Light-induced transformation of a supramolecular gel to a stronger covalent polymeric gel.

A polymerizable diacetylene gelator, containing urea and urethane groups, that congeals various non-polar solvents was synthesized. The gelator molecules self-assemble forming non-covalent polymers through intermolecular hydrogen bonding, as evidenced from FT-IR and concentration-dependent 1H NMR spectroscopy. The self-assembly positions the diyne units of adjacent molecules at proximity and in a geometry suitable for their topochemical polymerization. UV irradiation of the gel resulted in topochemical polymerization, transforming the non-covalent polymer to a covalent polymer, in situ, in the gel state. The polymerization was confirmed by characterizing the polydiacetylene (PDA) using UV-Vis and Raman spectroscopy. Time-dependent rheological studies revealed gradual strengthening of the gel with the duration of irradiation, suggesting that the degree of polymerization increases with the duration of irradiation. The PDA formed is a semiconductor, which might be useful for various applications.

Unclicking the Click: A Depolymerizable Clicked Polymer via Two Consecutive Single-Crystal-to-Single-Crystal Reactions.

We report here a clicked polymer that can be depolymerized by a declicking reaction. A designed dipeptide monomer, upon heating its crystals, underwent a single-crystal-to-single-crystal topochemical ene-azide cycloaddition polymerization to form a triazoline-linked polymer, which upon further heating, underwent a remarkable SCSC denitrogenation, resulting in an imine-linked polymer quantitatively. As both the TEAC polymerization and the denitrogenation occurred in SCSC fashion, the structures of the triazoline-linked polymer and the imine-linked polymer could be determined at atomic resolution by SCXRD. Acid hydrolysis of the imine-linked polymer leads to quantitative depolymerization yielding a dipeptide, showcasing the degradability and depolymerizability of such polymers. This solid-state click polymerization and denitrogenation yielding depolymerizable polymer is attractive over the usual click polymers that cannot be unclicked.

A Syndiotactic Polymer via Spontaneous Exoselective Single-Crystal-To-Single-Crystal Topochemical Diels-Alder Cycloaddition Reaction.

We designed and synthesized an amide-based monomer decorated with furan as the diene unit and maleimide as the dienophile unit at its termini. Single-crystal X-ray diffraction (SCXRD) analysis of its crystal revealed a head-to-tail arrangement of molecules with furan and maleimide groups of neighboring molecules proximally placed in an arrangement suitable for their topochemical Diels-Alder cycloaddition (TDAC) to form a linear polymer. The monomer underwent a spontaneous single-crystal-to-single-crystal (SCSC) polymerization at room temperature, yielding a linear polymer with oxa-bicyclic linkage. SCXRD analysis revealed that the cycloaddition occurred in an exoselective manner, and the absolute stereochemistry of the oxa-bicyclic linkage alternated in successive repeat units, leading to a syndiotactic linear polymer. The polymerization can be accelerated by heating the powder at 120 °C; the topochemical nature of the high-temperature reaction was established by time dependent differential scanning calorimetry (DSC), time-dependent powder X-ray diffraction (PXRD), and UV-visible spectroscopic analysis; the polymer was characterized using solid-state NMR spectroscopy and MALDI-TOF mass spectrometry.

A Self-Healing Crystal That Repairs Multiple Cracks.

We report both cracking and self-healing in crystals occurring during a thermal phase transition, followed by a topochemical polymerization. A squaramide-based monomer was designed where the azide and alkyne units of adjacent molecules are positioned favorably for a topochemical click reaction. The monomer undergoes spontaneous single-crystal-to-single-crystal (SCSC) polymerization at room temperature via regiospecific 1,3-dipolar cycloaddition, yielding the corresponding triazole-linked polymer in a few days. When heated at 60 °C, the polymerization completes in a SCSC manner in 24 h. Upon continuous heating from room temperature to 110 °C, the monomer crystals develop multiple cracks, and they self-heal immediately. The cracking occurs due to a thermal phase transition, as evidenced by differential scanning calorimetry (DSC). The cracks heal either upon further heating or upon cooling of the crystals due to the topochemical polymerization or reversal of the phase transition, respectively. Increasing the heating rate leads to the formation of longer and wider cracks, which also heal instantaneously. The self-healed crystals retained their integrity and the crystal structure of the self-healed crystals was analyzed by single-crystal X-ray diffraction. The quality of the self-healed crystals and their diffraction ability conform to those of the completely reacted crystals at room temperature or at 60 °C without developing cracks. This work demonstrates a novel mechanism for self-healing of molecular crystals that could expand the horizon of these materials for a plethora of applications.

Simultaneous and in situ syntheses of an enantiomeric pair of homochiral polymers as their perfect stereocomplex in a crystal.

Circumventing the issues of conventional stereocomplexation of preformed polymers, herein, we synthesize two enantiopure polymers of opposite chirality simultaneously and in situ as their 1:1 stereocomplex via topochemical polymerization. We design and synthesize an inositol-based achiral monomer for topochemical ene-azide cycloaddition (TEAC) polymerization. In the crystal, the monomer exhibits conformational enantiomerism, and its conformational enantiomers are self-sorted in an arrangement for TEAC polymerization to yield two enantiopure polymers of opposite chirality. Upon heating the monomer crystals, each self-sorted set of conformational enantiomers undergoes regio- and stereospecific polymerization in a single-crystal-to-single-crystal fashion, generating two 1, 4-triazolinyl-linked polymers of opposite chirality simultaneously. The new chiral carbons in all the triazoline rings of a particular polymer chain have the same absolute configuration. These homochiral polymer strands align parallelly, forming a layer, and such enantiopure layers of opposite chirality stack alternately, forming a perfect 1:1 stereocomplex, which we confirmed using single-crystal XRD analysis.

Hierarchical single-crystal-to-single-crystal transformations of a monomer to a 1D-polymer and then to a 2D-polymer.

Designing and synthesizing flawless two-dimensional polymers (2D-Ps) via meticulous molecular preorganization presents an intriguing yet challenging frontier in research. We report here the single-crystal-to-single-crystal (SCSC) synthesis of a 2D-P via thermally induced topochemical azide-alkyne cycloaddition (TAAC) reaction. A designed monomer incorporating two azide and two alkyne units is synthesized. The azide and alkyne groups are preorganized in the monomer crystal in reactive geometries for polymerizations in two orthogonal directions. On heating, the polymerizations proceed in a hierarchical manner; at first, the monomer reacts regiospecifically in a SCSC fashion to form a 1,5-triazolyl-linked 1D polymer (1D-P), which upon further heating undergoes another SCSC polymerization to a 2D-P through a second regiospecific TAAC reaction forming 1,4-triazolyl-linkages. Two different linkages in orthogonal directions make this an architecturally attractive 2D-P, as determined, at atomic resolution, by single-crystal X-ray diffraction. The 2D-P reported here is thermally stable in view of the robust triazole-linkages and can be exfoliated as 2D-sheets.

Large Molecular Rotation in Crystal Changes the Course of a Topochemical Diels-Alder Reaction from a Predicted Polymerization to an Unexpected Intramolecular Cyclization.

A designed anthracene-based monomer for topochemical Diels-Alder cycloaddition polymerization crystallized with head-to-tail arrangement of molecules, as revealed by single-crystal X-ray diffraction (SCXRD) analysis. The diene and dienophile units of adjacent monomer molecules are aligned at an average distance of 4.6 Å, suggesting a favorable crystalline arrangement for their intermolecular Diels-Alder cycloaddition reaction to form a linear polymer. Surprisingly, heating the monomer crystals at a temperature above 125 °C resulted in the formation of intramolecular Diels-Alder cycloadduct, which could be characterized by various spectroscopy and SCXRD analysis. Various time-dependent studies such as NMR, PXRD, and DSC, studies established that the reaction followed topochemical pathway. Schmidt's topochemical postulates are generally used to predict the topochemical reactivity and product, by analyzing the crystal structure of the reactant. Though the crystal arrangement predicted polymerization, upon heating, the molecule avoided this pathway by undergoing a large rotation to form an intramolecular cycloadduct. Theoretical calculations supported the feasibility of the rotation, exploiting the flexibility of the molecule and voids present. These findings caution that the reliance on Schmidt's criteria for topochemical reactions may sometimes be misleading, especially in heat-induced reactions.

Massive Molecular Motion in Crystal Leads to an Unexpected Helical Covalent Polymer in a Solid-state Polymerization.

We designed a proline-derived monomer with azide and alkene functional groups to enable topochemical ene-azide cycloaddition (TEAC) polymerization. In its crystal, the monomer forms supramolecular helices along the 'a' axis through various non-covalent interactions. Along the 'c' axis, the molecules arrange themselves head-to-tail in a wave-like pattern, positioning the azide and alkene groups of adjacent molecules in close proximity and anti-parallel orientation, complying with Schmidt's criteria for topochemical reaction. This prearranged configuration was expected to facilitate smooth topochemical polymerization, resulting in a 1,4-triazoline-linked polymer. Upon heating, the monomer underwent TEAC polymerization in a remarkable single-crystal-to-single-crystal fashion, but, to our surprise, it yielded an unexpected covalent helical polymer linked by 1,5-disubstituted triazoline units. Remarkably, the crystal avoids the ready-to-react arrangement for polymerization, but connects monomer molecules within the supramolecular helix through the cycloaddition of azide and alkene groups, even though they are not in close proximity nor in the expected orientation. This unexpected path, involving a substantial 134° rotation of the alkene group, yields hitherto unknown 1,5-disubstituted triazoline product regiospecifically. This study serves as a cautionary reminder that relying solely on topochemical postulates for predicting reactivity can sometimes be misleading.

Topochemistry for Difficult Peptide-Polymer Synthesis: Single-Crystal-to-Single-Crystal Synthesis of an Isoleucine-Based Polymer, a Hydrophobic Coating Material.

Polymers of hydrophobic amino acids are predicted to be potential coating materials for the creation of hydrophobic surfaces. The oligopeptides of hydrophobic amino acids are called "difficult peptides"; as the name suggests, it is difficult to synthesize them by conventional methods. We circumvented this synthetic challenge by adopting topochemical azide-alkyne cycloaddition (TAAC) polymerization of a hydrophobic dipeptide monomer. We designed an Ile-based dipeptide, decorated with azide and alkyne, which arrange in the crystal in a head-to-tail fashion with the azide and alkyne of the adjacent molecules in a ready-to-react orientation. The monomer, on mild heating of its crystals, undergoes regiospecific TAAC polymerization to yield a 1,4-disubstituted-triazole-linked polymer in a single-crystal-to-single-crystal fashion. The solid obtained after evaporation of the monomer solution also maintained crystallinity and underwent regiospecific topochemical polymerization as in the case of crystals. This topochemical polymerization could be studied using different techniques such as FTIR, NMR, DSC, GPC, MALDI, PXRD, and SCXRD. Since the polymer is insoluble in common solvents and hence difficult to coat surfaces, the monomer was first sprayed and evaporated on various surfaces and polymerized on the surface. Such polymer-coated surfaces exhibited water contact angles of up to 134°, showing that this Ile-derived polymer is very hydrophobic and can potentially be used as a coating material for various applications.

Two Structurally Different Polymers from a Single Monomer.

We designed and synthesized a malonamide-derived monomer, containing azide and alkyne units, for topochemical polymerization to yield nylon (n,3). This monomer on crystallization gave two concomitant polymorphs M1 and M2. Both the polymorphs show crystal packings that are suitable for topochemical azide-alkyne cycloaddition polymerization. On heating, polymorph M1 reacts regiospecifically to give 1,4-disubstituted-1,2,3-triazolyl-linked polymer, whereas polymorph M2 yields 1,5-disubstituted-1,2,3-triazolyl-linked polymer regiospecifically. In the case of polymorph M1, polymerization proceeds perpendicular to the hydrogen bonding direction, whereas in M2, the reaction occurs along the hydrogen bonding direction. This results in the two structurally different polymers having distinct topologies. These single-crystal-to-single-crystal polymerizations allowed us to study their structure at atomic resolution by single-crystal X-ray diffraction. This is the first report on the topochemical synthesis of two structurally isomeric polymers from a single monomer.

Single-Crystal-to-Single-Crystal Topochemical Synthesis of a Collagen-inspired Covalent Helical Polymer.

There is much demand for crystalline covalent helical polymers. Inspired by the helical structure of collagen, we synthesized a covalent helical polymer wherein the repeating dipeptide Gly-Pro units are connected by triazole linkages. We synthesized an azide and alkyne-modified dipeptide monomer made up of the repeating amino acid sequence of collagen. In its crystals, the monomer molecules aligned in head-to-tail fashion with proximally placed azide and alkyne forming supramolecular helices. At 60 °C, the monomer underwent single-crystal-to-single-crystal (SCSC) topochemical azide-alkyne cycloaddition polymerization, yielding a covalent helical polymer as confirmed by single-crystal X-ray diffraction (SCXRD) analysis. Compared to the monomer crystals, the polymer single-crystals were very strong and showed three-fold increase in Young's modulus, which is higher than collagen, many synthetic polymers and other materials. The crystals of this covalent helical polymer could bear loads as high as 1.5 million times of their own weight without deformation. These crystals could also withstand high compression force and did not disintegrate even at an applied force of 98 kN. Such light-weight strong materials are in demand for various technological applications.

Comparison of narrow-band imaging with autofluorescence imaging for endoscopic detection of squamous cell carcinoma of the tonsil.

PURPOSE: Early detection of mucosal neoplastic lesions is crucial for a patient's prognosis. This has led to the development of effective optical endoscopic diagnostic methods such as narrow band imaging (NBI) and autofluorescence (AFI). Independent of each other, both of these methods were proven useful in the detection of mucosal neoplasias. There are limited reported data comparing both methods for oropharyngeal cancer diagnostics. The aim of the study was to compare NBI and AFI endoscopic visualization of signs in identifying tonsillar squamous cell carcinoma (SCC) and assessing its extent and to determine whether the score was related to the evaluator's experience. METHODS: Patients with tonsillar SCC underwent endoscopic pharyngeal examination using NBI and AFI. Fiftyseven video sequences of examinations of lesions proven to be SCC were evaluated by three reviewers. The accuracy of determination of lesion extent and visualization of its endoscopic signs of malignancy were evaluated. RESULTS: Endoscopic visualization of tumour spread was significantly better using AFI than NBI (p = 0.0003). No significant difference was found between NBI and AFI in the visualization of endoscopic malignancy determining signs (p = 0.1405). No significant difference was found among the three reviewers in the visualization of tumour spread and for identifying malignancy-determining signs in NBI endoscopy or AFI endoscopy. CONCLUSIONS: The results show that AFI obtained better results for assessing the extent of tonsillar cancers than NBI. Both methods were proven to be equal in the visualization of endoscopic malignancy-determining signs. Both are useful even for less experienced evaluators.

Topochemical Syntheses of Polyarylopeptides Involving Large Molecular Motions: Frustrated Monomer Packing Leads to the Formation of Polymer Blends.

We report the topochemical syntheses of three polyarylopeptides, wherein triazolylphenyl group is integrated into the backbone of peptide chains. We synthesized three different monomers having azide and arylacetylene as end-groups from glycine, L-alanine and L-valine. We crystallized these monomers and the crystal structures of two of them were determined by single-crystal X-ray diffractometry. Due to the steric constraints, both of these monomers crystallized with two molecules, viz. conformers A and B, in the asymmetric unit. Consistently, in both cases, the A-conformers are antiparallelly π-stacked and B-conformers are parallelly slip-stacked, exploiting weak interactions. Though the arrangements of molecules in the pristine crystals were unsuitable for topochemical reaction, upon heating, they undergo large motion inside the crystal lattice to reach a transient reactive orientation and thereby the self-sorted conformer stacks react to give a blend of triazole-linked polyarylopeptides having two different linkages. Due to the large molecular motion inside crystals, the product phase loses its crystallinity.

Adamantoid Scaffolds for Multiple Cargo Loading and Cellular Delivery as ß-Cyclodextrin Inclusion Complexes.

There is huge demand for developing guests that bind ß-CD and can conjugate multiple cargos for cellular delivery. We synthesized trioxaadamantane derivatives, which can conjugate up to three cargos per guest. 1 H NMR titration and isothermal titration calorimetry revealed these guests form 1 : 1 inclusion complexes with ß-CD with association constants in the order of 103  M-1 . Co-crystallization of ß-CD with guests yielded crystals of their 1 : 1 inclusion complexes as determined by single-crystal X-ray diffraction. In all cases, trioxaadamantane core is buried within the hydrophobic cavity of ß-CD and three hydroxyl groups are exposed outside. We established biocompatibility using representative candidate G4 and its inclusion complex with ß-CD (ß-CD⊂G4), by MTT assay using HeLa cells. We incubated HeLa cells with rhodamine-conjugated G4 and established cellular cargo delivery using confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) analysis. For functional assay, we incubated HeLa cells with ß-CD-inclusion complexes of G4-derived prodrugs G6 and G7, containing one and three units of the antitumor drug (S)-(+)-camptothecin, respectively. Cells incubated with ß-CD⊂G7 displayed the highest internalization and uniform distribution of camptothecin. ß-CD⊂G7 showed higher cytotoxicity than G7, camptothecin, G6 and ß-CD⊂G6, affirming the efficiency of adamantoid derivatives in high-density loading and cargo delivery.

Rational design and topochemical synthesis of polymorphs of a polymer.

Packing a polymer in different ways can give polymorphs of the polymer having different properties. ß-Turn forming peptides such as 2-aminoisobutyric acid (Aib)-rich peptides adopt several conformations by varying the dihedral angles. Aiming at this, a ß-turn-forming peptide monomer would give different polymorphs and these polymorphs upon topochemical polymerization would yield polymorphs of the polymer, we designed an Aib-rich monomer N3-(Aib)3-NHCH2-C[triple bond, length as m-dash]CH. This monomer crystallizes as two polymorphs and one hydrate. In all forms, the peptide adopts ß-turn conformations and arranges in a head-to-tail manner with their azide and alkyne units proximally placed in a ready-to-react alignment. On heating, both the polymorphs undergo topochemical azide-alkyne cycloaddition polymerization. Polymorph I polymerized in a single-crystal-to-single-crystal (SCSC) fashion and the single-crystal X-ray diffraction analysis of the polymer revealed its screw-sense reversing helical structure. Polymorph II maintains its crystallinity during polymerization but gradually becomes amorphous upon storage. The hydrate III undergoes a dehydrative transition to polymorph II. Nanoindentation studies revealed that different polymorphs of the monomer and the corresponding polymers exhibited different mechanical properties, in accordance with their crystal packing. This work demonstrates the promising future of the marriage of polymorphism and topochemistry for obtaining polymorphs of polymers.

Cascading Effect of Large Molecular Motion in Crystals: A Topotactic Polymorphic Transition Paves the Way to Topochemical Polymerization.

A topochemical polymerization governed by a topotactic polymorphic transition is reported. A monomer functionalized with azide and an internal alkyne crystallized as an unreactive polymorph with two molecules in the asymmetric unit. The molecules are aligned in a head-to-head fashion, thereby avoiding the azide-alkyne proximity for the topochemical azide-alkyne cycloaddition (TAAC) reaction. However, upon heating, one of the two conformers underwent a drastic 180° rotation, leading to a single-crystal-to-single-crystal (SCSC) polymorphic transition to a reactive form, wherein the molecules are head-to-tail arranged, ensuring azide-alkyne proximity. The new polymorph underwent TAAC reaction to form a trisubstituted 1,2,3-triazole-linked polymer. These results, showing unexpected topochemical reactivity of a crystal due to the intermediacy of an SCSC polymorphic transition from an unreactive form to a reactive form, highlight that predicting topochemical reactivity by relying on the static crystal structure can be misleading.

Tuning the Regioselectivity of Topochemical Polymerization through Cocrystallization of the Monomer with an Inert Isostere.

Regiochemistry of topochemical reactions depends on the crystal packing and biasing the regiochemistry necessitates precise crystal engineering. The pristine crystals of monomer 1 upon topochemical azide-alkyne cycloaddition (TAAC) reaction give a 1 : 1 blend of 1,4- and 1,5-triazole-linked polymers due to the presence of two self-sorted reactive conformers in the crystal. We designed a binary isomorphous cocrystal of monomer 1 and a structurally similar dummy molecule 2 to limit the number of reactive conformers of 1 to one and thus to get one type of polymer. Equimolar solution of 1 and 2 in chloroform-acetone mixture gave two 1 : 1 cocrystals Co-I and Co-II. The Co-II, a chloroform adduct, on heating undergoes desolvation and polymorphic transition to Co-I. Co-I is isomorphic to 1 and 2 and possess self-sorted arrays of 1 and 2. Heating Co-I results in the TAAC polymerization giving 1,4-triazolyl-linked polymer of 1 selectively, showing the power of crystal engineering in regiocontrol.

Topochemical Cycloaddition Reaction between an Azide and an Internal Alkyne.

Here we report the synthesis of a trisubstituted-1,2,3-triazole-linked polymer using a topochemical azide-alkyne cycloaddition (TAAC) reaction. A cyclitol-derived monomer having an azide and an internal alkyne group was designed. The four hydroxy groups present in this monomer dictate its crystal packing such that the monomer molecules are arranged head-to-tail, thereby placing the internal alkyne and the azide units of adjacent molecules proximally. Although the alignment of the reactive groups in the monomer crystal is not favourable for a topochemical reaction, a reactive orientation can be achieved by the rotation of the reactive groups. Upon heating the crystals, the monomer underwent topochemical polymerization to yield the trisubstituted-1,2,3-triazole-linked-polycyclitol. This study demonstrates a new synthetic strategy for cycloaddition reaction between non-polarized internal alkynes and azides to yield trisubstituted triazoles.

Single-crystal-to-single-crystal translation of a helical supramolecular polymer to a helical covalent polymer.

Polymers possessing helical conformation in the solid state are in high demand. We report a helical peptide-polymer via the topochemical ene-azide cycloaddition (TEAC) polymerization. The molecules of the designed Gly-Phe-based dipeptide, decorated with ene and azide, assemble in its crystals as ß-sheets and as supramolecular helices in two mutually perpendicular directions. While the NH…O H-bonding facilitates ß-sheet-like stacking along one direction, weak CH…N H-bonding between the azide-nitrogen and vinylic-hydrogen of molecules belonging to the adjacent stacks arranges them in a head-to-tail manner as supramolecular helices. In the crystal lattice, the azide and alkene of adjacent molecules in the supramolecular helix are suitably preorganized for their TEAC reaction. The dipeptide underwent regio- and stereospecific polymerization upon mild heating in a single-crystal-to-single-crystal fashion, yielding a triazoline-linked helical covalent polymer that could be characterized by single-crystal X-ray diffraction studies. Upon heating, the triazoline-linked polymer undergoes denitrogenation to aziridine-linked polymer, as evidenced by differential scanning calorimetry, thermogravimetric analysis, and solid-state NMR analyses.

Azide-Alkyne Interactions: A Crucial Attractive Force for Their Preorganization for Topochemical Cycloaddition Reaction.

A new class of attractive intermolecular interaction between azide and ethynyl structural entities in a wide range of molecular crystals is reported. This interaction was systematically evaluated by using 11 geometrically different structural motifs that are preorganized to direct a solid-state topochemical azide-alkyne cycloaddition (TAAC) reaction. The supramolecular features of the azide-alkyne interaction were mapped by various crystallographic and quantum chemical approaches. Topological analysis shows the noticeable participation of electron density in the azide⋅⋅⋅alkyne interactions. Interestingly, reorientation of the atomic polarizabilities in vicinal azide and alkyne groups upon interaction in crystals favors soft orbital-guided TAAC reactions. Moreover, various solid-state and gas-phase energy decomposition methods of individual azide⋅⋅⋅alkyne interactions summarize that the strength (varies from -5.7 to -30.1 kJ mol-1 ) is primarily guided by the dispersion forces with a influencing contribution from the electrostatics.