Topochemical Azide-alkyne Cycloaddition Research Articles

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.

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.

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.

Regiospecific Synthesis of a Reprocessable Galactan-Mimic via Topochemical Polymerization

We synthesized a designed monomer with azide and alkyne units that mimic α-d-galactose for topochemical azide-alkyne cycloaddition polymerization to produce a cross-linkable galactan-mimic. The monomer molecules pre-organize in the crystals in a linear head-to-tail fashion, with the reactive units properly aligned for topochemical reaction. When the monomer crystals are heated, they undergo regiospecific topochemical azide-alkyne cycloaddition polymerization, resulting in a galactan-mimic with two vicinal diol units per repeating unit. We covalently cross-linked this galactan-mimic using bis-dioxaborolane as the dynamic covalent cross-linker. When compared to the parent galactan-mimic, the mesoporous cross-linked polymer had a sevenfold increase in porosity, a 200-fold increase in particle size, and higher thermal stability. We demonstrated that by varying the temperature, the extent of cross-linking and thus particle size can be reversibly tuned. Our findings show that topochemical polymerization can be used to create polymers with improved properties from monomers derived from naturally available feedstock materials.

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.

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

AbstractRegiochemistry 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.

Topochemical Cycloaddition Reaction between an Azide and an Internal Alkyne

AbstractHere 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.

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

AbstractA rigid inositol‐derived monomer functionalized with azide and alkyne as the complementary reactive groups (CRGs) crystallized as three distinct polymorphsI–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.

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.

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

AbstractWe have designed a heterochiral dipeptide monomer (N3‐D‐Ala‐L‐Val‐NHCH2C≡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 β‐sheet packing, and PII adopts antiparallel β‐sheet packing. In both the cases, molecules from adjacent β‐stacks are arranged in a head‐to‐tail manner. On heating, the polymorphs underwent TAAC reaction to form linear polymers having parallel β‐sheet‐like ordering (PI) and an antiparallel β‐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.

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 β-sheet packing, and PII adopts antiparallel β-sheet packing. In both the cases, molecules from adjacent β-stacks are arranged in a head-to-tail manner. On heating, the polymorphs underwent TAAC reaction to form linear polymers having parallel β-sheet-like ordering (PI) and an antiparallel β-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 β-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 β-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 β-meander structure. When dissolved in methanol, this pseudoprotein changes its secondary structure from β-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.

Secondary Structure Tuning of a Pseudoprotein Between β‐Meander and α‐Helical Forms in the Solid‐State

AbstractTuning 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 β‐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 β‐meander structure. When dissolved in methanol, this pseudoprotein changes its secondary structure from β‐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.

Solvent-Free and Catalyst-Free Synthesis of Cross-Linkable Polyfumaramides via Topochemical Azide-Alkyne Cycloaddition Polymerization

Unsaturated polymers are important materials having a lot of applications. Among polymers, polyamides possess a prime position due to their thermal and chemical stability. Herein, we report a simple, greener, catalyst-free, and solid-state synthesis of two unsaturated polyamides via a topochemical azide-alkyne cycloaddition reaction. Two designed fumaramide monomers M1 and M2, functionalized with complementary azide and alkyne reactive motifs at the termini, reacted upon heating their crystalline powders and resulted in the formation of triazolyl-linked unsaturated polyfumaramides P1 and P2, respectively. We have characterized the reaction using various time-dependent techniques such as NMR, FTIR, PXRD, and DSC measurements. Interestingly, the monomer M1 resulted in 1,5-disubstituted triazole-linked unsaturated polyfumaramide (P1), whereas the monomer M2 polymerized into a polyfumaramide having both 1,4-disubstituted and 1,5-disubstituted triazole linkages (P2). Also, the trans-olefinic bond of both the fumaramide monomers was unaffected in the polymerization process and hence yielded unsaturated polymers having trans-olefin units in the repeating unit. Demonstrating the scope of postsynthetic modification, we have shown that unsaturation can be exploited for cross-linking via a light-induced [2 + 2] cycloaddition reaction. This first report on the solid-state synthesis of unsaturated polyfumaramides will be of great interest.

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.

Designed Synthesis of a 1D Polymer in Twist-Stacked Topology via Single-Crystal-to-Single-Crystal Polymerization.

To synthesize a fully organic 1D polymer in a novel twist-stacked topology, we designed a peptide monomer HC≡CCH2 -NH-Ile-Leu-N3 , which crystallizes with its molecules H-bonded along a six-fold screw axis. These H-bonded columns pack parallelly such that molecules arrange head-to-tail, forming linear non-covalent chains in planes perpendicular to the screw axis. The chains arrange parallelly to form molecular layers which twist-stack along the screw axis. Crystals of this monomer, on heating, undergo single-crystal-to-single-crystal (SCSC) topochemical azide-alkyne cycloaddition (TAAC) polymerization to yield an exclusively 1,4-triazole-linked polymer in a twist-stacked layered topology. This topologically defined polymer shows better mechanical strength and thermal stability than its unordered form, as evidenced by nanoindentation studies and thermogravimetric analysis, respectively. This work illustrates the scope of topochemical polymerizations for synthesizing polymers in pre-decided topologies.

β-Sheet to Helical-Sheet Evolution Induced by Topochemical Polymerization: Cross-α-Amyloid-like Packing in a Pseudoprotein with Gly-Phe-Gly Repeats.

Protein-mimics are of great interest for their structure, stability, and properties. We are interested in the synthesis of protein-mimics containing triazole linkages as peptide-bond surrogate by topochemical azide-alkyne cycloaddition (TAAC) polymerization of azide- and alkyne-modified peptides. The rationally designed dipeptide N3 -CH2 CO-Phe-NHCH2 CCH (1) crystallized in a parallel β-sheet arrangement and are head-to-tail aligned in a direction perpendicular to the β-sheet-direction. Upon heating, crystals of 1 underwent single-crystal-to-single-crystal polymerization forming a triazole-linked pseudoprotein with Gly-Phe-Gly repeats. During TAAC polymerization, the pseudoprotein evolved as helical chains. These helical chains are laterally assembled by backbone hydrogen bonding in a direction perpendicular to the helical axis to form helical sheets. This interesting helical-sheet orientation in the crystal resembles the cross-α-amyloids, where α-helices are arranged laterally as sheets.