Cy and the thienothiophene ligand. Reversible transformation between the nonporous guest-free structure and the host–guest assembly, endows this system with excellent recyclability with minimal energy requirements.

Selective adsorptive separation of cyclohexane was realized from an equimolar benzene and cyclohexane mixture via crystalline thienothiophene cages with a selectivity of 94%.     

Direct evidence for distinct colour origins in ROY polymorphs

ROY is one of the most well-studied families of crystal structures owing to it being the most polymorphic organic material on record. The various red, orange, and yellow colours of its crystal structures are widely-believed to originate from molecular conformation, though the orange needle (ON) polymorph is thought to be an exception. We report high-pressure, single-crystal X-ray measurements which provide direct experimental evidence that the colour origin in ON is intermolecular, revealing that the molecule undergoes minimal deformation but still exhibits a pronounced, reversible, pale orange → dark red colour change between ambient pressure and 4.18 GPa. Our experimental data are rationalised with band structures, calculated using an accurate hybrid DFT approach, where we are able to account for the variation in colour for five polymorphs of ROY. We highlight the outlier behaviour of ON which shows marked π⋯π stacking interactions that are directly modified through application of pressure. Band structure calculations confirm these intermolecular interactions as the origin of the colour change.

Alternative colour origins in ROY polymorphs are conclusively determined for the first time, using high-pressure diffraction and hybrid DFT.     

Adsorptive separation of cyclohexanol and cyclohexanone by nonporous adaptive crystals of RhombicArene

As feedstock chemicals with similar boiling points, cyclohexanol (CHOL) and cyclohexanone (CHON) are often obtained as mixtures during production processes. Separation of mixed CHOL and CHON is important but energy-consuming by distillation. Here we report the development of a new macrocycle RhombicArene, which forms a host–guest complex with CHON through C–H⋯π interactions and hydrogen bonds. The nonporous adaptive crystals of RhombicArene exhibit excellent capability for rapid (30 minutes), exclusive (>99.9%), and recyclable vapor adsorption of CHON in the presence of CHOL under mild and user-friendly conditions.

The novel macrocycle RhombicArene features excellent capability for rapid, exclusive, and recyclable vapor adsorption of cyclohexanone in the presence of cyclohexanol, showing potential for energy-saving separation of these feedstock chemicals.     

DNA-templated control of chirality and efficient energy transport in supramolecular DNA architectures with aggregation-induced emission

Two conjugates of tetraphenylethylene with d-2′-deoxyuridine (1d) and l-2′-deoxyuridine (1l) were synthesized to construct new supramolecular DNA-architectures by self-assembly. The non-templated assemblies of 1d and 1l show strong aggregation-induced emission and their chirality is exclusively controlled by the configuration of their sugar part. In contrast, the chirality of the DNA-templated assemblies is governed by the configuration of the DNA, and there is no configuration-selective binding of 1d to d-A₂₀ and 1l to l-A₂₀. The quantum yield of the assembly of 1d along the single-stranded DNA A₂₀ is 0.40; approximately every second available binding site on the DNA template is occupied by 1d. The strong aggregation-induced emission of these DNA architectures can be efficiently quenched and the excitation energy can be transported to Atto dyes at the 5′-terminus. A multistep energy transport “hopping” precedes the final energy transfer to the terminal acceptor. The building block 1d promotes this energy transport as stepping stones. This was elucidated by reference DNA double strands in which 1d was covalently incorporated at two distinct sites in the sequences, one near the Atto dye, and one farther away. This new type of completely self-assembled supramolecular DNA architecture is hierarchically ordered and the DNA template controls not only the binding but also the energy transport properties. The high intensity of the aggregation-induced emission and the excellent energy transport properties make these DNA-based materials promising candidates for optoelectronic applications.

DNA architectures with tetraphenylethylene are assembled in a non-covalent way. The strong aggregation-induced emission of the chromophores is quenched and the energy is transported to Atto dyes by a multistep energy “hopping”.     

By-design molecular architectures via alkyne metathesis

Shape-persistent purely organic molecular architectures have attracted tremendous research interest in the past few decades. Dynamic Covalent Chemistry (DCvC), which deals with reversible covalent bond formation reactions, has emerged as an efficient synthetic approach for constructing these well-defined molecular architectures. Among various dynamic linkages, the formation of ethynylene linkages through dynamic alkyne metathesis is of particular interest due to their high chemical stability, linearity, and rigidity. In this review, we focus on the synthetic strategies of discrete molecular architectures (e.g., macrocycles, molecular cages) containing ethynylene linkages using alkyne metathesis as the key step, and their applications. We will introduce the history and challenges in the synthesis of those architectures via alkyne metathesis, the development of alkyne metathesis catalysts, the reported novel macrocycle structures, molecular cage structures, and their applications. In the end, we offer an outlook of this field and remaining challenges.

The recent synthesis of novel shape-persistent 2D and 3D molecular architectures via alkyne metathesis is reviewed and the critical role of catalysts is also highlighted.     

Uncovering an oxide ion substitution for the OH− + CH3F reaction

Theoretical investigations on chemical reactions allow us to understand the dynamics of the possible pathways and identify new unexpected routes. Here, we develop a global analytical potential energy surface (PES) for the OH⁻ + CH₃F reaction in order to perform high-level dynamics simulations. Besides bimolecular nucleophilic substitution (S_N2) and proton abstraction, our quasi-classical trajectory computations reveal a novel oxide ion substitution leading to the HF + CH₃O⁻ products. This exothermic reaction pathway occurs via the CH₃OH⋯F⁻ deep potential well of the S_N2 product channel as a result of a proton abstraction from the hydroxyl group by the fluoride ion. The present detailed dynamics study of the OH⁻ + CH₃F reaction focusing on the surprising oxide ion substitution demonstrates how incomplete our knowledge is of fundamental chemical reactions.

Reaction dynamics simulations on a high-level ab initio analytical potential energy surface reveal a novel oxide ion substitution channel for the OH⁻ + CH₃F reaction.     

When are two hydrogen bonds better than one? Accurate first-principles models explain the balance of hydrogen bond donors and acceptors found in proteins

Hydrogen bonds (HBs) play an essential role in the structure and catalytic action of enzymes, but a complete understanding of HBs in proteins challenges the resolution of modern structural (i.e., X-ray diffraction) techniques and mandates computationally demanding electronic structure methods from correlated wavefunction theory for predictive accuracy. Numerous amino acid sidechains contain functional groups (e.g., hydroxyls in Ser/Thr or Tyr and amides in Asn/Gln) that can act as either HB acceptors or donors (HBA/HBD) and even form simultaneous, ambifunctional HB interactions. To understand the relative energetic benefit of each interaction, we characterize the potential energy surfaces of representative model systems with accurate coupled cluster theory calculations. To reveal the relationship of these energetics to the balance of these interactions in proteins, we curate a set of 4000 HBs, of which >500 are ambifunctional HBs, in high-resolution protein structures. We show that our model systems accurately predict the favored HB structural properties. Differences are apparent in HBA/HBD preference for aromatic Tyr versus aliphatic Ser/Thr hydroxyls because Tyr forms significantly stronger O–H⋯O HBs than N–H⋯O HBs in contrast to comparable strengths of the two for Ser/Thr. Despite this residue-specific distinction, all models of residue pairs indicate an energetic benefit for simultaneous HBA and HBD interactions in an ambifunctional HB. Although the stabilization is less than the additive maximum due both to geometric constraints and many-body electronic effects, a wide range of ambifunctional HB geometries are more favorable than any single HB interaction.

Correlated wavefunction theory predicts and high-resolution crystal structure analysis confirms the important, stabilizing effect of simultaneous hydrogen bond donor and acceptor interactions in proteins.     

Tuning energy landscapes and metal–metal interactions in supramolecular polymers regulated by coordination geometry

Herein, we exploit coordination geometry as a new tool to regulate the non-covalent interactions, photophysical properties and energy landscape of supramolecular polymers. To this end, we have designed two self-assembled Pt(ii) complexes 1 and 2 that feature an identical aromatic surface, but differ in the coordination and molecular geometry (linear vs. V-shaped) as a result of judicious ligand choice (monodentate pyridine vs. bidentate bipyridine). Even though both complexes form cooperative supramolecular polymers in methylcyclohexane, their supramolecular and photophysical behaviour differ significantly: while the high preorganization of the bipyridine-based complex 1 enables an H-type 1D stacking with short Pt⋯Pt contacts via a two-step consecutive process, the existence of increased steric effects for the pyridyl-based derivative 2 hinders the formation of metal–metal contacts and induces a single aggregation process into large bundles of fibers. Ultimately, this fine control of Pt⋯Pt distances leads to tuneable luminescence—red for 1vs. blue for 2, which highlights the relevance of coordination geometry for the development of functional supramolecular materials.

In this article, we exploit coordination geometry as a new tool to control the energy landscape and photophysical properties (red vs. blue luminescence) of supramolecular polymers.     

Design and recognition of cucurbituril-secured platinum-bound oligopeptides

Platinum terpyridyl complexes, stacked on top of one another and secured as dimers with cucurbit[8]uril (CB[8]) in aqueous medium, were functionalized quantitatively and in situ with a pair of pentapeptides Phe-(Gly)₃-Cys by grafting their cysteine residues to the Pt centers. The resulting CB[8]·(Pt·peptide)₂ assemblies were used to target secondary hosts CB[7] and CB[8] via their pair of phenylalanine residues, again in situ. A series of well-defined architectures, including a supramolecular “pendant necklace” with hybrid head-to-head and head-to-tail arrangements inside CB[8], were obtained during the self-sorting process after combining only 3 or 4 simple building units.

A platinum terpyridyl complex, pentapeptide Phe-(Gly)₃-Cys and cucurbit[8]uril assemble into a “pendant necklace” with hybrid head-to-head and head-to-tail arrangements in aqueous medium.     

Observations of tetrel bonding between sp3-carbon and THF

We report the direct observation of tetrel bonding interactions between sp³-carbons of the supramolecular synthon 3,3-dimethyl-tetracyanocyclopropane (1) and tetrahydrofuran in the gas and crystalline phase. The intermolecular contact is established via σ-holes and is driven mainly by electrostatic forces. The complex manifests distinct binding geometries when captured in the crystalline phase and in the gas phase. We elucidate these binding trends using complementary gas phase quantum chemical calculations and find a total binding energy of −11.2 kcal mol⁻¹ for the adduct. Our observations pave the way for novel strategies to engineer sp³-C centred non-covalent bonding schemes for supramolecular chemistry.

sp³-C⋯THF tetrel bonding was observed in the crystalline state and in the gas phase. Density functional calculations revealed interaction energies up to −11.2 kcal mol⁻¹ and showed that these adducts are held together mainly by electrostatics.     

Analog quantum simulation of chemical dynamics

Ultrafast chemical reactions are difficult to simulate because they involve entangled, many-body wavefunctions whose computational complexity grows rapidly with molecular size. In photochemistry, the breakdown of the Born–Oppenheimer approximation further complicates the problem by entangling nuclear and electronic degrees of freedom. Here, we show that analog quantum simulators can efficiently simulate molecular dynamics using commonly available bosonic modes to represent molecular vibrations. Our approach can be implemented in any device with a qudit controllably coupled to bosonic oscillators and with quantum hardware resources that scale linearly with molecular size, and offers significant resource savings compared to digital quantum simulation algorithms. Advantages of our approach include a time resolution orders of magnitude better than ultrafast spectroscopy, the ability to simulate large molecules with limited hardware using a Suzuki–Trotter expansion, and the ability to implement realistic system-bath interactions with only one additional interaction per mode. Our approach can be implemented with current technology; e.g., the conical intersection in pyrazine can be simulated using a single trapped ion. Therefore, we expect our method will enable classically intractable chemical dynamics simulations in the near term.

Dynamics governing ultrafast chemical reactions can be efficiently simulated using analog quantum simulators composed of a coupled system of qudits and bosonic modes.     

Bottom-up supramolecular assembly in two dimensions

The self-assembly of molecules in two dimensions (2D) is gathering attention from all disciplines across the chemical sciences. Attracted by the interesting properties of two-dimensional inorganic analogues, monomers of different chemical natures are being explored for the assembly of dynamic 2D systems. Although many important discoveries have been already achieved, great challenges are still to be addressed in this field. Hierarchical multicomponent assembly, directional non-covalent growth and internal structural control are a just a few of the examples that will be discussed in this perspective about the exciting present and the bright future of two-dimensional supramolecular assemblies.

The self-assembly of molecules in two dimensions (2D) is gathering attention from all disciplines across the chemical sciences. This perspective discusses the main strategies to direct the supramolecular self-assembly of organic monomers in 2D.