We have designed, synthesized, and crystallized 36 compounds,e ach containing an azide group and an oxygen atom separated by three bonds.C rystal structure analysis revealed that each of these molecules adopts aconformation in which the azide and oxygen groups orient syn to each other with as hort O•••N b 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 ac rystal packinge ffect. Quantum topological analysis using BadersA toms 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.N BO analysis suggested aw eak orbital-relaxation (charge-transfer) contribution of energy for af ew (sp2) O-donor systems.N atural population analysis (NPA) and molecular electrostatic potential mapping (MESP) of these crystal structures further revealed the existence of favorable azide-oxygen interaction. ACSD 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.

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.

Tuning the secondary structure of ap rotein or polymer in the solid-state is challenging. Here we report the topochemical synthesis of ap seudoprotein and its secondary structure tuning in the solid-state.W ed esigned the dipeptide monomer N 3 -Leu-Ala-NH-CH 2 -CCH (1)f or topochemical azide-alkyne cycloaddition (TAAC) polymerization. Dipeptide 1 adopts an anti-parallel b-sheet-like stacked arrangement in its crystals.U pon heating,t he dipeptide undergoes quantitative TAAC polymerization in ac rystal-to-crystal fashion yielding large polymers.T he reaction occurs between the adjacent monomers in the H-bonded anti-parallel stack, yielding pseudoprotein having a b-meander structure.W hen dissolved in methanol, this pseudoprotein changes its secondary structure from b-meander to a-helical form and it retains the new secondary structure upon desolvation. This work demonstrates an ovel paradigm for tuning the secondary structure of apolymer in the solid-state.

Protein Structures In their Research Article (e202113129), Kana M. Sureshan et al. report the secondary structure tuning of a pseudoprotein between β‐meander and α‐helical forms in the solid state.

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.