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Solvent-free autocatalytic supramolecular polymerization

Solvent-free chemical manufacturing is one of the awaited technologies for addressing an emergent issue of environmental pollution. Here, we report solvent-free autocatalytic supramolecular polymerization (SF-ASP), which provides an inhibition-free template-assisted catalytic organic transformation that takes great advantage of the fact that the product (template) undergoes a termination-free nucleation–elongation assembly (living supramolecular polymerization) under solvent-free conditions. SF-ASP allows for reductive cyclotetramerization of hydrogen-bonding phthalonitriles into the corresponding phthalocyanines in exceptionally high yields (>80%). SF-ASP requires the growing polymer to form hexagonally packed crystalline fibres, which possibly preorganize the phthalonitriles at their cross-sectional edges for their efficient transformation. With metal oleates, SF-ASP produces single-crystalline fibres of metallophthalocyanines again in exceptionally high yields, which grow in both directions without terminal coupling until the phthalonitrile precursors are completely consumed. By taking advantage of this living nature of polymerization, multistep SF-ASP without/with metal oleates allows for the precision synthesis of multi-block supramolecular copolymers. The solvent-free conversion of phthalonitrile derivatives into phthalocyanines in the bulk is described, involving a reductive cyclotetramerization step and the formation of one-dimensional single-crystalline fibres. This solvent-free autocatalytic supramolecular polymerization may enable for a sustainable fabrication of multi-block supramolecular copolymers.


reversibly preorganize reactants A and B in the form of a ternary complex [A•T•B], which facilitates the reaction between A and B
to produce T•T (refs. 21,22 ). However, if T•T does not serve as the template, the expected autocatalytic behaviour would not emerge unless T•T dissociates into monomeric T. This is called 'product inhibition' . In 2010, Otto and coworkers reported a seminal work that, in the reversible oxidative cyclization of a dithiol having a β-sheet-forming peptide spacer, macrocyclic products with certain ring sizes, such as cyclic hexamers and heptamers, are selectively produced with a typical sigmoidal time-course profile if a shear force is continuously applied to the reaction mixture 23 . Why does the shear force have to be applied? In this case, the macrocycles selectively produced serve to template the macrocyclization. However, they tend to stack into nanofibres in the reaction medium, and such nanofibres also tend to combine together at their cross-sectional edges. Consequently, the concentration of active templates decreases, thereby hampering the autocatalytic process. However, if a shear force is continuously applied, the nanofibres can be cut into numerous short pieces with active edges for templating the reaction 24 . The decrease in active template concentration due to product inhibition and/or template aggregation is an essential problem in nonbiological organic autocatalysis and usually makes the expected sigmoidal time-course profile very obscure [25][26][27] . Otto and coworkers successfully avoided this problem. However, because the oxidative cyclization they used is intrinsically reversible, they have also suggested a possibility that the observed selectivity might be partly due to an equilibrium shift caused by the removal of preferred products as nanofibres 23 . In contrast with organic autocatalysis described above, some inorganic nanocrystals are known to form in an inhibition-free autocatalytic manner, where precursor metal ions in aqueous media preferentially adsorb onto the surface of seed nanocrystals and are electronically reduced to become a part of the nanocrystals to grow 28,29 .
How can inhibition-free organic autocatalysis be achieved? Autocatalysis generally requires high dilution to avoid the assembly of products that act as templates. This creates a high barrier for its practical application to the large-scale manufacturing of chemicals. In contrast, self-replication events in living organisms usually operate far from thermodynamic equilibrium and, along this line, artificial out-of-equilibrium systems using chemical fuels 30 , chemical oscillations 31 , kinetic trapping 32,33 and microfluidic diffusion 34 as driving forces have recently been investigated. The SF-ASP ( Fig.  1a) reported here is very unique, because the monomer is autocatalytically produced in situ from its precursor in a very high yield. The monomers for SF-ASP are phthalocyanine ( H PC Cn ) derivatives (Fig. 1b, left), which are produced via reductive cyclotetramerization of their phthalonitrile (PN Cn ) precursors ( Fig. 1c) that adopt a fan shape with H-bonding amide groups. In SF-ASP, H PC Cn monomer, if any is produced, nucleates and initiates H-bonding-mediated supramolecular polymerization to give one-dimensional (1D) single-crystalline fibres, which possibly preorganize PN Cn molecules via an H-bonding interaction at the cross-sectional fibre edges and efficiently template their reductive cyclotetramerization to give H PC Cn in an autocatalytic manner (Fig. 1a). When SF-ASP is conducted in the presence of metal oleates, metal complexes of phthalocyanines ( M PC C4 ; Fig. 1b, right) solely form in an autocatalytic manner without contamination of their free bases. We serendipitously found the basic principle of SF-ASP (Figs. 1a and 2a,b) during a study on the ferroelectric nature of H-bonding PN derivatives 35 , where green-coloured thin fibres formed and elongated on heating liquid-crystalline PN C4 (Fig. 1c) on a hot stage. As described in Methods, a powdery sample of PN C4 , sandwiched between glass plates, was heated to a hot melt and kept at 160 °C for 15 h. Approximately 4 h after heating, numerous green-coloured thin fibres began to appear and then developed entirely and elongated abruptly ( Fig. 2c and Supplementary Video 1). By matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (Fig. 2d, black), we found that the fibres obtained in 24 h were composed of phthalocyanine H PC C4 (Fig. 1b), while no precursor PN C4 was detected. This crude product, when simply washed with methanol, gave analytically pure H PC C4 (Supplementary Fig. 1). A change in the absorption intensity at 700 nm assignable to H PC C4 ( Supplementary Fig. 1d) clearly showed a sigmoidal time-course profile (Fig. 2a, black). Further systematic studies revealed that SF-ASP using PN C4 can be considerably affected by the reaction temperature . As shown in Fig. 2b and Supplementary Table 1, when SF-ASP was carried out by elevating the temperature from 160 to 190 °C, the yield of H PC C4 after 24 h was considerably enhanced from 53 to 83%. This value is far better than those reported for the ordinary solution-phase synthesis of H PC derivatives (20-25%, Supplementary Methods). However, when the temperature was elevated further, the yield of H PC C4 started to drop due to the formation of a considerable amount of side products. Similar to the case of PN C4 , SF-ASP using PN C3 carrying shorter hydrocarbon side chains (Fig. 1c) showed a sigmoidal kinetic profile (Fig. 2a, green), affording thin fibres of H PC C3 (Figs. 1b and 2e) in high yield (87%) and high selectivity (Fig. 2d, green).
We likewise heated PN C5 and PN C6 containing longer hydrocarbon chains than PN C4 (Fig. 1c) but did not observe any autocatalytic feature (Fig. 2a, orange and blue, respectively). For example, the reaction mixture of PN C6 on heating at 160 °C was entirely green with no fibrous assembly (Fig. 2e). MALDI-TOF mass spectrometry of the reaction mixture (Fig. 2d, blue) showed poor selectivity for H PC C6 ( Fig. 1b and Supplementary Table 2). Although heating PN C5 at 160 °C resulted in the formation of short green fibres (  Table 2).
A study using polarizing optical microscopy (POM) (Fig.  3a) revealed that the as-formed H PC C4 fibres obtained by SF-ASP were highly crystalline. Powder X-ray diffraction (PXRD) analysis ( Fig. 3b) of the crystalline fibres of as-formed H PC C4 , denoted hereafter as [ H PC C4 ] CF (CF refers to crystalline fibre), displayed intense diffraction peaks that were indexed to those for a hexagonally packed columnar assembly (Fig. 3b, inset). Notably, through-view two-dimensional (2D) small-angle X-ray scattering (SAXS) analysis of a single fibre of [ H PC C4 ] CF (Fig. 3c) revealed a single-crystal-like pattern, where spot-type reflections assignable to the (100), (110) and (300) planes of the hexagonal geometry appeared only in the direction perpendicular to the c axis of the crystalline lattice. This result demonstrates that the crystalline lattice of [ H PC C4 ] CF aligns along the longer axis of the fibre (Fig. 3b, inset). Its selected-area electron diffraction (SAED) pattern ( Fig.  3d) displayed two symmetric spots that were indexed to the (001) plane in the direction along the longer axis of the fibres, suggesting that each column comprised a cofacial π-stack of H PC C4 ( Except for H PC C4

N-Me
, chromatographically isolated H PC Cn (n = 3-6), on being slowly cooled from their hot melts, all assembled into a hexagonal columnar structure ([ H PC Cn ] COL ; Supplementary  Fig. 6). As expected, the intercolumnar distance was larger as the hydrocarbon side chains were longer. We also found that their melting behaviours are different from one another and possibly affect the SF-ASP profile. For SF-ASP to occur properly, precursor PN Cn should be in hot melts, while produced H PC Cn must be in the form of hexagonally packed crystalline fibres [ H PC Cn ] CF . By means of differential scanning calorimetry (DSC) ( Supplementary Fig. 7), we evaluated the thermal behaviours of PN Cn (n = 3-6) as well as those of the corresponding columnar assemblies of [ H PC Cn ] COL (n = 3-6). The observed thermal behaviours were consistent with the optical images shown in Fig. 2e,c. The crystalline fibres of [ H PC C3 ] CF and [ H PC C4 ] CF are stable enough thermally to survive in the hot melts of PN C3 and PN C4 , respectively, and promote SF-ASP. However, once their fibrous crystalline features were lost due to overheating, the autocatalytic activity could no longer be retrieved even though the temperature was properly readjusted later. Note that SF-ASP is difficult or impossible when PN C5 and PN C6 are used, because the resulting H PC C5 and H PC C6 do not assemble into thermally stable crystalline fibres.
As illustrated in Fig. 1a Fig. 8a,b). In the subsequent stage, the formation of new crystalline fibres subsided, but the preformed fibres still became continuously thicker to increase the total cross-sectional area, thereby promoting the autocatalytic transformation of PN C4 into H PC C4 (Supplementary Fig. 8c). Namely, H PC C4 was produced MALDI-TOF mass spectra of the reaction mixtures obtained by SF-ASP using PN C3 , PN C4 , PN C5 , PN C6 and PN C4     continuously without product inhibition at the cross-sectional fibre edges until PN C4 was completely consumed. Equally important, terminal coupling of the crystalline fibres, leading to a decrease in the total cross-sectional area for templating the reaction, barely occurred in SF-ASP, certainly due to their very sluggish diffusion in the hot melt of PN C4 under solvent-free conditions. Analogous to other reported examples of organic autocatalysis 15,24 , the transformation of PN C4 into H PC C4 in the fibre elongation stage (7-11 h) showed a pseudo first order kinetics ( Supplementary Fig.  9), where no intermediate transition was suggested by tracking with FT-IR and electronic absorption spectroscopy (Supplementary Fig.  10). In support of the template-assisted mechanism, when PN C4 containing separately prepared crystalline fibres of [ H PC C4 ] CF as the seed was heated to 160 °C, the fibres immediately elongated (Supplementary Video 2) without any induction period (Supplementary Fig. 11a). In relation to the mechanism of SF-ASP, we found that H PC C4 N-Me with N-methylated amide units in its side chains interferes with SF-ASP. For example, when PN C4 containing H PC C4 N-Me (20 wt%, 5 mol%) was heated to 160 °C, fibrous [ H PC C4 ] CF was not produced in 10 h (Supplementary Fig. 11b) Fig. 11c). Here, H PC C4 N-Me certainly adsorbs onto the active edges of the nuclei or crystalline fibres and interferes with the preorganization of PN C4 for its autocatalytic transformation into H PC C4 .
Although the mechanism has yet to be clarified 37 , the cyclotetramerization of PN C4 into H PC C4 is a H + -mediated reductive process: 4PN C4 + 2H + + 2e − → H PC C4 . Therefore, the solution-phase synthesis of phthalocyanines is often conducted in protic solvents, such as alcohols. For SF-ASP, we consider that surface silanol groups on the glass substrate may play a similar role to alcohols. Although the number of surface silanol groups is limited, a siloxane bridge (≡Si-O-Si≡) on heating over 160 °C was reported to cleave off homolytically to produce radical species ≡Si• and •O-Si≡, which in turn react with a water molecule to generate H + and e -(refs. 38,39 ). This process is considered essential for the H + -mediated reductive cyclotetramerization of PN C4 . Accordingly, when PN C4 was freeze-dried and used for SF-ASP in a dry N 2 atmosphere, the yield of H PC C4 dropped notably from 81 to 32% (Supplementary Fig. 12).
SF-ASP also works for the selective synthesis of metallophthalocyanines, which have the higher potential for practical applications than free-base phthalocyanines [40][41][42] . Examples in the present work include zinc (Zn), iron (Fe), cobalt (Co) and copper (Cu) phthalocyanines ( M PC C4 , Fig. 1b), which were selectively produced in high yields (77-90%, Supplementary Table 2) simply by heating PN C4 in the presence of metal oleate salts (Methods). Typically, a 2:1 molar mixture of PN C4 and Zn(oleate) 2 , sandwiched between glass plates, was heated to 160 °C for 12 h, where a change in its absorption intensity at 700 nm due to Zn PC C4 (Supplementary Fig. 13a) clearly displayed a sigmoidal time-course profile (Fig. 4a, blue) with a shorter induction period than that without Zn(oleate) 2 (Fig. 2a, black). We also found that, after the induction period, green-coloured crystalline fibres developed entirely (Fig. 4b, blue). By means of elemental mapping using scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX; Supplementary Fig. 13b) together with MALDI-TOF mass spectrometry ( Supplementary Fig. 13c), we confirmed that the as-formed fibres are composed solely of Zn PC C4 without any trace of free-base H PC C4 . The same held true for SF-ASP using PN C4 in the presence of other oleate salts of Fe (Fig.  4a,b, orange and Supplementary Fig. 14), Co (Fig. 4a,b, purple and Supplementary Fig. 15) and Cu (Fig. 4a,b, red and Supplementary  Fig. 16). Heating free-base H PC C4 with the above metal oleates for 24 h resulted in only poor yields of M PC C4 (Supplementary Fig. 17), suggesting that the metal ion is involved in the transition state of the autocatalytic process of SF-ASP.
Although SF-ASP using PN C4 to form [ H PC C4 ] CF or [ M PC C4 ] CF should, in principle, follow the step-growth mechanism, due to the sluggish diffusion kinetics under solvent-free conditions, chain coupling is prevented, so that the crystalline fibres grow continuously in both directions until PN C4 is completely consumed, similar to living chain-growth processes [43][44][45][46] . Hence, we envisioned that one could synthesize block copolymers by multistep SF-ASP using PN C4 in combination with different metal oleates (Methods). As a typical example, active seeds of [ Cu PC C4 ] CF were prepared by chopping its as-formed fibres for 10 s in methanol, and the resulting suspension was cast onto a glass plate and air-dried. This glass plate was covered with powdery PN C4 , and the mixture was sandwiched between glass plates and heated to 180 °C, where [ Cu PC C4 ] CF in a hot melt of PN C4 started to grow uniformly in both directions, affording the ABA-type of triblock copolymer Supplementary Fig. 18d). Although its block segments were easily differentiated by their intrinsic colours (Fig. 4c, Supplementary Fig. 19) allowed us to confirm that copper, as expected, was localized only in its middle block segment, whereas sulfur was distributed over the entire fibre. Meanwhile, the through-view 2D SAXS patterns collected from the [ Cu PC C4 ] CF and [ H PC C4 ] CF segments ( Supplementary Fig. 20) revealed that their structural integrities were both very high. These observations allow us to conclude that the cross-sectional fibre edges template the epitaxial growth of the [ H PC C4 ] CF segment, affording a 1D supramolecular heterojunction [47][48][49][50] . However, note that SF-ASP in the second stage, when conducted for more than 4 h (Fig. 2c), concomitantly gave a nonnegligible amount of homotropic [ H PC C4 ] CF . After struggling, we eventually found that this unfavourable process was suppressed when SF-ASP was conducted using glass plates coated with an amorphous perfluoropolymer called CYTOP ( Supplementary  Fig. 21) and successfully obtained a variety of ABA and even ABCBA types of multi-block copolymer ( Fig. 4c and Supplementary Fig. 18). Another important key to obtain well-defined multi-block copolymers was to combine block segments whose intercolumnar distances should match with less than a 2% difference (Supplementary Fig. 22 and Table 3). In fact, in the multistep SF-ASP using PN C4 Table 4), the blocked segments were highly branched (Fig. 4d,e).  3 (orange), Co(oleate) 2 (purple) and Cu(oleate) 2 (red), sandwiched between glass plates on heating at 160 °C. b, Optical images of the reaction mixtures obtained by SF-aSP using PN C4 with Zn(oleate) 2 (blue), Fe(oleate) 3 (orange), Co(oleate) 2 (purple) and Cu(oleate) 2 (red) on heating at 160 °C for 12 h. Scale bars, 100 µm. c, Optical images of the reaction mixtures obtained on heating at 180 °C for 2-4 h by multistep SF-aSP using PN C4 with/without Zn(oleate) 2 , Fe(oleate) 3  Finally, we point out that in SF-ASP, the growth direction of the crystalline fibres can be controlled by the type of substrate used. For example, when PN C4 was heated between glass plates whose surfaces were rubbed in advance with a polytetrafluoroethylene (PTFE) rod and parallelly oriented, the resulting [ H PC C4 ] CF were preferentially oriented along the rubbed direction (Fig. 4f, left)  interest, when single-crystalline potassium bromide (KBr) plates were used to sandwich PN C4 , SF-ASP gave grid-like 2D crosslinked crystalline fibres (Fig. 4f, right). We also found that SF-ASP using PN C4 , when conducted with Fe(oleate) 3 in a 10 T magnetic field, resulted in the formation of [ Fe PC C4 ] CF that were preferentially oriented orthogonal to the magnetic flux line (Fig. 4g, left). In contrast, SF-ASP using PN C4 (Fig. 4g, right) and PN C4 /Co(oleate) 2 (Fig. 4g, middle) under the same conditions did not form oriented crystalline fibres. Since [ Fe PC C4 ] CF once formed were not magnetically orientable afterwards, we consider that the magnetic field surely affected the nucleation process of SF-ASP. Computational simulations ( Supplementary Fig. 23) suggested that crystalline nuclei consisting of roughly 10 5 molecules of Fe PC C4 probably align perpendicular to the magnetic flux line, whereas those consisting of H PC C4 and Co PC C4 align randomly.

Outlook
There exists a preconception that, in a solvent-free condensed phase, supramolecular polymerization would not properly proceed because many undesirable kinetic traps possibly interfere the delicate noncovalent chain propagation event. However, in this article, we updated this preconception through detailed investigation of our serendipitous finding that green-coloured thin fibres formed and elongated on heating a liquid-crystalline PN on a hot stage. SF-ASP developed here provides an inhibition-free template-assisted catalytic organic transformation that takes great advantage of the termination-free nucleation-elongation assembly (living supramolecular polymerization) of its product (template) under solvent-free conditions. Considering its potential applicability to the synthesis of other π-electronic and macrocyclic monomers, SF-ASP that allows for precision macromolecular engineering using in situ produced monomers under solvent-free conditions might be one of the ideal forms of polymer manufacturing for the sustainable future.

Online content
Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/ s41563-021-01122-z.