Combinatorial Library Approach to Realize 2-Aminothiazole-Based

Article pubs.acs.org/crystal

Combinatorial Library Approach to Realize 2‑Aminothiazole-Based Two-Component Hydrogelator: A Structure−Property Correlation Priyanka Yadav,† Pradip Kr. Dutta,‡ and Amar Ballabh*,† †

Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur 741252, West Bengal, India

‡

S Supporting Information *

ABSTRACT: Crystal engineering and supramolecular synthons approach are applied to synthesize a series of 2aminothiazole (and its methyl derivatives) salts/cocrystals with various dicarboxylic acids. On the basis of combinatorial library approach, 24 new salts/cocrystals of 2-aminothiazole and its methyl derivatives with various dicarboxylic acid (aliphatic unsaturated and saturated backbone) were synthesized and characterized. All the synthesized salts were subjected to gelation test in various solvents (polar and nonpolar). Interestingly, one of the salts/cocrystals, i.e., B3A6 (5methyl-2-aminothiazolium hydrogen decandioate) was found to be capable of immobilizing water at slightly higher minimum gelator concentration (MGC). A structure−property correlation between various cocrystals/salts based on single crystal X-structure of 11 compounds was undertaken. The gelation property of 2-aminothiazole-based gelling agent was found to be governed by the position of a methyl group on the thiazole ring, a length of the aliphatic carbon chain of dicarboxylic acid, and formation of hydrogen bonded network (HBN) leading to void in the single crystal structure. The comparison of single crystal X-ray structures of nongelators and a gelator were undertaken to understand the probable mechanism of hydrogelation in the series of 2-aminothiazole-based salts/cocrystals.

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INTRODUCTION Crystal engineering, a subdiscipline of supramolecular chemistry, is a fascinating area of research, which has its foundation on understanding noncovalent interactions predominantly observed in crystals and exploiting those interactions for developing novel materials such as gas-storage materials, pharmaceutical active ingredient using the concept of polymorphism, magnetic, optical materials, etc.1−4 Supramolecular synthons,5 frequently observed noncovalent interactions, which govern the overall assembly in crystal, provide a tool to design materials of choice. Recently, crystal engineering and supramolecular synthons concepts are employed to design some physical gels or supramolecular gels.6 Low molecular organic gelators (LMOGs) or supramolecular gels7−11 are colloidal systems containing a small amount of low molecular mass organic compounds (mol wt < 3000), as dispersed phase, and a large quantity of solvent (organic and aqueous), as dispersion medium. Hydrogen bonds, coordination bond, π−π interaction, and charge transfer interactions are frequently being used as reliable tools to design and synthesize a new supramolecular gelator. Multicomponent supramolecular gelators,12 a member of huge family of supramolecular gelators, enjoy a special position among single component gelators mainly due to the following reasons: (i) a systematic change of the single component of the gelling system is useful to understand the gelation/nongelation property (structure−property correla© 2014 American Chemical Society

tion); (ii) the role of functional groups (types and position) may be studied meticulously; (iii) the effect of hydrophobic/ hydrophilic interactions on gelation property can be envisage by gradual change in alkyl chain; (iv) ease of synthesis of a large number of compounds (combinatorial library approach). Organic salts/cocrystal-based gelators represent a special class of multicomponent LMOGs. Organic salt/cocrystals have a distinguished advantage over other classes of gelators such as ease of synthesis, almost quantitative yield, availability of carboxylic acids/amines with various backbone (aliphatic, aromatic, and alicyclic), etc. In the present work, we present a combinatorial library approach to synthesize and characterize various 2-aminothiazole-based (and its methyl derivatives) organic salts/cocrystals with potential application as a gelling agent (Table 1). The main driving force for the present study was our success with melamine-13 and thiazole-based14,15 gelator, specifically thiazole moiety, which turned out to be a quite reliable scaffold for organo/hydrogelation. Moreover, predictable hydrogen bonded networks (HBN) of 2-aminothiazole moiety and carboxylic acid/carboxylate ion provide an opportunity to design supramolecular assemblies with various dimensionality, Received: August 2, 2014 Revised: September 8, 2014 Published: September 19, 2014 5966

dx.doi.org/10.1021/cg501156p | Cryst. Growth Des. 2014, 14, 5966−5975

Crystal Growth & Design

Article

Table 1. Combinatorial Library Approach to Synthesize a Series of Cocrystals/Saltsa

a

acid

A1

A2

A3

A4

A5

A6

A6

A7

amine

(1:1)

(1:1)

(1:1)

(1:1)

(1:1)

(1:1)

(1:2)

(1:1)

B1 B2 B3

B1A1 B2A1 B3A1

B1A2 B2A2 B3A2

B1A3 B2A3 B3A3

B1A4 B2A4 B3A4

B1A5 B2A5 B3A5

B1A6 B2A6 B3A6

B1A6a B2A6a B3A6a

B1A7 B2A7 B3A7

Values in parentheses, i.e., (1:1) and (1:2), indicate the molar ratio of acid/amine.

Scheme 1. Probable Supramolecular Synthon in (A) 2-Aminothiazole-Monocarboxylic Acid Cocrystals, (B) 2-AminothiazoliumMonocarboxylate Salts, (C) 2-Aminothiazolium Hydrogen-Dicarboxylate (1:1 Organic Salts) Having Carboxylic Dimer Synthon and (D) 2-Aminothiazolium Hydrogen-Dicarboxylate (1:1 Organic Salts) Having Carboxylic Catemer Synthon

with all possible substitution along with COOH/COO− moiety, resulted in 20 hits of which 15 are two-component 2aminothiazole-based salts/cocrystals (Supporting Information, Table S1). Surprisingly, all the 15 salts displayed cyclic heterosynthon of graph set representation R22 (8), which is in agreement with literature on 2-aminoheterocylic-carboxylic acid.18 Interestingly, the CSD search of structurally similar 2aminothiazoline salts/cocrystal resulted in eight hits with persistent occurring heterosynthon R22 (8) (Supporting Information, Table S1). The regular occurrence of cyclic

which may act as potential LMOGs (Scheme 1). 2-Aminothiazole moiety may create zero-dimensional (0D) network when reacted with mono- and di-carboxylic acids (1:1 molar ratio) through the formation of cyclic hydrogen bonded motifs A and B (fourth and fifth most probable motifs with 82% and 76% of probability, respectively).16 The reliability of cyclic hydrogen bonded motif of graph set representation17 R22 (8) of 2-aminothiazoles (or its derivatives) salts/cocrystals was further supported by the CSD search (CSD version 5.35 updates November 2013). A CSD search of 2-aminothiazole moiety 5967



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heterosynthon of graph set R22 (8) in 2-aminothiazole/2aminothiazoline-based salts/cocrystals and predictable hydrogen bonded network inspired us to design and synthesize a new series of 2-aminothiazole-based organic salts/cocrystals. Moreover, the presence of additional hydrogen bonding site of amine functionality along with probable secondary interactions such as C−H···S/C−H···N, C−H···O, S···O, etc., capable of extending 0D network to one-dimensional (1D) or two-dimensional (2D) hydrogen bonded network, are quite promising for designer supramolecular architecture. In addition, a suitable position of the methyl group on thiazole moiety may provide an opportunity to understand the role of (methyl)C−H···S/N (thiazole) in gelation/nongelation behavior of these salts/ cocrystals as seen in our earlier work on 2-amidothiazole systems.14 One of the major challenges in the area of supramolecular gelator is to design a molecule with predictable gelling properties toward solvents of choice. Even though designing an organogelator based on crystal engineering approach, where 1D HBN favors organogelation and 2D and 3D HBNs may lead to formation of a weak gel or nongelation at all,6,19 is quite successful, no such strategies are available for synthesis of a new hydrogelator. However, Dastidar and co-workers20 reported the formation of a porous hydrogen bonded network, interacting with their gelling solvent, as a probable cause of hydrogelation. Many such studies are required to understand how water gets immobilized in complex HBN and are the supramolecular assemblies observed in the crystal structure retained in the gel state or not? Another driving force for the present study is the availability of limited reports on organic salts/cocrystals of 2aminothiazole and its derivatives21−31 (Supporting Information, Table S1), especially methyl derivatives of 2-aminothiazole, which limit our understanding of weak hydrogen bonds such as (methyl)C−H···N or (methyl)C−H···S, and its use as reliable supramolecular synthons.32 In the present study, 24 new salts/ cocrystals of 2-aminothiazole (and its methyl derivatives) were synthesized and characterized (Chart 1). Eleven out of 24 salts/

aminothiazole (B1), 4-methyl-2-aminothiazole (B2), and 5methyl-2-aminothiazole (B3), and various dicarboxylic acids. In the present study, 24 salts were synthesized out of which 21 compounds were reacted in the molar ratio 1:1 (acid/amine) and three compounds in the molar ratio 1:2 (acid/amine). The formations of cocrystals/salts were established by FT-IR and 1 HNMR (see Supporting Information). Maleic acid (A1) when reacted with amines B1, B2, and B3 in the molar ratio (1:1) resulted in the formation of monocarboxylate salts (B1A1, B2A1, and B3A1). The formation of monocarboxylate salts were confirmed by the presence of parent Maleic acid strong CO asymmetric stretching peak in the range of 1701−1704 cm−1 along with the presence of additional peak characteristic of carboxylate (asymmetric CO stretching) in the range of 1650−1550 cm−1. The formations of monocarboxylate salt were further confirmed by the 1H NMR and single crystal X-ray studies. Similarly, fumaric acid (A2) and malonic acid (A3) also showed the formation of monocarboxylate salt (one carboxylic acid CO asymmetric (1667−1669 cm−1) and one carboxylate CO stretching (1616 cm−1)) with B1, B2, and B3. Understandably, very low pK1 values of fumaric acid, maleic acid, and malonic acid, as compared with 2-aminothiazole, lead to the formation of monocarboxylate salts of these acids (difference between pK of acid and amine (ΔpK) =3 or more leads to the formation of salts),33,34 whereas other aliphatic dicarboxylic acids resulted in the formation of cocrystals except decanedioic acid (A6) formed monocarboxylate (B3A6) as well as dicarboxylate salts (B3A6a). The formations of cocrystals/ salts were confirmed by single crystal X-ray studies in most of the cases. Gelation Studies. All the newly synthesized compounds were subjected to gelation test in various solvents with varying degree of polarity including highly polar solvent, i.e., water (see Supporting Information, Table S2). Most salts/cocrystals showed fewer tendencies to immobilize the solvents used in the present study except 2-amino-5-methylthiazolium hydrogen 1,8-decanedicarboxylate (B3A6), which displayed excellent capability to immobilize water. A series of 1:2 salts of sebacic acids and 2-aminothiazole derivatives were synthesized to establish the role of free carboxylic acid in the gelation process. Interestingly, the salt B3A6a turned out to be nongelators. It establishes the role of free COOH in generating a 1D hydrogen bonded chain as one of the requirements of gelation (see Scheme 1). As gelation was not shown by 1,6-octanedioic acid and 1,10-dodecanedioic acid salts, recommending a critical chain length (methylene group, n= 8), is required to impart the gelation behavior in this series of compounds. In order to explore the strength of hydrogel formed by B3A6 salt, a graph of Tgel versus concentration of gelator molecules (in weight % w/v) was plotted. The plot showed a gradual increase in Tgel up to a certain concentration of gelator (8 wt %); afterward Tgel values were found to be independent of gelator concentration (Figure 1). Understandably, the increase in gelator concentration improves the self-aggregation and stability of supramolecular assembly not beyond certain critical concentration. The nature of graph for Tgel versus concentration of gelator is frequently observed for supramolecular gelators. To get an insight into the gelator morphology, SEM studies were carried out on xerogel (dried gel) of B3A6. Xerogel of gelator B3A6 showed an entangled fibrous network of molecules, which might have immobilized the solvent through various noncovalent interactions (Figure 2).

Chart 1. List of Compounds Synthesized in the Present Study

cocrystals were characterized by X-ray crystallography to understand the role of various noncovalent interactions on gelation/nongelation behavior especially in bulk/xerogel state.

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RESULTS AND DISCUSSION A simple mixing of amine with dicarboxylic acids (1:1 and 1:2) in a suitable solvent resulted in the formation of cocrystals/ salts, depending upon the pKa difference of bases, 25968



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one molecule of malonic acid and one molecule of 2aminothiazole. Propanedioic acid was found in a monocarboxylate form containing intramolecular hydrogen bond, i.e., O− H···O(O···O= 2.481 Å; ∠O−H···O= 150.81°). Components were found to be strongly hydrogen bonded with each other through cyclic N−H···O interactions forming R22 (8) graph set. Interestingly, the 0D hydrogen bonded network extends to 1D network through unusual noncovalent interaction of (carbonyl)O···S(thiazole) (O···S = 3.033 Å). We would like to mention that similar O···S interactions were found in the series of amidothiazole gelator14 and most of the known 2aminothiazole salts/cocrystals21−29,31 (Supporting Information, Table S1) 2. Bis-(2-aminothiazolium)-hexanedioate-hexanedioic Acid Monohydrate (B1A4·H2O). B1A4·H2O salt crystallizes out in a Triclinic space group P1̅. The asymmetric unit contains a half hexanedioic acid and a half of hexanedioate moiety along with one molecule each of 2-aminothiazole and water. The structure contains well-defined a 1D hydrogen bonded network of COOH···COO−, which is extended to another direction by a dicarboxylate species hydrogen bonded to two 2-aminothiazole moieties (+N−H···O− and N−H···O interactions). Supramolecular assembly of B1A4·H2O is found to contain a welldefined void occupied by water molecules (see Figure 4 A,B). Water molecules are found to be hydrogen bonded to the carbonyl oxygen of adipic acid moiety. 3. 2-Aminothiazole/Octanedioic Acid Cocrystal (B1A5). B1A5 crystallized out in the monoclinic P21/n space group. The asymmetric unit contains one 2-aminothiazole molecule and half a molecule of octanedioic acid sitting in a special position. The two species were found to be strongly hydrogenbonded through N−H···O (N···O = 2.873 Å; ∠N−H···O = 171.5°) and O−H···N (O···N = 2.641 Å; ∠O−H···N = 153.18°) cyclic supramolecular synthons (Scheme 1). The overall assembly is found to be 2D through the amine proton noncovalent interaction to the neighboring carbonyl oxygen of A5 molecules (N−H···O = 2.873; ∠N−H···O = 149.70°). A secondary interaction C−H···S14 is also observed in the B1A5 crystal structure leading to 3D network (C−H···S = 3.809 Å; ∠C−H···S = 154.42°) (Figure 5). 4. 2-Aminothiazole/Decanedioic Acid Cocrystal (B1A6). B1A6 crystallizes in a monoclinic space group P21/c (Figure 6). The asymmetric unit contains one molecule of 2-aminothiazole and a half molecule of decanedioic acid sitting in a special position. The B1 and A6 molecules are joined through cyclic supramolecular synthon of R22 (8) graph set (O−H···N = 2.636

Figure 1. Effect of gelator B3A6 concentration (in wt %) on sol-to-gel transition temperature (Tgel).

Figure 2. SEM image of xerogel of B3A6 prepared in water (4 wt % w/v).

Single Crystal X-ray Studies. Single crystal X-ray studies of synthesized compound were carried out to understand the probable cause of hydrogelation/nongelation of 2-aminothiazole-based salts/cocrystals with dicarboxylic acid. Single crystal studies of gelling/nongelling compounds provide an opportunity to look inside the packing pattern of molecules to ascertain the probable cause of gelation at least to xerogel (dried gel) state. Fortunately, we are able to obtain the X-ray structures of gelator molecule (B3A6) along with structures of 10 nongelator molecules. 1. 2-Aminothiazolium-hydrogen Propanedioate (B1A3). B1A3 crystallizes out in the noncentrosymmetric monoclinic space group P21 (Figure 3). The asymmetric unit consists of

Figure 3. View of B1A3: 2D network of N−H···O and O···S interactions. 5969



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Figure 4. View of B1A4·H2O: (A) 2D hydrogen bonded network containing water molecules; (B) hydrogen bonded network after removal of water molecules (space fill model).

Figure 5. View of B1A5: (A) 2D hydrogen bonded network of N−H···O and O−H···N ; (B) a weak noncovalent interaction of C−H···S (thiazole) present in the structure.

Figure 6. View of B1A6: (A) 2D hydrogen bonded network mediated by N−H···O and O−H···N interactions (heterosynthon R22 (8) is shown with ball and stick model); (B) weak C−H···π interaction between the neighboring 2-aminothiazole moieties.

Figure 7. View of B2A5: (A) 1D hydrogen bonded network through cyclic N−H···O and O−H···N noncovalent interactionss; (B) weak C−H···O interaction between adjacent acid and amine.

thiazole moiety π-electrons (C−H···thiazolecentroide = 3.772; β ∠C−H···thiazolecentroide = 133.9°; α ∠thiazolecentroide-C···H(thiazole ring) = 12.44°). 5. 2-Amino-4-methylthiazole/Octanedioic Acid Cocrystal (B2A5). B2A5 crystallizes out in centrosymmetric monoclinic space group P21/c. The asymmetric unit contains one molecule

Å; ∠O−H···N = 170.68°; N−H···O = 2.949 Å; ∠N−H···O = 163.2°) forming 0D HBN. The supramolecular assembly is extended to 2D due to the presence of hydrogen bond between one of the amine hydrogen and carbonyl oxygen of acid moiety. A critical examination of the structure showed C−H···π interaction between thiazole ring hydrogen and neighboring 5970



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amino-5-methylthiazolium and maleic acid. The one hydrogen of carboxylic acid is found to be intramolecularly hydrogen bonded between two carboxylic acid groups. The robust cyclic supramolecular synthons between thiazole ring nitrogen, amine hydrogen, and charged oxygen atoms was also observed in B3A1. A 0D network of acid/amine extends into twisted 1D HBN through the additional amine hydrogen with the carbonyl oxygen. Furthermore, the 1D chain extends to a more complex assembly through weak interactions (thiazole)C−H···O (C···O = 3.727 Å; ∠C−H···O= 162.18°) and (methyl)C−H···O (C··· O = 3.409 Å; ∠C−H···O = 154.99°). 8. Crystal Structure of 2-Amino-5-methylthiazolium Fumarate: Fumaric Acid (B3A2). The asymmetric unit of salt B3A2 (monoclinic, C2/c) contains a half molecule of fumaric acid and a half molecule of fumarate ion along with one molecule of 2-amino-5-methylthiazolium. The fumarate ion is H-bonded with other fumaric acid molecules leading to a 1D chain along with interacting with 2-amino-5-methylthiazolium ion resulting in a 2D network (Figure 10A). Interestingly, the 2D network of salt B3A2 extends to 3D through the unusual Hbond, CO···S(thiazole). The carbonyl oxygen of the carboxylate group, not the carbonyl group of carboxylic acid, is interacting with the thiazole sulfur (O···S = 3.194 Å). The other secondary force observed in the crystal structure is C− H···S (C−H···S = 2.791 Å; ∠C−H···S = 144.35°) and leads to a complex hydrogen bonded network (Figure 10B). 9. Crystal Structure of 2-Amino-5-methylthiazolium Hydrogen 1,10-Decanedioate (B3A6). B3A6 crystallizes in the space group monoclinic P 21/n space group. The asymmetric unit contains monocarboxylate salt of A6 and B3. The robust 1D hydrogen bonded network of COOH···COO− was observed along with N−H···O and O−H···N(thiazole) cyclic supramolecular synthons. The additional Hydrogen bonding sites of amines lead to the 2-D network through the bifurcated H-bond with CO. The overall supramolecular assembly found to have well-defined void (Figure 11). These spaces or opening seen in the space fill model of B3A6 suggests probable sites where solvents may entrap or weakly H-bonded. 10. Crystal Structure of bis(2-Amino-5-methylthiazolium) 1,10-Decanedioate (B3A6a). The salt B3A6a crystallizes out in the monoclinic crystal system with space group P21/n. The asymmetric unit of crystalline phase contains two molecules of 2-amino-5-methylthiazole and one molecule of 1,10-decanedioic acid. The one-dimensional hydrogen bonded network of B3A6a comprises two different hydrogen bond motifs, namely, R22 (8) [(thiazole) N−H···O (N···O = 2.609 Å; ∠N−H···O =

of 2-amino-4-methylthiazole and half a molecule of octanedioic acid sitting in a special position. One-dimensional hydrogen bonded network is formed by strong O−H···N and N−H···O cyclic supramolecular synthon as shown in Scheme 1. The supramolecular assembly extends to 2D sheet-like structure through the formation of C−H···O (C···O = 3.465 Å; ∠C−H··· O = 164.71°) interactions between the thiazole ring hydrogen and hydroxyl oxygen of acid. Interestingly, the methyl proton of 2-amino-4-methylthiazole is found not interacting with any neighboring atoms (Figure 7). 6. 2-Amino-4-methyl Thiazole/Decanedioic Acid Cocrystal (B2A6). B2A6 also crystallizes out in one of the most common space groups, i.e., P21/c. The two components of cocrystal were found in the asymmetric unit having one molecule of 2-amino4-methylthiazole and a half molecule of decanedioic acid. The cyclic supramolecular synthon with R22 (8) graphic set is observed in the crystal structure leading to a 0D network, which is extended to a 2D network through the strong H-bond between carbonyl oxygen and free amine N−H proton, i.e., N− H···O (N···O = 2.979 Å; ∠N−H···O = 161.31°) (Figure 8). The crystal structure of B2A6 does not show any other significant weak noncovalent interactions as observed in the other crystal structures.

Figure 8. View of B2A6: zigzag supramolecular assembly containing N−H···O and O−H···N interactions.

7. 2-Amino-5-methylthiazolium Hydrogen Maleate (B3A1). The reaction of B3 with A1 resulted in molar ratio 1:1 in the formation of monocarboxylate salt (B3A1) (Figure 9). B3A1 crystallizes out in a monoclinic P21/n space group. The asymmetric unit of B3A1 contains one molecule of 2-

Figure 9. View of B3A1: (A) 1D hydrogen bonded zigzag structure through N+−H···O− and N−H···O; (B) presentation of the weak interactions, such as (thiazole)C−H···O and (methyl)C−H···O,(alkene)C−H···O. 5971



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Figure 10. (A) Supramolecular synthons observed in B3A2; (B) 3D hydrogen bonded network of B3A2.

Figure 11. A) 3D network of B3A6 in capped sticks model (red colored and blue colored capped sticks represents dicarboxylic acids and thiazole amines, respectively) and B) Space fill model of B3A6.

Figure 12. (A) One-dimensional hydrogen bonded network of B3A6a; (B) secondary noncovalent interactions of C−H···O present in B3A6a.

Figure 13. One-dimensional hydrogen bonded network of B3A7.

165.13°), (amine) N−H···O (N···O = 2.772 Å; ∠N−H···O = 166.61°)] and R24 (8) [N···O = 2.817 Å; ∠N−H···O = 148.63°; N···O = 2.834 Å; ∠N−H···O = 142.97°; N···O = 2.762 Å; ∠N−H···O = 169.56°; N···O = 2.772 Å; ∠N−H···O = 166.61°) (see Figure 12A). The 1D hydrogen-bonded networks extend to 2D by the presence of multiple weak C−H···O interaction [(thiazole)C···O = 3.373 Å; C−H···O = 169.32°]

(Figure 12B). The space fill model of the structure of B3A6a depicts no void as seen in the structure of monocarboxylate salt (B3A6) compounds. 11. Crystal Structure of 2-Amino-5-methylthiazolium/ 1,12-dodecanedioic Acid Cocrystal (B3A7). The nongelator structure B3A7 crystallizes out in a triclinic (P1̅) space group with one molecule of acid and amine in the asymmetric unit. 5972



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the earlier CSD database analysis.18 However, the hydrogen bond distances (2O′···1N′ and 1O′···2N′) in supramolecular synthon B was found to be well above 0.2 Å. The bond angles between 2N−2C−1N (or 2N′−2C′−1N′) of 2-aminothiazole moiety salts/cocrystals were found to lie between 122.98° to 125.50° in accord with previous reported crystal structure analysis.18 Our study supports the formation of the 2-aminothiazole/ carboxylic acid heterosynthon R22 (8) as a reliable supramolecular motif despite the change in environment (carboxylic acid backbone and substitution on 2-aminothiazole). The other important supramolecular synthon observed in this series of salt/cocrystal is the cyclic bifurcated H-bond between carbonyl oxygen and amino group hydrogen, i.e., heterosynthon with graph set R24 (8). Interestingly, the sulfur atom of thiazole moiety is found to be involved in many secondary interactions such as S···O and C−H···S, which are less known supramolecular synthons.36−38 We believe that the presence of a bunch of weak interactions such as C−H···O, C−H···S, S···O, etc., provide the extra stability to supramolecular assembly and may be playing an important role in the formation of a gel/ crystalline phase. In order to understand the role of methyl functionality on gelation behavior, gelator molecule (B3A6) packing was compared with molecules having the same alkyl chain (B1A6 and B2A6), i.e., similar hydrophobic forces. Single crystal packing of structurally similar gelling compound (B3A6) and nongelling compounds (B1A6 and B2A6) brought the striking fact that B1A6 and B2A6 both formed hydrogen bonded 2D sheets, whereas gelling compound B3A6 formed a 3D network with a void. Moreover, B3A6 hydrogen bonded network was stabilized by the presence of weak (thiazole)C−H···O bond, which was absent in the case of nongelling compounds. Evidently, the role of position of a methyl group on the thiazole moiety in the series of organic salts/cocrystals (B1A6, B2A6, and B3A6) was to provide the steric hindrance in the packing of overall supramolecular assemblies leading to a distorted Hbond network with a cavity, where solvent may be immobilized. We would like to stress that very few examples are reported in the literature where gelator molecules were found to be interacting with their gelling solvent, based on single crystal and computational studies13,20,39−41 having a well-defined void to accommodate the solvent molecules. In an elegantly designed experiment, Uday Maitra and his group were able to establish the formation of hydrophobic void during hydrogelation.42 Interestingly, the salt B1A4, a nongelator, also displayed the formation of a well-defined void having two molecules of water occupy the empty space (see Figure 4B). The single crystal data collected at 25 °C show the water molecules held strongly hydrogen bonded without any distortion in thermal ellipsoid. Understandably, strongly held water molecules in the guest molecule support the crystalline phase instead of the metastable gel phase. The observation makes us believe that hydrophobic forces due to alkyl chain are critical for inducing gelation of water. Many such examples need to be explored to support the hypothesis that hydrogelation is favored by small molecules capable of the formation of a 3D network with an appropriate cavity to immobilize water.

One-dimensional hydrogen bonded network of B3A7 is created by the combination of two hydrogen bonded motifs, i.e., R22 (8) and R24 (8) graph set. No significant secondary interaction is observed in the structure (Figure 13). Powder X-ray Diffraction Study. One of the commonly followed methods , to ascertain the packing of molecules inside the gelator fibers, is comparing the powder X-ray diffraction (PXRD) patterns of bulk solid, simulated single crystal structure (if any), xerogel (dried gel), and gel network containing solvent.35 This method is useful in determining the gelator molecules packing in the xerogel state with certainty, if the single crystal structure of gelator is known, but lacks the concrete evidence to propose packing inside the gelator fibers in the gelled state (due to strong scattering by the solvents). The simulated and xerogel PXRD of the salt B3A6 were found nearly superimposable, while PXRD patterns of the bulk did not match well with that of the simulated or xerogel PXRDs (Figure 14). This means that the single crystal structure

Figure 14. Powder X-ray diffraction pattern of B3A6 in bulk, xerogel, and simulation (single crystal X-ray structure).

of the salt concerned represents the xerogel, whereas the corresponding bulk material contains different crystalline phases. We are not in a position to comment on the packing of B3A6 molecule in gelator fibers in the gel state, due to strong masking of diffraction peaks by water molecules. The single crystal structures of 11 salts/cocrystals displayed robust supramolecular synthons (A and B), cyclic N−H··· O/+N−H···O− with graph set R22 (8), between 2-aminothiazole and carboxylic/carboxylate functional groups (Scheme 2). A detailed list of bond distances and bond angles of atoms involved in the formation of heterosynthon R22 (8) obtained from the single crystal studies are tabulated in Table 2. The difference between the distance of 2O···1N and 1O···2N in supramolecular synthon A in all the reported salt crystal structures was found to be well below 0.2 Å in agreement with Scheme 2. Naming Scheme Adopted for Study of R22 (8) Graph Set Representation of Supramolecular Synthons A and B Observed in the Crystal Structures

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EXPERIMENTAL SECTION

Materials and Physical Measurements. 2-Aminothiazole, 2amino-4-methylthiazole, 2-amino-5-methylthiazole, maleic acid, fumaric acid, malonic acid, adipic acid, suberic acid, sebacic acid, and

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Table 2. Distances (Å) and Angle (deg) for the Geometrical Features in the Heterosynthon R22 (8) in Various Salts and Cocrystals bond distances (in Å) salts

cocrystals

name of compound

type of synthon

B1A3 B1A4·H2O B3A1 B3A2 B3A6 B3A6a

A A A A A A

2

O···1N

1

O···2N

2.778 2.689 2.733 2.697 2.694 2.609

name of compound

type of synthon

B1A5 B1A6 B2A5 B2A6 B3A7

B B B B B

2

O′···1N′

dodecanoic acid (all from Aldrich) were used as received. The other chemicals were of the highest commercial grade available and were used without further purification. The liquids used for the preparation of gels were reagent grade. All solvents used in the synthesis were purified, dried, and distilled as required. FTIR spectra were recorded on a PerkinElmer-RX FTIR instrument. Solid samples were recorded as an intimate mixture with powdered KBr. The 1H-NMR spectra were measured by using a BRUKER AVANCE, 400 MHz with TMS as internal standard. The morphological analysis of xerogel of B3A6 was carried out on SEM (JEOL JSM5610 LV microscope). The powder Xray diffraction patterns were recorded on an XPERT (Cu Kα radiation) diffractometer. Single Crystal X-ray Study. Crystals of B1A3, B1A4, B1A5, B3A1, B3A2, and B1A6, B3A6a, B2A5, B2A6, B3A6, B3A7 were obtained from 80/20 methanol/water mixture and methanol, respectively, in a slow evaporative condition at room temperature (25 °C). The crystals of B3A6 and B3A6a were obtained after lots of effort with highly anisotropic growth (thin fibers). Diffraction data for B1A6, B2A6, B3A2, and B3A6 was collected using (BRUKER KAPPA APEX II CCD Duo) with graphite monochromatic Mo Kα radiation (0.71073 Å), and B1A3, B1A4, B1A5, B2A5, B3A1, B3A6a, and B3A7 were collected using CuKα (λ = 1.5418 Å) radiation on an Xcalibur, Eos, Gemini diffractometer. All structures were solved and refined using the Olex2 software43 and ShelXL44 refinement package. Graphics were generated using MERCURY 3.3. All structures were solved by direct methods and refined in a routine manner. In all cases, non-hydrogen atoms were treated anisotropically. Whenever possible, the hydrogen atoms were located on a difference Fourier map and refined. In other cases, the hydrogen atoms are geometrically fixed. Synthesis. All the compounds were prepared by mixing the dicarboxylic acids (A1−A7) with corresponding amines (B1−B3) in hot methanolic solution in a 1:1/1:2 molar ratio. The mixtures were cooled slowly and kept at room temperature (25 °C) for drying (if necessary under vacuum). The organic salts/cocrystals were obtained in almost quantitative yield, which were subjected to characterization by various physicochemical techniques. Gelation Studies. Salt B3A6 was tested for their gelation behavior in various solvents of different polarity by the test tube inversion method. Ten milligrams of the sample test tube and 1 mL of solvent were added to a test tube. The suspension of salt in solvent was heated in an oil-bath for a few minutes until the solute dissolved completely. The hot solution was kept at room temperature for observation. The inverted test tube method was used to verify the gel formation. Tgel (gel-to-sol conversion temperature) was measured using small glass beads (weighing about 63 mg) placed on the upper surface of gel formed in a glass tube. The test tube was heated in oil-bath until the glass ball fell to the bottom of the test tube. The temperature at which

N···2C

bond angles 2

N···2C

(2N−C−1N) 125.25 123.02 125.50 125.13 122.98 123.54 bond angles

2.765 2.767 2.812 2.862 2.790 2.772 bond distances

1.33 1.325 1.327 1.320 1.322 1.318 (in Å)

1.295 1.312 1.311 1.323 1.331 1.326

O′··· 2N′

1

2

1

2.641 2.636 2.587 2.664 2.614

1

2.884 2.949 2.914 2.951 2.953

N′···2C, 1.316 1.309 1.303 1.313 1.308

N′···2C′

(2N−2C−1N)

1.329 1.326 1.333 1.339 1.339

123.98 123.28 123.52 123.97 123.45

the semisolid mass lost its weight bearing capacity and gel convert into a sol was noted as Tgel (see Figure 1).

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CONCLUSIONS A new series of 2-aminothiazole-based salts were synthesized and characterized for their gelation behavior. Eleven single crystals of gelator and nongelling compounds were solved to understand the probable cause of gelation of water in this series of compounds. It is very clear from our study that the formation of void along with sufficient hydrophobic interaction may help in hydrogelation. Single crystals of two compounds, namely, B1A4 (nongelator) and B3A6 (gelator), showed the supramolecular assembly leading to the formation of void suggested the crucial role of the hydrophobic carbon chain in inducing the immobilization of solvent in these voids. We believe more such studies need to be undertaken so that the hypothesis that 3D supramolecular assembly having hydrophobic pockets supports hydrogelation will be established.

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ASSOCIATED CONTENT

S Supporting Information *

Physicochemical characterization data of salts/cocrystals, CSD search result on 2-aminothiazole salts/cocrystals, gelation table, crystallographic information table, and CIF files of B1A3, B1A4, B1A5, B1A6, B2A5, B2A6, B3A1, B3A2, B3A6, B3A6a, and B3A7. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

* Fax: +91-265-2795569. Tel: +91-265-2795552. E-mail: [email protected] or amar.ballabh-chem@msubaroda. ac.in. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS P.Y. is thankful to UGC, New Delhi for a research fellowship (SMS/F.4-1/2006/XI Plan-BSR) and A.B. would like to 5974



Article

acknowledge UGC, New Delhi for financial support [MRP F. No.37-379/2009 (SR)]. The authors would like to acknowledge the DST-PURSE program for funding the single crystal Xray diffractometer facility at the Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat (India).

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Combinatorial Library Approach to Realize 2-Aminothiazole-Based

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