Heterochiral Diastereomer-Discriminative Diphanes That Form Hierarchical Superstructures with Nonlinear Optical Properties

In order to study the emergence of homochirality during complex molecular systems, most works mainly concentrated on the resolution of a pair of enantiomers. However, the preference of homochiral over heterochiral isomers has been overlooked, with very limited examples focusing only on noncovalent interactions. We herein report on diastereomeric discrimination of twin-cavity cages (denoted as diphanes) against heterochiral tris-(2-aminopropyl)amine (TRPN) bearing triple stereocenters. This diastereomeric selectivity results from distinct spatial orientation of reactive secondary amines on TRPN. Homochiral TRPNs with all reactive moieties rotating in the same way facilitate the formation of homochiral and achiral meso diphanes with low strain energy, while heterochiral TRPNs with uneven orientation of secondary amines preclude the formation of cage-like entity, since the virtual diphanes exhibit considerably high strain. Moreover, homochiral diphanes self-assemble into an acentric superstructure composed of single-handed helices, which exhibits interesting nonlinear optical behavior. Such a property is a unique occurrence for organic cages, which thus showcases their potential to spawn novel materials with interesting properties and functions.


■ INTRODUCTION
Life employs chirality as a pervasive tool from molecular to macroscopic scales to realize self-reproduction and physiological functions, 1 and yet the selection of homochirality remains mysterious. 2 Since Pasteur's seminal work on chiral resolution of enantiomers from tartrate racemates during crystallization, 3 numerous artificial systems have been developed for a mechanistic interpretation of emergence of homochirality in molecular 4 and supramolecular 5 levels. The majority of these works focused on deracemization and/or chiral resolution from a pair of enantiomers. On the other hand, how homochiral isomers are favored over their heterochiral counterparts in multiple diastereomer-containing systems has been rarely studied, 6 and the insofar limited examples exclusively exploited noncovalent interactions.
In the present work, we have devised a model study to investigate if nonchiral molecules can distinguish homochiral isomers from their heterochiral analogues. To this end, a nonchiral hourglass-like hexa-aldehyde precursor is chosen to react with tris-(2-aminopropyl)amine (TRPN) bearing three chiral centers, which might form a twin-cavity cage denoted as diphane (Figure 1). 7 An organic cage 8 is deemed as an ideal model for such a purpose: (i) the reversible nature of dynamic covalent chemistry (DCC) involved in its synthesis favors the formation of the thermodynamic product; (ii) its formation results from a delicate interplay between its three-dimensional framework and the spatial orientation of the multiple stereocenters within TRPN. By using experimental and theoretical approaches, we will elucidate the rationale behind the selective formation of homochiral diphanes and their achiral meso counterpart.
We also investigate the self-assembly of homochiral and achiral diphanes, which serve as supramolecular building blocks for the construction of hierarchical superstructures. With the aids of single-crystal X-ray diffraction (SC-XRD) and circular dichroism (CD), we reveal that this configurational change of the cages yields superstructures with dramatically different molecular packing. 9 It in turn results in distinct emergent functions, as demonstrated by their second-order nonlinear optical (NLO) properties as a proof of concept ( Figure 1).
with NaBH(AcO) 3 , which yielded rac-3 in the amine form so as to facilitate the product purification. The careful characterization of rac-3 will be discussed in the next session ( Figure 2). On the other hand, the reaction between precursor 1 and heterochiral TRPN was unable to yield any cage entity. This scenario was exemplified with hetero-2 containing equal amount of epimers (2R1S)-and (1R2S)-TRPN ( Figure S4). Out of 21 possible isomeric diphanes ( Figure S7), none was formed with hetero-2, as they were even undetectable by MALDI-TOF MS (Figures S18 and S19).
This striking difference is that during the formation of a cage-like entity with a three-dimensional skeleton, nonchiral hexa-aldehyde 1 obviously prefers the homochiral to heterochiral isomers, although the reaction with the latter cannot be excluded in the resulting oligomers with an illdefined structure. Taking (3R)-TRPN (one enantiomer in rac-2) and (2R1S)-TRPN (one epimer in hetero-2) for comparison, their different spatial orientation can be revealed by density functional theory (DFT with geometry optimization, M06-2X/6-31G*, Figure 3a). The three aliphatic chains of (3R)-TRPN all rotate anticlockwise, with three secondary amines being positioned in the same way; while the three aliphatic chains of (2R1S)-2 are arranged in an uneven fashion, as one secondary amine rotates to the opposite direction of the other two.
We reasoned that the spatial orientation of these reactive amines might dramatically alter the formation possibility of diphanes. This hypothesis was probed by the comparison of SE of the diphanes (or virtual products) in the imine form ( Figure  3b). 7b DFT calculations show that (3R,3R)-3′ exhibits a similar strain to that of mesomer (3R,3S)-3′ (122.6 vs 119.9 kJ mol −1 ). This strain is lower than those of virtual diphanes formed with heterochiral precursors, with the representative examples of (2R1S,2R1S)-3′ with SE = 127.6 kJ mol −1 and (2R1S,1R2S)-3′ with SE = 127.2 kJ mol −1 . Together with the experimental evidence, this significantly different SE therefore precludes the reaction with heterochiral TRPN during the formation of diphanes.

Formation of Homochiral and Achiral Meso Diphanes
As mentioned above, the condensation between precursor 1 with rac-2 successfully yielded diphane in the imine form, which was then converted to the corresponding rac-3 in the amine form to facilitate product purification ( Figure 2a). We successfully resolved rac-3 by chiral HPLC, which consists of three isomeric fractions in a 1:1:2 ratio (Figure 2b), respectively assigned to a pair of homochiral (3R,3R)-3 and (3S,3S)-3, and an achiral mesomer (3R,3S)-3 with reference compounds synthesized beforehand ( Figures S5 and S6). In the 1 H NMR spectrum of rac-3, the sharp singlet at δ = 7.03 ppm and the doublet at δ = 4.06 ppm refer to homochiral diphane (3R,3R)-3 or (3S,3S)-3, while the broad peak at δ = 7.06 ppm and the doublet at δ = 3.95 ppm correspond to the mesomer (3R,3S)-3 (lower panel in Figure 2c, see assignment in Figure S64). This product distribution in rac-3 is in accordance with DFT calculations, which showed little SE difference between the diphanes in the imine form ( Figure 3, vide supra).
Electronic CD spectra of the three diphanes in tetrahydrofuran (THF) solutions were recorded ( Figure 2d). Owing to similar structures, they share almost identical UV−vis absorption spectra. They all display a featureless absorption peak at ca. 250 nm, which is assigned to the π → π* transitions of the twisted arenes in the cage skeleton. Obviously, meso diphane (3R,3S)-3 is CD-silent due to the presence of the inversion center, while the two homochiral diphanes exhibit a mirror-image profile over the range between 220 and 300 nm, as expected for the enantiomeric pair.
Diphane (3R,3R)-3 displays a positive cotton effect at 263 nm, followed by a negative one at 250 nm. This bisignate CD curve from longer to shorter wavelength (300−245 nm) is assigned to the P-configuration of three biphenyl arms of each propeller-like cavity. Similarly, the negative-to-positive bisignate curve is attributed to the M-configuration of diphane (3S,3S)-3. As compared to the previously reported singlecavity cages, 10,11 the value for the anisotropy factor of two chiral diphanes is relatively low (g abs = 0.0004 at 240 nm). This low value probably results from the relatively higher symmetry of the upper and lower halves of the diphanes (Figure 4a, vide infra).

3D Hierarchical Structures Self-Assembled by Homochiral and Meso Diphanes
We 9b,12b,c and other groups 8b,10b,12a,d,e have demonstrated that cage-like compounds could serve as promising self-assembling tectons for the search of novel supramolecular materials. As part of our continuous endeavor, we investigated the selfassembly behavior of homochiral and achiral meso diphanes in their crystalline phases. We were particularly interested in the effect of configurational change on the resulting hierarchical superstructures.
Its crystallographic analysis confirms the proposed structure of (3R,3R)-3 with two identical cavities (Figures 4a and S9). Each cavity exhibits a diameter of 10.6 Å and a height of 6.4 Å. From the top view of a diphane, three aliphatic chains of each cavity adopt a clockwise rotation (cyan arrows, Figure 4a), which also holds true for the three methyl groups at the Rstereogenic centers. This clockwise rotation also induces the Pconfiguration of three biphenyl arms surrounding each cavity, in line with its CD spectrum (Figure 2d, vide supra).
Careful inspection of molecular packing of the homochiral diphanes reveals that each crystalline phase is a hierarchical superstructure, which share the similarity with those formed by biomacromolecules, block copolymers, and dendimers. 13 Serving as the primary structure, two (3R,3R)-3 molecules self-assemble into a supramolecular dimer (secondary structure), simplified with a cuboid model, where the two adjacent diphanes are packed via quadruple C−H···π interactions (with d 1 = 2.9 Å and d 2 = 3.1 Å, Figures 4b and  S10).
These dimers are arranged off crystallographic c-axis, around which a dimer rotates by 120°with respect to another, forming a single-handed 3 2 -helix (tertiary structure) with a pitch of 41.9 Å (Figure 4c). Besides, along the helix, each diphane in the dimer below is packed with another diphane in the dimer above via C−H···π interaction with a distance of 2.8 Å (Figure 4c and S10). One helix is consequently packed in parallel with six neighboring helices via a network of C−H···π interactions (d 4 = 2.8 Å), as presented with the simplified spring-like model (Figures 4d and S11). This hierarchical self-assembly thus yields an acentric trigonal crystalline phase (quaternary structure), which is composed of an array of left-handed helices. 6c,6,14 The superstructure of achiral (3R,3S)-3 was also examined by XRD analysis of the single crystals obtained via slow evaporation of its solution in CHCl 3 /CH 3 OH = 1:4 (v/v) at a concentration of 15 mg/mL. (3R,3S)-3 molecules instead crystallized into centrosymmetric crystalline phase of triclinic

JACS Au pubs.acs.org/jacsau
Article space group P1̅ . The detailed structural analysis of this superstructure is illustrated in Figure S14.

NLO Properties of Hierarchical Superstructures Self-Assembled by Homochiral and Achiral Meso Diphanes
As mentioned above, diphanes (3S,3S)-/(3R,3R)-3 and (3R,3S)-3 respectively self-assemble into acentric and centrosymmetric superstructures, which may endow them with different properties and functions. As a proof of concept, we explored their quadratic NLO effect, namely, SHG activity. In a typical SHG process, as mediated by the transition through a virtual energy state, two incident photons with frequency ω interact within an acentric medium, which subsequently are converted into an emitted photon with a doubled frequency 2ω (inset in Figure 5c). Compared to conventional inorganic dielectrics and semiconductors, organic NLO counterparts exhibit advantages such as light weight, large nonlinear coefficient, and flexibility, 15 which thus hold promise for the application in soft photo-electronics and photonics. We first irradiated the single crystals of diphanes (3S,3S)-3, (3R,3R)-3, and (3R,3S)-3 with a Nd-yttrium-aluminum-garnet (Nd:YAG) laser beam (1064 nm, 20 Hz, 8 ns) at an angle of 45°. As shown with partial optical (Figure 5a) and SHG mapping (Figure 5b) images of a (3R,3R)-3 single crystal, for example, it exhibits a clear SHG response at 532 nm (right side of the dashed line), which is only active for the noncentrosymmetric crystalline phase. This is evident when compared with the substrate on which the crystal is deposited (left side of the dashed line, Figure 5b), where negligible output was observed. On the other hand, no SHG signal was detected for the centrosymmetric crystalline phase of achiral (3R,3S)-3 ( Figure S15c). When the SHG response of the three diphanes was recorded in the transmission direction, the difference is unambiguous, as both homochiral (3S,3S)-3 and (3R,3R)-3 display strong and sharp peaks, while that of (3R,3S)-3 is near zero (Figure 5b). It is worth noting that we intentionally selected different sizes of single crystals of the two diphanes, so as to avoid the overlap of their SHG intensity. 16 To further explore the NLO property of the superstructures formed by homochiral diphanes, at a fixed pumping power, the wavelength-dependent SHG behavior 15b,16 of a (3R,3R)-3 single crystal was investigated with different wavelengths (λ ex = 840−1080 nm, Figure 5d). It shows that the intensity of optical signals indeed varies with wavelength, with the highest photoluminescence intensity under excitation at λ ex = 960 nm. Moreover, both the fitted linear relationship between SHG intensity (λ em = 480 nm) and excitation power (W, λ ex = 960 nm) on a logarithmic scale also reveals a typical second-order NLO behavior (Figure 5e).

■ CONCLUSIONS
In summary, we showed that among heterochiral and homochiral TRPN diastereomers, only the enantiomeric pair of homochiral isomers were selected by nonchiral hexaaldehyde precursor 1 via cycloimination, forming the corresponding homochiral cages with twin-cavity (denoted (3R,3R)-/(3S,3S)-diphane) and their mesomer (3R,3S)diphane. As revealed by DFT calculations, this discrimination of heterochiral isomers results from the different spatial orientation of reactive amines of TRPN. This example is distinct from the previous findings showing a similar reactivity of diastereomeric synthons under DCC conditions. 17 We also showed that the self-assembly of homo-and achiral diphanes is dramatically different. The former forms an array of single-handed supramolecular helices with interesting secondorder NLO properties, while the latter self-assembles into the centrosymmetric supramolecular columnar phase. Different from the current research focus of organic cages on their design, synthesis, and host−guest utility of their porosity, 8 our study showcases their promise with a tailored shape and structure for the search of a novel hierarchical superstructure with emergent properties and functions, which include but are not limited to nonlinear optics, bulk photovoltaics, and organic ferroelectrics. These topics are currently ongoing in our laboratories, which will be reported in due course.

General Instrumentation
Nuclear magnetic resonance (NMR) spectra were performed on a Bruker Avance III HD 400 spectrometer at room temperature. MALDI-TOF MS was performed on a solariX XR 7.0 T hybrid quadrupole−FT ICR mass spectrometer (Bruker Daltonics, Bremen, Germany), using an ESI/APCI/MALDI ion source and external ion accumulation in positive ion mode. SC-XRD data were collected on a Bruker D8 Venture diffractometer. CD spectra were recorded on a Jasco J-1500 spectrometer at 25°C. Analytical HPLC was conducted on a Shimadzu LC-20 AD system at 30°C. The SHG measurement was conducted using a titanium−sapphire pulsed laser (Coherent, 140 fs pulse width, 80 MHz repetition rate).