Crystengcomm Accepted Manuscript

CrystEngComm Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/crystengcomm Page 1 of 14 PleaseCrystEngComm do not adjust margins Journal Name ARTICLE Propeller-shaped molecules with thiazole Received 00th January 20xx, Accepted 00th January 20xx hub: structural landscape and hydrazone DOI: 10.1039/x0xx00000x www.rsc.org/ cap mediated tunable host behavior in 4- hydrazino-1,3-thiazoles Manuscript Sarah Titus and Kumaran G. Sreejalekshmi* Propeller-shaped molecules with 2,4,5-trisubstituted-1,3-thiazole as hub and tunable blades ( B1-B3) were synthesized as trivariant scaffolds. B1-B3 were Accepted modulated by varying hydrazone capping in B1, isothiocyanate in B2 and α- haloketone in B3 and the structural landscapes examined. Multicomponent molecular crystals formed nitrogen rich channels (NRC) of varying shapes and dimensions which were largely steered by substitution pattern in B1 and established by varying carbonyl components. Isopropylidene derivatives 2 (IPHAT) stabilized single file water inside NRC (~34 Å ) between B1 and B2, benzylidene derivative (BzHAT) formed a constricted NRC and accommodated solvates inside a hydrophobic cavity between B1 and B3 whereas a pincer-shaped NRC devoid of guest molecules was formed by cyclohexylidene derivative (CyHAT). Hydrazone substituent-driven variation in solid state landscapes indicates wide scope of expandability in these CrystEngComm thiazole templates as supramolecular synthons for tunable hosts. Introduction a. Department of Chemistry, Indian Institute of Space Science and Technology, Valiamala Post, Thiruvananthapuram – 695 547, India † Electronic Supplementary Informaon (ESI) available: CCDC reference numbers 1002352,1002353,1052981,1052982,1052983. See DOI: 10.1039/x0xx00000x This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins PleaseCrystEngComm do not adjust margins Page 2 of 14 ARTICLE Journal Name The implicit interdependency of crystal engineering and drug design is well assimilated given the significance of molecular interactions in both. 1, 2 The determination of crystal structures being imperative for drug design, 3, 4 development and formulations, identifies the role of molecular structure in crystal packing and its influence on physicochemical properties of the drug candidate. 5 Whereas drug design seek parent scaffolds that endorse molecular diversity 6-11 and are likely to afford crucial interactions (eg: intramolecular hydrogen bonds), similar considerations arise in the design of supramolecular synthons 12-15 for custom-made materials from first Fig. 1 Multicomponent molecular crystals of 4-hydrazinothiazoles as principles. For example, the correlation of intramolecular hydrogen synthetic hosts. 16 bonding with improved membrane permeability motivate drug Results and Discussion Manuscript designer to incorporate donor/acceptor sites in the chosen The impetus for design of 4-alkylidene/arylidenehydrazino-5- molecular fragments while a plethora of factors encourage a (substituted)aroyl-2-(substituted)amino-1,3-thiazole (Fig. 2) stems synthetic expert in supramolecular domain in doing so. 17-19 Our from likely vast diversity multiplication and scaffold enrichment by recent research focuses on design and synthesis of materials based varying carbonyl component, isothiocyanate or active methylene on thiazole scaffolds for molecular therapeutics. 20-22 It is a well unit, thus making a trivariant system (Table 1). Furthermore, the known fact that despite huge costs involved in the drug discovery Accepted parent scaffold encompasses a range of donor-acceptor groups with process and largely static output in terms of launching new imbalances in their numbers, thus amenable to intra and drugs, 23,24 a large number of molecular fragments bear the burden intermolecular interactions and the formation of multicomponent ‘of no use’ and get discarded. 25-27 Having mentioned the similar crystals (hydrates/solvates) 34, 35 was also predicted. Geometry features in the design of drug and supramolecular synthon, and optimizations (6-31G basis set, Gaussian 09 program) indicated (Fig. successful application of crystal engineering in pharmaceutics 28-32 S1) the molecules to adopt a propeller shape with a thiazole hub we felt it worthy to investigate the solid state structures of novel 4- encased by three blades ( B1-B3), and encouraged synthesis and hydrazino-1,3-thiazoles 33 as supramolecular synthons, in an attempt studies of solid state landscapes in these novel systems. to explore and expand its applicability in materials science along with its potential applications in drug discovery. In the present CrystEngComm study we spotlight on the supramolecular assemblages and potentially tunable guest encapsulations in these propeller-shaped trivariant systems by varying the substituents at the hydrazono position (Fig. 1). 2 | J. Name ., 2012, 00 , 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 14 PleaseCrystEngComm do not adjust margins Journal Name ARTICLE transport of protons in Gramicidin A membrane channels, 46-50 cytochrome oxidase, 51-56 and bacteriorhodopsin. 57-59 The probable role of water in protein folding 60, 61 and correlation of water pathways to the activation of G-coupled receptors 62 all point towards the topical interest in water channels. Albeit the implicit significance of water pores, biomimetic design of synthetic water channels 63 kept low pace, except for a few complex architectures Fig.2 General structure of 4-hydrazino-5-aroyl-2-amino-1,3-thiazole. inspired by aquaporin water 64, 65 or influenza A proton channel 66, 67 Table 1 Variations in B -B . 1 3 till recently. Both inorganic and organic molecules have proven as Entry R1 R2 R3 R4 host lattices for water in restricted environments. The huge IPHAT 1 -CH 3 -CH 3 -C6H5 -C6H5 potential of organic molecules, which have a tendency to crystallize IPHAT 2 -CH 3 -CH 3 -C6H5 4-ClC 6H4 as hydrate 68-74 and the factors stabilizing the hydrates 75 all provide BzHAT -C6H5 -H -C6H5 4-ClC 6H4 Manuscript cue to mimic natural systems among which urea based76-78 or CyHAT -C6H10 - -C6H5 -C6H5 79, 80 imidazole based, were demonstrated as functional channels for Modular synthesis of the molecules was achieved in a versatile ions or water (protons) whereas calixpyrroles 81 were reported to sequential multicomponent reaction (SMCR) for [4+1] thiazole ring stabilize 1D water chains. In yet another perspective, water in formation under mild conditions. In the present communication, hydrates has been utilized as a design element in crystal focus is on providing variants at the hydrazone site by varying 82, 83 engineering. Expanding the crystal database of organic hydrates Accepted carbonyl components and to inspect their influence on the crystal further, we present the synthesis and structural landscapes in landscape and possible supramolecular assemblages. Interestingly, hitherto unexplored molecular crystals with a thiazole core. while probing crystal structures, we found multicomponent Providing acetone as the carbonyl capping for hydrazine unit in B1, molecular crystals from these novel systems to manifest as we accomplished the synthesis of IPHAT 1 and IPHAT 2 as 33 synthetic hosts for one dimensional (1D) water chains, polar protic previously reported by our group. Diffraction quality crystals were solvents and in some cases to house unoccupied voids, all obtained by slow evaporation from aqueous ethanolic solutions. Both systems evolved as monohydrates belonging to non- attributed to the variations in the carbonyl capping units employed centrosymmetric space group P2 /c with Z= 4 with packing for hydrazone formation implying tunable hosts. 1 coefficients of 0.680 (IPHAT 1) and 0.690 (IPHAT 2), whereby the 1D water chains CrystEngComm basic building block appeared as a butterfly-shaped dimer (Fig. 3) One dimensional (1D) water chains/water wires and design of their formed by the antiperiplanar arrangement of thiazole rings pushing synthetic hosts attract enormous research interest owing to their the C=O in B3 to the exterior and aligning B1 and B2 to key roles in fundamental biological processes 36-39 exemplified by accommodate the water molecules in between. selective transport of water across cells in protein aquaporin, 40-45 This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 3 Please do not adjust margins PleaseCrystEngComm do not adjust margins Page 4 of 14 ARTICLE Journal Name Planar arrangement of layered

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