Helical Preorganization of Molecules Drives Solid-State Intermolecular

Dec 7, 2016 - †Centre for Materials Characterization and §Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune, Maharashtra 41100...
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Helical Preorganization of Molecules Drives Solid-State Intermolecular Acyl-Transfer Reactivity in Crystals: Structures and Reactivity Studies of Solvates of Racemic 2,6-Di‑O‑(4-fluorobenzoyl)myo-inositol 1,3,5-Orthoformate Shobhana Krishnaswamy,*,†,# Mysore S. Shashidhar,§ and Mohan M. Bhadbhade∥ †

Centre for Materials Characterization and §Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune, Maharashtra 411008, India ∥ Mark Wainwright Analytical Centre, University of New South Wales, Sydney, New South Wales 2052, Australia S Supporting Information *

ABSTRACT: Racemic 2,6-di-O-(4-fluorobenzoyl)-myo-inositol 1,3,5-orthoformate yielded structurally dissimilar solventfree and solvated crystals depending upon the solvent of crystallization. The solvated crystals exhibited helical assembly of host molecules, due to the interaction of the guest molecules with the orthoformate moiety of the host. Some of the solvates showed specific but incomplete benzoyl group transfer reactivity below the phase transition temperature, whereas the reaction in solvent-free crystals led to a mixture of several products. These results reveal the necessity of helical molecular packing of the reacting molecules in their crystals to facilitate specific intermolecular acyl transfer reactivity. The crystal structures of the fluorobenzoate solvates were similar to those of the solvates of the analogous chloro and bromobenzoates. The latter could be thermally transformed into their solvent-free form via melt crystallization, resulting in the conversion of a helical molecular packing into a nonhelical molecular packing.

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INTRODUCTION “Halogen bonding” refers to the attractive interaction between the electrophilic region of a halogen atom and a neutral or anionic Lewis base.1,2 The tendency to engage in halogen bonding interactions follows the order I > Br > Cl > F among the halogens in order of decreasing polarizability. Fluorine is highly electronegative and has low polarizability; therefore, its ability to participate in halogen and hydrogen bonding interactions is significantly reduced.3−5 A number of studies have reported the use of halogen atoms for directing the formation of desired molecular assemblies for specific functions.6−9 Halogen atoms located on aromatic rings at the periphery of large molecules can participate in hydrogen/ halogen bonding interactions and influence the molecular organization in the crystalline state.10−12 From our laboratory, we had previously reported facile intermolecular acyl transfer reactions in crystals of racemic 2,6di-O-benzoyl-myo-inositol 1,3,5-orthoesters 1−3 (Scheme 1).13−16 Our solid-state reactivity and structure correlation experiments had suggested that one of the factors that facilitates clean intermolecular acyl transfer reactivity in molecular crystals (comparable to that achieved with high specificity only by enzymes17,18) is the favorable helical molecular preorganization which brings the electrophile (El, the ester CO) and the nucleophile (Nu, OH) in the right orientation for the acyl © XXXX American Chemical Society

Scheme 1

transfer reaction. Therefore, in our quest for similar molecules that could support acyl transfer in the solid state, we prepared halogen substituted benzoates of myo-inositol 1,3,5-orthoformate (halogen X = chlorine, bromine, fluorine, Chart 1).19,20 The crystal structures of the halobenzoates 10 and 11 turned out to be widely different from those of the dibenzoates 1−3 due to halogen bonding interactions in the former. The solventfree dimorphs of racemic halobenzoates 10 and 11 revealed one-dimensional isostructurality in their organization; both Received: September 6, 2016 Revised: December 1, 2016 Published: December 7, 2016 A

DOI: 10.1021/acs.cgd.6b01322 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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in a helical manner with the intervention of the included solvent. Hence, they proved to be good molecular systems for testing the importance of helical assembly for the occurrence of intermolecular acyl transfer in crystals (Scheme 1). The results of these investigations do suggest that helical assembly of molecules in crystals is crucial for the occurrence of intermolecular acyl transfer reactivity in them.

Chart 1. Molecular Structure of Mono-, Di-, and Trihalobenzoatesa

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a

EXPERIMENTAL SECTION

Synthesis and Crystallization. Diesters racemic 2,6-di-O-(4bromobenzoyl)-myo-inositol 1,3,5-orthoformate (10), racemic 2,6-diO-(4-chlorobenzoyl)-myo-inositol 1,3,5-orthoformate (11),19 and the triesters 2,4,6-tri-O-(4-bromobenzoyl)-myo-inositol 1,3,5-orthoformate (13) and 2,4,6-tri-O-(4-chlorobenzoyl)-myo-inositol 1,3,5-orthoformate (14)21 were synthesized as reported earlier. Detailed procedure and characterization data for the fluoro benzoates 12, 15 and the diols 16−18 are given in the Supporting Information. Crystallization of 10, 11,20 and 12 from most organic solvents (chloroform, acetone, dichloromethane, nitromethane, tetrahydrofuran (THF), dioxane, dimethyl sulfoxide (DMSO), 1,2-dichloroethane, pxylene, benzene, toluene, o-xylene) yielded inclusion crystals, while crystallization from methanol (or ethyl acetate) yielded solvent-free crystals. The monoclinic inclusion crystals were robust square or hexagonal plates while the triclinic inclusion crystals (of 12) were rectangular plates. All the solvates were stable at ambient temperature for 3−7 days. Details of differential scanning calorimetry (DSC) and hot stage microscopy (HSM) are given in the Supporting Information. Single Crystal X-ray Diffraction. Intensity data were collected for all crystals on a Bruker SMART APEX CCD diffractometer with graphite-monochromatized (Mo Kα = 0.71073 Å) radiation. Diffraction intensities were measured with a ω scan width of 0.3° at different settings of φ (0°, 90°, 180°, and 270°) keeping the sample-todetector distance fixed at 6.145 cm and the detector position (2θ) fixed at −28°. The X-ray intensities at low temperatures (in some experiments) were measured using an OXFORD LN2 cryosystem. The X-ray data acquisition was monitored by SMART.22 The automatic cell determination routine collected reflections at three different orientations of the detector and SAINT22 was used for determining the unit cell parameters. The data were corrected for Lorentz-polarization effects. A semiempirical absorption correction (multiscan) based on symmetry equivalent reflections was applied using SADABS.22 Lattice parameters were refined from least-squares analysis of all reflections. The structures were solved by direct methods and refined by full matrix least-squares, based on F2 using SHELX201423 and WinGX.24 Molecular overlaps and packing diagrams were generated using Mercury CSD 3.3.25 Geometrical calculations were

Diesters 10−12 are racemic.

forms contained O−H···O linked molecular chains bridged via C−H···O contacts across the inversion center.19 In the major dimorph, these bilayers were connected by halogen bonding (C−X···OC, X = Cl, Br) contacts, whereas in the minor dimorph they were linked by C−H···X contacts. The nonhalogen-bonded structure exhibited a thermal crystal-to-crystal phase transition to the halogen-bonded structure. We could however obtain crystalline solvates,20 wherein the halobenzoate molecules assembled in a helical fashion (induced by the included solvent molecules), around the crystallographic 21screw axis, akin to the molecular organization in crystals of 1− 3.13−16 Adjacent helices were found to be linked by C−H···X, C−X···O (X = Cl, Br), and X···X (X = Cl) interactions involving the participation of the aryl halogen atoms. Fluoride and hydrogen ions are sterically similar; their valence shells are either fully occupied or empty and hence replacement of a hydrogen atom by a fluorine atom (unlike bromine or chlorine) is considered an isosteric substitution. Hence, we prepared p-fluorobenzoate 12 from myo-inositol orthoformate by substituting the benzoyl groups at the axial and equatorial positions in 1 by p-fluorobenzoyl groups. We now report crystal structures of the solvent-free di-O-pfluorobenzoate (12•FI) and the helically assembled solvates of 12, the solid-state transesterification reactivity of the solvates of 10−12, and correlation of the solid-state reactivity with crystal structures and their thermal behavior. Although the halobenzoates crystallized from methanol (and ethyl acetate) showed a nonhelical molecular assembly, by changing the solvent of crystallization they could be guided into assembling

Figure 1. ORTEP of the molecule in crystals of (a) 12•FI and (b) 12•CH3COCH3. Thermal ellipsoids are drawn at the 50% probability level and hydrogen atoms are shown as small spheres of arbitrary radii. B

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Table 1. Summary of Crystallographic Data for 12, 15, 18 and Solvates of 12 12•FI Chemical formula Mr Temperature (K) Crystal system Space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Dcalc (g cm−3) Unique reflns Rint GoF R1[I > 2σ(I)] wR2[I > 2σ (I)] R1_all data wR2_all data CCDC No. Chemical formula Mr Temperature (K) Crystal system Space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Dcalc (g cm−3) Unique reflns Rint GoF R1[I > 2σ(I)] wR2[I > 2σ (I)] R1_all data wR2_all data CCDC No. Chemical formula Mr Temperature (K) Crystal system Space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Dcalc (g cm−3)

C21H16F2O8 434.34 297(2) Monoclinic P21/n 11.5791(18) 6.7493(10) 24.277(4) 90 92.685(3) 90 1895.2(5) 4 1.522 3316 0.045 1.01 0.040 0.081 0.073 0.092 1495458 12•CH3NO2 C21H16F2O8•CH3NO2 495.38 133(2) Monoclinic P21/c 11.5876(16) 9.6180(13) 19.653(3) 90 95.241(2) 90 2181.2(5) 4 1.509 3837 0.0165 1.031 0.0466 0.1225 0.0515 0.1267 1495462 12•C2H4Cl2 C21H16F2O8•C2H4Cl2 533.29 133(2) Monoclinic P21/n 13.3061(12) 10.0518(9) 17.0729(15) 90 98.5050(10) 90 2258.4(3) 4 1.568

12•CHCl3 C21H16F2O8•CHCl3 553.70 133(2) Monoclinic P21/n 12.869(3) 10.168(2) 17.234(4) 90 99.870(4) 90 2221.6(9) 4 1.655 3487 0.065 1.157 0.051 0.119 0.059 0.124 1495459 12•C4H8O C21H16F2O8•C4H8O 506.44 133(2) Monoclinic P21/n 12.6350(14) 10.2016(11) 17.8698(19) 90 101.388(2) 90 2258.0(4) 4 1.490 3970 0.055 0.93 0.055 0.139 0.061 0.145 1495463 12•p-C6H4(CH3)2 C21H16F2O8•0.5p-C6H4(CH3)2 487.42 133(2) Monoclinic P21/c 11.2679(13) 9.3620(11) 20.990(2) 90 93.908(2) 90 2209.1(4) 4 1.466 C

12•CH3COCH3

12•CH2Cl2

C21H16F2O8•CH3COCH3 492.41 133(2) Monoclinic P21/c 11.476(2) 9.5127(17) 20.424(4) 90 90.219(3) 90 2229.6(7) 4 1.467 3917 0.049 1.11 0.060 0.167 0.062 0.169 1495460 12•CCl4

C21H16F2O8•CH2Cl2 519.26 133(2) Monoclinic P21/n 12.8215(15) 10.1040(12) 17.172(2) 90 100.146(2) 90 2189.8(4) 4 1.575 3865 0.0159 1.038 0.0408 0.0990 0.0429 0.1007 1495461 12•CH3SOCH3

C21H16F2O8•CCl4 588.15 133(2) Monoclinic P21/n 12.425(2) 10.3074(16) 18.643(3) 90 102.994(3) 90 2326.5(6) 4 1.679 4085 0.0398 1.03 0.048 0.115 0.056 0.121 1495464 12•C6H6 C21H16F2O8•C6H6 512.44 133(2) Triclinic P1̅ 6.7449(4) 11.5178(8) 15.5671(10) 77.7590(10) 88.9710(10) 88.3540(10) 1181.28(13) 2 1.441

C21H16F2O8•CH3SOCH3 512.46 133(2) Monoclinic P21/c 11.5353(10) 9.5572(8) 20.5755(17) 90 91.3960(10) 90 2267.7(3) 4 1.501 3984 0.0168 1.054 0.0600 0.1341 0.0674 0.1389 1495465 12•C6H5CH3 C21H16F2O8•C6H5CH3 526.47 133(2) Triclinic P1̅ 6.8762(8) 11.6387(13) 15.4094(18) 81.028(2) 89.700(2) 87.389(2) 1216.9(2) 2 1.437

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Table 1. continued 12•C2H4Cl2 Unique reflns Rint GoF R1[I > 2σ(I)] wR2[I > 2σ (I)] R1_all data wR2_all data CCDC No. Chemical formula Mr Temperature (K) Crystal system Space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Dcalc (g cm−3) Unique reflns Rint GoF R1[I > 2σ(I)] wR2[I > 2σ (I)] R1_all data wR2_all data CCDC No.

3969 0.026 1.07 0.054 0.139 0.058 0.141 1495466

12•p-C6H4(CH3)2 3870 0.018 1.03 0.035 0.087 0.038 0.089 1495467 12•o-C6H4(CH3)2

12•C6H6 4141 0.016 1.11 0.038 0.095 0.039 0.097 1495468 15

C21H16F2O8•o-C6H4(CH3)2 540.50 133(2) Triclinic P1̅ 6.7954(10) 11.6754(17) 16.069(2) 95.891(2) 90.066(2) 91.056(2) 1267.9(3) 2 1.416 4431 0.022 0.89 0.039 0.108 0.041 0.111 1495470

C28H19F3O9 556.43 297(2) Monoclinic P21/n 14.060(3) 10.592(3) 17.702(4) 90 110.548(4) 90 2468.4(10) 4 1.497 4342 0.022 1.04 0.042 0.095 0.057 0.102 1495471

performed using PLATON.26 Thermal ellipsoid plots were generated using ORTEP-3.24 The hydroxyl H atoms in all the solvates were located in difference Fourier maps and refined isotropically. All the other hydrogen atoms were placed in geometrically idealized positions and refined isotropically (for details of structure refinement in solvates with disordered solvents see Supporting Information). Solid-State Acyl Transfer Reactivity of SolvatesGeneral Procedure. Solid sodium carbonate was activated by placing a finely powdered sample for 12 h in a furnace maintained at 270 °C. Freshly grown crystals of the p-halodibenzoates (∼1 equiv) were ground together with activated solid Na2CO3 (∼9 equiv) into a fine powder using a mortar and pestle. This powder was transferred to a hard glass test tube and heated under an inert atmosphere in an oil bath maintained at or below the temperature of solvent escape (as determined from DSC graph, see Supporting Information Figure S2) from the solvate. The reaction mixture was extracted with chloroform (5 × 5 mL) and the organic extract was evaporated under reduced pressure. The residue obtained was analyzed by TLC (and 19F NMR spectroscopy in the case of 12•CH3NO2 and 12•FI, see Supporting Information). Authentic samples of the mono-, di-, and tribenzoates, 18, 12, and 15 (Chart 1) respectively were used as reference samples for analyzing the mixture of products. The results are summarized in Table 2.

12•C6H5CH3 4257 0.032 1.21 0.069 0.155 0.080 0.160 1495469 18 C14H13FO7 312.24 297(2) Orthorhombic Pbcn 19.047(4) 10.1896(19) 13.462(3) 90 90 90 2612.8(9) 8 1.588 2297 0.028 1.05 0.036 0.087 0.043 0.093 1495472

such as Cl and Br. However, crystallization of racemic fluorobenzoate 12 produced solvent-free crystals (12•FI) (Figure 1a) from methanol and solvated crystals (Figure 1b) from most of the other organic solvents (also see Supporting Information, Figure S1). In all solvates the crystal lattice contained one molecule of host per one molecule of the guest (guests showed full occupancy) except in 12•p-C6H4(CH3)2 and 12•C6H6. In 12•p-C6H4(CH3)2 half a molecule of p-xylene with full occupancy was present per molecule of the host whereas in 12•C6H6 two half molecules of benzene were present per molecule of the host. The crystal structures of the solvates of 12 could be classified into two distinct groups: group I (12•CHCl3; 12•CH3COCH3; 12•CH2Cl2; 12•CH3NO2; 12•C4H8O; 12•CCl4; 12•(CH3)2SO; 12•ClCH2CH2Cl; 12•p-C6H4(CH3)2), containing solvates belonging to the monoclinic space groups P21/n and P21/c and group II (12•C6H6; 12•C6H5CH3; 12•o-C6H4(CH3)2), containing the triclinic solvates (space group P1)̅ . The lengths of the a and b axes in the group I solvates of 12 are very similar to those of the P21/n and P21/c solvates of 10 and 11 while the unique axis length is similar (∼10 Å) in all the monoclinic solvates of 10− 12. The group II triclinic solvates are isomorphous. However, their unit cell parameters differ greatly from those of the monoclinic solvates (Table 1). The superimposition of the host molecules in the solvates of 12 showed conformational differences in their p-fluorobenzoyl groups (Figure 2). The overlap of host molecules in group I

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RESULTS AND DISCUSSION It was expected that the replacement of the para-hydrogen atoms with fluorine atoms in the aromatic rings of the ester groups of 1 would have minor effects on the molecular structure and organization in the solid state as compared to the effect of introducing larger and more polarizable halogen atoms D

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4−46°. The equatorial and axial esters of group II triclinic solvates 12•C6H5CH3, 12•C6H6, and 12•o-C6H4(CH3)2 overlapped well with those of the solvent-free crystals 12•FI (Figure 2b). The overlay of host molecules in the corresponding solvates of 10, 11, and 12 revealed minor conformational differences in the range of 2−7° for the C2−O-(p-halobenzoyl) groups, whereas the C6−O-(p-halobenzoyl) groups showed larger variation in orientation with conformational differences in the range of 4−57° (Figure S4, Supporting Information). The larger variation in the orientation of the axial ester group may be due to the involvement of the halogen atoms in 10 and 11 in hydrogen and halogen bonding interactions in the corresponding solvates.20 The overlap of the form I solvent-free crystals of 10 and 11 with 12•FI revealed a conformational difference of 9° for the equatorial ester and 4° for the axial ester while that of the form II solvent-free crystals of 10 and 11 with 12•FI revealed a conformational difference of 1° for the equatorial ester and 2° for the axial ester group (Figure S5, Supporting Information). Assembly of the Diester Molecules in Crystals of 12. The molecules in the solvent-free crystals (12•FI) of 12 do not

Figure 2. Overlap of (a) host molecules in group I solvates and solvent-free crystals of 12 (purple-12•FI; blue-12•CHCl3; orange12•ClCH2CH2Cl and red-12•p-C6H4(CH3)2) and (b) host molecules in group II solvates and solvent-free crystals of 12 (purple-12•FI; orange-12•C6H6; green-12•C6H5CH3 and blue-12•o-C6H4(CH3)2) shows relative orientation of benzoyl groups.

solvates of 12 and solvent-free crystals revealed four major conformations adopted by the axial C6−O-(p-fluorobenzoyl) group (Figure 2a). The conformational difference of C6−O-(pfluorobenzoyl) groups was in the range 21−31° while that between C2−O-(p-fluorobenzoyl) groups lay in the range of

Figure 3. Molecules in crystals of 12 exhibit (a) bilayer assembly in 12•FI (solvent-free crystal of 12) and (b) helical assembly across the crystallographic 21 axis via O−H···O and C−H···O interactions in 12•CH3COCH3. (c) Bilayers in crystals of 12•FI are linked by weak C−H···F interactions. Hydrogen atoms not involved in bonding are omitted for the sake of clarity. E

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assemble in helical fashion. Strong O−H···O hydrogen bonding (Table S1, Supporting Information) between the hydroxyl group (O4−H4A) and orthoester oxygen (O1) along with C− H···π and linear C−H···O (C1−H1···π and C14−H14···O4) interactions forces the formation of homochiral molecular chains, which are linked by C−H···O interactions (C7−H7··· O8, C6−H6···O5, and C5−H5···O8) between the orthoformate and inositol ring protons and orthoester and axial ester carbonyl oxygen to form bilayers (Figure 3a, Table S1, Supporting Information). This pattern of molecular assembly is similar to that observed in the Form I solvent-free crystals of 10 and 11. These bilayers, in the absence of stronger interactions, seem to be interconnected by weak C20−H20··· F2 interactions (Figure 3c).27−29 In contrast, the difluorobenzoate molecules in the monoclinic inclusion crystals of 12 assemble helically around the crystallographic twofold screw axis (b-axis) (Figure 3b). As observed earlier in the solvates of 10 and 11,20 each helix is built from a single enantiomer of the racemic host while its neighbor is formed from the other enantiomer (shown in light gray and dark gray, Figure 4). The molecules along the helix are linked by strong O−H···O hydrogen bonding between the −OH group of C-4 and the carbonyl oxygen O7 of the equatorial C2−O-p-halobenzoyl group. This is similar to the molecular assembly observed in crystals of 1.13,14 The H4A···O7 distances are in the range 1.90−2.11 Å and the angle of approach is slightly more linear than in solvates of 10 and 11 (169−178°, Table S1, Supporting Information). Additional support for the helical architecture is provided by C5−H5···O4 and linear C11−H11···O1 interactions between the neighboring 21-screw related molecules along the helix. The C−H···π interactions between the inositol protons and the aromatic ring of the axial ester along the helix are weak (distances >3 Å) and marginal in the solvates as compared to those in crystals of 1−3. The included guest solvents are mostly involved in hydrogen bonding interactions with the orthoformate headgroup of the host. The host molecules in the triclinic solvates of 12 assemble in the form of molecular bilayers as observed in 12•FI, accounting for a perfect overlap of the axial and equatorial ester groups in their structures and the solventfree crystals (Figure 2b). The included solvents (o-xylene, toluene, benzene) interact with the aromatic rings of the axial ester groups of the host unlike the guests in the monoclinic solvates. The different modes of guest interaction with the host could be a plausible reason for the formation of two types of solvates observed in 12. Interlinking of the Bilayers and Helices. The molecular helices in the P21/n and P21/c group I solvates are linked differently in the two directions along the diagonal to the acplane and the c-axis. In P21/c solvates, the helices are linked by weak C−H···F interactions in the ac-diagonal plane (Figure 4a), similar to the C−H···Br/Cl interactions observed in solvates of 10 and 11.20 In the dichloroethane solvate 12•ClCH2CH2Cl (P21/n) the helices are linked by weak C−H···F and π···π interactions (Figure 4b), whereas in the other P21/n solvates (12•CH2Cl2, 12•CHCl3, 12•CCl4, and 12•C4H8O) helices are linked by weak C18−H18···π and π···π interactions (Figure 4c, Table S2, Supporting Information). A view of the molecular assembly along the b-axis shows the arrangement of the helices and the cavities created as a consequence of host assembly. In the P21/c solvates of group I, centrosymmetric C14−H14···O8 contacts and π···π interactions connect the neighboring helices (Figure 5a) along the c-axis. Weak C13−H13···O8 and π···π

Figure 4. Association of helices along the ac-diagonal in (a) 12•CH3COCH3 (P21/c), (b) 12•ClCH2CH2Cl(P21/n), and (c) 12•CH2Cl2 (P21/n) solvates. Enantiomers are shown in dark gray and light gray colors. Solvent molecules are omitted for the sake of clarity.

interactions connect helices along the c-axis in the P21/n solvates (Figure 5b), presumably due to the conformational differences in the C6−O-p-fluorobenzoyl group in these crystals. The network of the helices creates voids which are occupied by the guest solvents. F

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whereas adjacent bilayers along the c-axis are separated by channels occupied by the guest solvent (toluene/o-xylene/ benzene). Details of host−guest interaction in the solvates are listed in the Supporting Information. Solid-State Structure−Reactivity Correlation of the Halobenzoate Crystals. Helical molecular assembly via O− H···O bonding along the crystallographic twofold axis is a common feature in the organization of the host in all the monoclinic solvates20 and reactive crystals.13−16 A comparison of the intermolecular acyl transfer reactivity in molecular crystals with their structures had revealed strong dependence of the reactivity on the relative orientation of the electrophile (El, ester CO) and the nucleophile (Nu, OH) as well as helical assembly of the molecules. Hence, we looked for these two attributes (Figure 7) in crystals of the halobenzoates 10−12

Figure 7. Schematic representation of El-Nu geometry in diesters, required for efficient acyl transfer reaction (acetone solvate is shown here). See Figure S4 (Supporting Information) for a comparison of packing of molecules in reactive crystals of 1 with those of the solvates of the halobenzoates 10−12.

Figure 5. Association of the helices in (a) 12•CH3COCH3 (P21/c) and (b) 12•ClCH2CH2Cl (P21/n) solvates. Enantiomers are shown in dark gray and light gray colors. Guest is omitted for the sake of clarity.

It is interesting to note that the reactive dibenzoates 1−3 achieve a closer packing of helices in their crystals (due to the absence of solvent occupied cavities) in comparison to the solvates of the halogenated diesters and the interactions that bind the helices in 1−3 are stronger than those in their halogenated solvated counterparts (Figure S6, Supporting Information). The bilayers along the b-axis in the triclinic solvates (Figure 6) are linked by moderately strong C13−H13···O3 contacts (Table S2, Supporting Information) and C4−H4···π contacts,

and compared them with the crystals of the reactive diesters 1− 3. The geometrical parameters for the relative orientation of the Nu and the El in the five brominated and chlorinated solvates (whose solid-state reactivities were studied, Table 2) did not approach the values observed in the reactive diesters 1−3 (Figure 7, distance O4···C15O8−3.1−3.3 Å; ∠O4···C15 O8−84−90°; see Supporting Information Table S4 for geometrical parameters for electrophile−nucleophile interactions in crystals of 10−12). The distance of approach of the nucleophile toward the electrophile in the solvates of 10 was consistently greater than 4 Å and the angle of approach varied between 44° and 83°. In the solvates of 11, the El-Nu distance lay between 3.9 and 4.3 Å while the angle of approach was in the range of 83−84° in only three cases (11•CH3NO2, 11•ClCH2CH2Cl, and 11•CH3CN). Among the solvated crystals of 12 it was observed that the P21/c solvates 12•CH3COCH3, 12•CH3NO2, and 12•p-C6H4(CH3)2 possessed reasonably good El-Nu geometry (distance 3.3−3.6 Å, angle: 83−87°, Supporting Information Figure S7). The solvent-free crystals of 10−12 do not assemble in helical fashion, but instead the O−H···O hydrogen bonding between the hydroxyl hydrogen H4A and the orthoester oxygen atom O1 leads to the formation of a molecular chain-like assembly (Figure 3a). This pattern of molecular aggregation does not bring the electrophile and nucleophile in close proximity for the acyl transfer reaction. Hence, these solvent-free crystals were expected to exhibit poorer reactivity as compared to some of the solvates. All in all, we expected crystals of the halobenzoates

Figure 6. Linkage of bilayers in 12•C6H5CH3 (triclinic solvate). Enantiomers are shown in dark gray and light gray colors. Guest is omitted for the sake of clarity. G

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Table 2. Summary of Acyl Transfer Reaction Experiments in Solvates of Racemic 10−12 expt

crystal

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

10•CHCl3 10•CH3COCH3 10•CH2Cl2 10•CH3NO2 10•ClCH2CH2Cl 11•CHCl3 11•CH3COCH3 11•CH3NO2 11•ClCH2CH2Cl 11•CH3CN 12•CH3COCH3 12•CH2Cl2 12•CH3NO2 12•C4H8O 12•ClCH2CH2Cl 12•p-C6H4(CH3)2 12•FI

g (mmol) 0.028 0.028 0.028 0.028 0.035 0.024 0.027 0.026 0.024 0.024 0.022 0.023 0.080 0.043 0.026 0.024 0.027

Na2CO3 g (mmol)

(0.041) (0.045) (0.043) (0.045) (0.053) (0.041) (0.051) (0.049) (0.042) (0.047) (0.045) (0.044) (0.16) (0.085) (0.049) (0.049) (0.06)

0.050 0.043 0.043 0.043 0.050 0.045 0.045 0.042 0.043 0.045 0.043 0.045 0.170 0.085 0.051 0.045 0.045

(0.45) (0.4) (0.4) (0.4) (0.48) (0.4) (0.4) (0.4) (0.4) (0.4) (0.4) (0.42) (1.6) (0.8) (0.48) (0.4) (0.4)

°C (h)

Observationa

80 (72) 80 (42) 90 (72) 90 (71) 82 (72) 90 (72) 80 (72) 90 (48) 85 (48) 90 (82) 80 (47) 80 (71) 105 (72) 60 (41) 70 (40) 100 (72) 115 (48)

A A B B A C C C A C A B A B B C C

a

A: TLC showed the formation of only the corresponding triester and the diol; major amount of the diester remained unreacted. B: No reaction; C: TLC showed the formation of several products; major amount of the diester remained unreacted. No attempt was made to separate individual products in any experiment.

10−12 to be much less reactive than the crystals of benzoates 1−3; however, the acyl transfer reactivity in solvated crystals of 12 was expected to be better than in solvated crystals of 10 and 11. In order to arrive at an optimum temperature to test the reactivity of the solvated halobenzoates 10−12, we analyzed their thermal behavior by performing DSC experiments. Heating the solvated crystals of 10•ClCH2CH2Cl and 11•CH3NO2 beyond the temperature of solvent escape (as indicated in the DSC curves20) also resulted in the loss of the included solvent and apparent loss of crystallinity. The opaque mass, when touched with a pin, revealed the formation of small rectangular crystals (see Figure S3, Supporting Information for images). These crystals, identified as form I solvent-free crystals19 (10•FI/11•FI) by determination of the unit cell parameters, when heated further up to a few degrees below the melting point of the compound transformed into the form II solvent-free crystals (10•FII/11•FII). Heating other solvates of 10 and 11 yielded similar results, indicating the phase transition of the solvated crystal to a solvent-free form (10•FI/11•FI) which further underwent a single-crystal-to-single-crystal phase transition to the halogen-bonded (10•FII/11•FII) solvent-free crystals.19 The DSC curves (see Figure S2, Supporting Information) of the solvated crystals of 12 showed an endotherm much before the melting curve of the crystals, attributed to the escape of solvent molecules from the inclusion crystal lattice. Heating the solvates of 12 resulted in the loss of solvent and apparent loss of crystallinity; however, fragmented crystals suitable for further structural investigation could not be obtained. The solid-state acyl transfer reactivity in the solvated crystals of 10−12 was studied by heating the freshly grown crystals (below the temperature of solvent escape from the solvated crystal) in the presence of activated sodium carbonate. Heating the reaction mixture at even slightly elevated temperatures (after the onset of solvent escape from crystals) resulted in a mixture of many products in most cases, due to ensuing phase transitions as revealed by DSC. The expected products due to intermolecular acyl-transfer reaction in crystals of 10−12 are shown in the three equations below.

2(10) + Na 2CO3 → (13) + (16) 2(11) + Na 2CO3 → (14) + (17) 2(12) + Na 2CO3 → (15) + (18)

It is pertinent to mention that these intermolecular acyl-transfer reactions proceed only in the presence of a base (Na2CO3). Heating the crystals of these diesters in the absence of sodium carbonate does not lead to any reaction. Sodium carbonate initiates the reaction at the surface of the crystals by activating the hydroxyl group for nucleophilic attack on the carbonyl group. The transesterification is not a crystal-to-crystal reaction, but rather the lattice of the reactant molecules collapses with progress in the reaction.14 The acyl-transfer reactivity exhibited by solvates of 10−12 could be grouped into three categories (Table 2). The solvates which gave only the expected triester and the diol indicating specific acyl transfer (reactivity A); the solvates which did not undergo detectable reaction (reactivity B); the solvates which gave many products indicating indiscriminate acyl transfer (reactivity C). As a control experiment, the solid-state reactivity of the solvent-free crystals 12•FI was carried out at 115 °C. As expected, the reaction resulted in a mixture of several products, attributed to the unfavorable molecular preorganization in the crystal. The extent of “goodness” of a solid-state reaction (at a given temperature) can be rated based on three parameters: (i) extent of conversion of the reactant to productsmore the better (i.e., yield); (ii) number of (unexpected) products formedlesser the better (i.e., specificity); (iii) rate of conversion of the reactant to productsfaster the better (i.e., reactivity). In all the reactions shown in Table 2, the yield and reactivity were low due to lower reaction temperature, to prevent escape of the solvent and change in crystal structure of the reactant. Hence, the relative efficacy of the reactions in solvated crystals of 10−12 could not be based on either percentage or rate of consumption of the starting halobenzoates. The specificity of the reactions could however be compared since the number of products generated could be revealed by analytical thin layer chromatography or by NMR H

DOI: 10.1021/acs.cgd.6b01322 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design spectroscopy. Hence, broadly, the crystalline solvates that exhibited reactivity A (i.e., better specificity) were considered to have supported acyl transfer reactivity better than others. The reason for the poor reactivity of the solvates of 10−12 can be rationalized based on their structural features and thermal behavior. The helices in the solvatomorphs are linked by weak interactions (C−Cl···O, C−H···Cl, C−H···F, π stacking, and C−H···π interactions) and are not packed as densely in their crystals as compared to 1 and other reactive diesters.13−16 A comparison of the length of the helix per turn in the solvates of 10−12 and reactive crystals revealed that the values for the reactive crystals lay in the range of 9.3−9.8 Å, whereas values for solvates that were unreactive or yielded a mixture of products lay in the range of 10.0−10.2 Å. The values for most solvates which exhibited reasonably good El-Nu geometry for reactivity lay in the range of 9.5−9.9 Å, close to the values observed for the reactive crystals (Supporting Information Table S4). The C−H···π interactions which hold the migrating axial benzoyl group in the right orientation in crystals of 1−3 for the acyl transfer are weak and marginal in the solvates of 10−12. The reason could be change in the orientation of the axial ester group due to the involvement of the substituted halogen atoms in the interlinking of the helices. Acyl transfer in the solid state is absent or occurs at a slower rate at temperatures below 100 °C.13−16,30 The solvates, when heated to ∼100 °C, are transformed (with loss of solvent) into solvent-free forms which do not possess the required geometry for acyl transfer. Hence, the slight reactivity shown by some of the solvates of 12 can be attributed to the helical assembly of the host molecules, akin to the reactive dibenzoates 1−3. This is supported by the observation that some solvated crystals of 12 which possessed the favorable electrophile−nucleophile geometry exhibited specific reactivity (leading to the formation of only the corresponding tribenzoate and the diol) although in low yields, as compared to the solvent-free crystals, wherein the reaction led to the formation of several products, (see Supporting Information for a comparison of the 19F NMR spectra). This is because the neighboring molecules in crystals of solvent-free halobenzoate do not conform, even remotely, to the relative geometry required for the acyl transfer reaction (Figure 7, Supporting Information Table S4). Although exact correlation between crystal structure and reactivity is not possible due to dynamic nature of the crystalline solvates at the reaction temperature, it can be concluded that the solvates of the fluorobenzoate 12 exhibit better reactivity than the corresponding solvent-free crystals, due to helical organization of the reacting molecules in the former crystals. The substitution of a hydrogen atom by a fluorine atom (or a chlorine/bromine) results in a helical molecular assembly with inclusion of solvent in the crystal, unlike the solvent-free helical assemblies of the reactive diesters. While the solvent clearly plays a role in creating and stabilizing favorable molecular organization for acyl transfer, its removal from the crystal lattice results in the disruption of the desired assembly and inhibition of solid-state reactivity. As expected, among the three halobenzoates, molecules in the solvated fluorobenzoate crystals were better organized for the intermolecular acyl transfer reaction as compared to the solvated crystals of the chloro- and bromobenzoates. This may be attributed to the relative sterics and the ability of the halogens to form halogen bonding interactions.

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CONCLUSIONS

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ASSOCIATED CONTENT

Article

Reactions in molecular crystals have not been developed to a great extent in organic chemistry barring the exception of photochemical reactions in crystals of olefins, presumably due to lack of methods for obtaining suitably structured crystals that facilitate covalent bond formation.31−34 However, group transfer reactions in solids have immense implications in chemistry related to the production and formulation of drugs and pharmaceuticals.35−39 We had previously obtained several molecular crystals and cocrystals capable of supporting intermolecular acyl transfer reaction in them.13−15 Since additives have a profound effect on the process of crystallization, they can be used to fine-tune and engineer crystals for specific intermolecular acyl transfer reaction.16 Recently, we have been working toward exploiting the ability of solvents to influence crystallization behavior of small molecules to construct molecular crystals capable of undergoing acyl transfer reactions.30 We had also demonstrated that analysis of intermolecular interactions and prior assessment of the molecular organization can help in the identification of reactive crystals from the crystal structure database.40 The results presented here suggest that the intervention of solvents can also be beneficial in obtaining the desired organization of molecules in their crystals, and thereby facilitate engineering of supramolecular assemblies with desired properties. S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01322. Experimental details for the preparation of 12, 15, 16, 17, and 18, details of crystal structure refinement, ORTEPs of the solvates of 12, DSC curves for the solvates of 12, HSM (hot stage microscopy) images, 19F NMR spectra for 12, 15, 18 and the solid-state reaction products of 12•CH3NO2 and 12•FI, figures of the molecular overlaps in corresponding solvates of 10−12, figures of the molecular overlaps in solvent-free crystals of 10−12, intermolecular interactions in crystals and solvates of 12, figures showing comparison of the molecular assembly in solvates of 10−12 and reactive crystals of 1, electrophilenucleophile geometry in solvates of 12, host−guest interactions in solvates of 12, comparison table of electrophile-nucleophile geometry in crystals of 1−3 and 10−12 and summary of crystallographic data for 12•FI, 15, 18 and solvates of 12 (PDF) Accession Codes

CCDC 1495458−1495472 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Present Address #

Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600036, India I

DOI: 10.1021/acs.cgd.6b01322 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Notes

(30) Krishnaswamy, S.; Shashidhar, M. S.; Bhadbhade, M. M. CrystEngComm 2011, 13, 3258−3264. (31) MacGillivray, L. R. J. Org. Chem. 2008, 73, 3311−3317. (32) MacGillivray, L. R.; Papaefstathiou, G. S.; Friscic, T.; Hamilton, T. D.; Bucar, D.; Chu, Q.; Varshney, D. B.; Georgiev, I. G. Acc. Chem. Res. 2008, 41, 280−291. (33) Natarajan, A.; Bhogala, B. R. Bimolecular Photoreactions in the Crystalline State. In Supramolecular Photochemistry, Ramamurthy, V.; Inoue, Y., Eds.; Wiley: Hoboken, 2011; pp 175−228. (34) Biradha, K.; Santra, R. Chem. Soc. Rev. 2013, 42, 950−967. (35) Troup, A. E.; Mitchner, H. J. Pharm. Sci. 1964, 53, 375−379. (36) Jacobs, A. L.; Dilatush, A. E.; Weinstein, S.; Windheuser, J. J. J. Pharm. Sci. 1966, 55, 893−895. (37) Koshy, K. T.; Troup, A. E.; Duvall, R. N.; Conwell, R. N.; Shankle, L. L. J. Pharm. Sci. 1967, 56, 1117−1121. (38) Byrn, S. R.; Xu, W.; Newman, A. W. Adv. Drug Delivery Rev. 2001, 48, 115−136. (39) Ballard, J. M.; Zhu, L.; Nelson, E. D.; Seburg, R. A. J. Pharm. Biomed. Anal. 2007, 43, 142−150. (40) Tamboli, M. I.; Krishnaswamy, S.; Gonnade, R. G.; Shashidhar, M. S. Chem. - Eur. J. 2013, 19, 12867−12874.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.K. thanks CSIR, India for a research fellowship. This work was supported by the Science and Engineering Research Board (grant number SB/S1/OC-23/2013), New Delhi.

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REFERENCES

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DOI: 10.1021/acs.cgd.6b01322 Cryst. Growth Des. XXXX, XXX, XXX−XXX