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.

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.

Topochemical Postulates: Are They Relevant for Topochemical Reactions Occurring at Elevated Temperatures?

A rigid inositol-derived monomer functionalized with azide and alkyne as the complementary reactive groups (CRGs) crystallized as three distinct polymorphs I-III. Despite the unsuitable orientation of CRGs in the crystals for complete polymerization, all the three polymorphs underwent regiospecific and quantitative topochemical azide-alkyne cycloaddition (TAAC) polymerization upon heating to yield three different polymorphs of 1,2,3-triazol-1,4-diyl-linked-poly-neo-inositol. The molecules in these polymorphs exploit the weak intermolecular interactions, free space in the crystal lattice, and heat energy for their large and cooperative molecular motion to attain a transient reactive orientation, ultimately leading to the regiospecific TAAC reaction yielding distinct crystalline polymers. This study cautions that the overreliance on topochemical postulates for the prediction of topochemical reactivity at high temperatures could be misleading.

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.

Topochemical Synthesis of a Heterochiral Peptide Polymer in Different Polymorphic Forms from Crystals and Aerogels.

We have designed a heterochiral dipeptide monomer (N3 -D-Ala-L-Val-NHCH2 C≡CH) modified with an azide group and an alkyne at its termini for topochemical azide-alkyne cycloaddition (TAAC) polymerization. We obtained two different polymorphs: PI (P21 ) from a DCM-toluene mixture, and PII (P-1) from a hexane-ethyl acetate mixture. PI adopts parallel ß-sheet packing, and PII adopts antiparallel ß-sheet packing. In both the cases, molecules from adjacent ß-stacks are arranged in a head-to-tail manner. On heating, the polymorphs underwent TAAC reaction to form linear polymers having parallel ß-sheet-like ordering (PI) and an antiparallel ß-sheet structure (PII). PI reacted spontaneously at room temperature and the crystals showed cracking after the reaction, but PII was intact even after complete reaction. The dipeptide congealed various solvents, and the aerogels were identical to PI. These aerogels also underwent spontaneous TAAC reaction at room temperature to yield a pseudoprotein with alternate D- and L-amino acids.

Secondary Structure Tuning of a Pseudoprotein Between ß-Meander and α-Helical Forms in the Solid-State.

Tuning the secondary structure of a protein or polymer in the solid-state is challenging. Here we report the topochemical synthesis of a pseudoprotein and its secondary structure tuning in the solid-state. We designed the dipeptide monomer N3 -Leu-Ala-NH-CH2 -C≡CH (1) for topochemical azide-alkyne cycloaddition (TAAC) polymerization. Dipeptide 1 adopts an anti-parallel ß-sheet-like stacked arrangement in its crystals. Upon heating, the dipeptide undergoes quantitative TAAC polymerization in a crystal-to-crystal fashion yielding large polymers. The reaction occurs between the adjacent monomers in the H-bonded anti-parallel stack, yielding pseudoprotein having a ß-meander structure. When dissolved in methanol, this pseudoprotein changes its secondary structure from ß-meander to α-helical form and it retains the new secondary structure upon desolvation. This work demonstrates a novel paradigm for tuning the secondary structure of a polymer in the solid-state.

Single-crystal-to-single-crystal synthesis of a pseudostarch via topochemical azide-alkyne cycloaddition polymerization.

There is high demand for polysaccharide-mimics as enzyme-stable substitutes for polysaccharides for various applications. Circumventing the problems associated with the solution-phase synthesis of such polymers, we report here the synthesis of a crystalline polysaccharide-mimic by topochemical polymerization. By crystal engineering, we designed a topochemically reactive crystal of a glucose-mimicking monomer decorated with azide and alkyne units. In the crystal, the monomers arrange in head-to-tail fashion with their azide and alkyne groups in a ready-to-react antiparallel geometry, suitable for their topochemical azide-alkyne cycloaddition (TAAC) reaction. On heating the crystals, these pre-organized monomer molecules undergo regiospecific TAAC polymerization, yielding 1,4-triazolyl-linked pseudopolysaccharide (pseudostarch) in a single-crystal-to-single-crystal manner. This crystalline pseudostarch shows better thermal stability than its amorphous form and many natural polysaccharides.

Topochemical Ene-Azide Cycloaddition Reaction.

Topochemical reactions, high-yielding solid-state reactions arising from the proximal alignment of reacting partners in the crystal lattice, do not require solvents, catalysts, and additives, are of high demand in the context of green processes and environmental safety. However, the bottleneck is the limited number of reactions that can be done in the crystal medium. We present the topochemical ene-azide cycloaddition (TEAC) reaction, wherein alkene and azide groups undergo lattice-controlled cycloaddition reaction giving triazoline in crystals. A designed monomer that arranges in a head-to-tail manner in its crystals pre-organizing the reacting groups of adjacent molecules in proximity undergoes spontaneous cycloaddition reaction in a single-crystal-to-single-crystal fashion, yielding the triazoline-linked polymer. A unique advantage of this reaction is that the triazoline can be converted to aziridine by simple heating, which we exploited for the otherwise challenging post-synthetic backbone modification of the polymer. This reaction may revolutionize the field of polymer science.

Azide⋠⋠⋠Oxygen Interaction: A Crystal Engineering Tool for Conformational Locking.

We have designed, synthesized, and crystallized 36 compounds, each containing an azide group and an oxygen atom separated by three bonds. Crystal structure analysis revealed that each of these molecules adopts a conformation in which the azide and oxygen groups orient syn to each other with a short O⋅⋅⋅Nß contact. Geometry-optimized structures [using M06-2X/6-311G(d,p) level of theory] also showed the syn conformation in all 36 of these cases, suggesting that this is not merely a crystal packing effect. Quantum topological analysis using Bader's Atoms in Molecules (AIM) theory revealed bond paths and bond critical points (BCP) in these structures suggesting its nature and energetics to be similar to weak hydrogen bonding. The NCI-RDG plot clearly revealed the attractive interaction consisting of electrostatic or dispersive components in all the 36 systems. NBO analysis suggested a weak orbital-relaxation (charge-transfer) contribution of energy for a few (sp2) O-donor systems. Natural population analysis (NPA) and molecular electrostatic potential mapping (MESP) of these crystal structures further revealed the existence of favorable azide-oxygen interaction. A CSD search indicated the frequent and consistent occurrence of this interaction and its role dictating the syn conformation of azide and oxygen in molecules where these groups are separated by 2-4 bonds.

Novel Substrates for Kinases Involved in the Biosynthesis of Inositol Pyrophosphates and Their Enhancement of ATPase Activity of a Kinase.

IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four scyllo-inositol polyphosphates-scyllo-IP5, scyllo-IP6, scyllo-IP7 and Bz-scyllo-IP5-from myo-inositol and studied their activity as substrates for mouse IP6K1 and the catalytic domain of VIP1, the budding yeast variant of PPIP5K. We incubated these scyllo-inositol polyphosphates with these kinases and ATP as the phosphate donor. We tracked enzyme activity by measuring the amount of radiolabeled scyllo-inositol pyrophosphate product formed and the amount of ATP consumed. All scyllo-inositol polyphosphates are substrates for both the kinases but they are weaker than the corresponding myo-inositol phosphate. Our study reveals the importance of axial-hydroxyl/phosphate for IP6K1 substrate recognition. We found that all these derivatives enhance the ATPase activity of VIP1. We found very weak ligand-induced ATPase activity for IP6K1. Benzoyl-scyllo-IP5 was the most potent ligand to induce IP6K1 ATPase activity despite being a weak substrate. This compound could have potential as a competitive inhibitor.

Polymers with advanced structural and supramolecular features synthesized through topochemical polymerization.

Polymers are an integral part of our daily life. Hence, there are constant efforts towards synthesizing novel polymers with unique properties. As the composition and packing of polymer chains influence polymer's properties, sophisticated control over the molecular and supramolecular structure of the polymer helps tailor its properties as desired. However, such precise control via conventional solution-state synthesis is challenging. Topochemical polymerization (TP), a solvent- and catalyst-free reaction that occurs under the confinement of a crystal lattice, offers profound control over the molecular structure and supramolecular architecture of a polymer and usually results in ordered polymers. In particular, single-crystal-to-single-crystal (SCSC) TP is advantageous as we can correlate the structure and packing of polymer chains with their properties. By designing molecules appended with suitable reactive moieties and utilizing the principles of supramolecular chemistry to align them in a reactive orientation, the synthesis of higher-dimensional polymers and divergent topologies has been achieved via TP. Though there are a few reviews on TP in the literature, an exclusive review showcasing the topochemical synthesis of polymers with advanced structural features is not available. In this perspective, we present selected examples of the topochemical synthesis of organic polymers with sophisticated structures like ladders, tubular polymers, alternating copolymers, polymer blends, and other interesting topologies. We also detail some strategies adopted for obtaining distinct polymers from the same monomer. Finally, we highlight the main challenges and prospects for developing advanced polymers via TP and inspire future directions in this area.