Supporting information

S1

Positional isomerism and conformational flexibility directed structural

variations in the molecular complexes of dihydroxybenzoic acids

Sunil Varughese

*, Anna A. Hoser

*, Katarzyna N. Jarzembska

, V. R.

Pedireddi

and Krzysztof Woźniak

S2 Experimental Section

All the acids and N-donor compounds were obtained commercially and the crystallization experiments were carried out by dissolving them in spectroscopic grade solvents, as the case may be. Single crystals suitable for x-ray diffraction were obtained, over a period of one week time, by slow-evaporation of the respective solution at room temperature.

A general procedure for the synthesis of complexes

In a typical co-crystallization experiment, dihydroxybenzoic acid (0.100 mmol) and the N-donor ligand (0.100 mmol), as the case may be, were dissolved in solvents (10 mL) in a 25 mL conical flask by warming on a water bath. The resultant solution was allowed to evaporate under ambient conditions and single crystals were obtained over a period of one week to ten days. Different solvents (methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetone and acetonitrile) and 1:1 solvent mixtures (mwater, water, ethanol-acetonitrile and ethanol-acetonitrile-dichloromethane) were employed for crystallization.

X-ray diffraction.Data collectionfor single crystals of all studied systems was carried out at 100 K on  - axis KM4CCD diffractometer with MoK radiation monochromated by graphite by applying omega scan technique. Crystals were positioned at a 65mm distance from CCD 1024 × 1024 pix. camera. The 2θ angle range was extended from ca. 2° up to 57°. All structures were solved by direct methods and refined using SHELX.1 The refinement was based on squared structure factors (F2) for all reflections except for those with very negative F2. Hydrogen atoms were found from difference electron density maps. All calculations of intermolecular interactions were done with the HBOND NORM option of PLATON.2

References

(1) Sheldrick, G. M. SHELX97 programs for crystal Strucutre Analysis. 1998. Institüt für Anorganische Chemie der Universität.

(2) Spek, A. L. PLATON, Molecular Geometry Program, University of Utrecht, The Netherlands, 1995.

S3 Periodic calculations.

All the structures were optimized periodically in the CRYSTAL09 program1 prior to further computational analyses. Cohesive energy values were computed within the supermolecular method using CRYSTAL09, whereas molecular complex interaction energies were estimated employing the counterpoise method available in the Gaussian09 package.2 In all the cases DFT(B3LYP)/6-31G**3,4 level of theory was applied. The energy results were corrected both for BSSE and dispersion (Grimme approach).5,6 Ghost atoms were selected up to 5 Å distant from the studied molecule in a crystal lattice, and were used for the basis set superposition error estimation. The evaluation of Coulomb and exchange series was controlled by five thresholds, set to values of 10−7, 10−7, 10−7, 10−7, 10−25. The condition for the SCF convergence was set to 10−7 on the energy difference between two subsequent cycles. The cohesive energy (𝐸_coh) was calculated following the procedure described in the literature:6

𝐸coh =

1

𝑍𝐸bulk− 𝐸mol

where 𝐸_bulk is the total energy of a system (calculated per unit cell) and 𝐸_mol is the energy of an isolated molecule extracted from the bulk (with the same geometry as in the crystal phase). 𝑍 stands for the number of molecules in the unit cell.

Prior to the cohesive energy calculations each crystal structure was optimised at the DFT(B3LYP)/6-31G** level of theory. During the optimization procedure all atomic coordinates were varied, whereas the unit cell parameters were kept fixed at the experimental values. All CRYSTAL input files were prepared using the CLUSTERGEN program. 7

References

(1) Dovesi, R.; Saunders, V. R.; Roetti, R.; Orlando, R.; Zicovich-Wilson, C. M.; Pascale, F.; Civalleri, B.; Doll, K.; Harrison, N. M.; Bush, I. J.; D'Arco, P.; Llunell, M. CRYSTAL09, University of Torino: Torino, 2009.

(2) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.;

S4

Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Gaussian, Inc.: Wallingford, CT, USA, 2009.

(3) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.

(4) Lee, C. R.; Yang, W.; Parr, R. G., Phys. Rev. B 1988, 37, 785.

(5) Grimme, S., Accurate Description of van der Waals Complexes by Density Functional Theory Including Empirical Corrections. J. Comput. Chem. 2004, 25, 1463–1473.

(6) Grimme, S., Semiempirical GGA-Type Density Functional Constructed with a Long-Range Dispersion Correction. J. Comput. Chem. 2006, 27, 1787-1799.

S5

Fig. S1 ORTEP of molecular complexes

23EE_I

23EE_II

S6

24EE

24EA

25EE

S7

26EE

26EA

S8

34EA

35EE

S9 Table S1: Crystallographic Information for the molecular complexes

23EE_I 23EE_II 23EA 24EE 24EA 25EE

Formula C12 H10 N2, C7 H6 O4 C12 H12 N2, 2(C7 H5 O4) C12 H13 N2, C7 H5 O4 C12 H10 N2, C7 H6 O4 C12 H12 N2, C7 H6 O4 C12 H12 N2, 2(C7 H5 O4) CCDC Number CCDC1056683 CCDC615221 CCDC297520 CCDC297522 CCDC297521 CCDC615222 Formula Wt. 336.34 490.46 338.35 336.34 338.35 490.46

Crystal habit Plates Blocks Blocks Blocks Blocks Blocks

Crystal color Colorless Brick red Colorless Colorless Colorless Brick red Crystal system Triclinic Monoclinic Triclinic Triclinic Monoclinic Triclinic

Space group Pī P21/c P P1 P21/c P a (Å) 7.7094(7) 9.588(10) 8.265(2) 3.811(1) 9.552(2) 6.8270(1) b (Å) 10.510(1) 10.4310(10) 9.398(2) 10.342(3) 10.806(2) 8.734(2) c (Å) 11.0988(12) 13.1870(10) 10.574(3) 10.844(3) 16.346(3) 9.852(2) α (deg) 113.937(10) 90.00 91.080(2) 65.84(3) 90.00 77.060(3) β (deg) 105.773(9) 123.940(5) 91.070(2) 85.83(3) 102.34(2) 72.840(3) γ (deg) 92.455(7) 90.00 98.670(2) 89.45(3) 90.00 87.220(3) V (Å 3) 778.91(13) 1094.16(18) 811.6(3) 388.8(2) 1648.3(6) 546.94(2) Z 2 2 2 1 4 1 Dcalc (g cm-3) 1.434 1.489 1.385 1.436 1.363 1.489 T(K) 100(2) 298(2) 298(2) 298(2) 298(2) 298(2) Mo kα 0.71073 0.71073 0.71073 0.71073 0.71073 0.71073 μ(mm-1) 0.102 0.112 0.098 0.102 0.097 0.112 2 range (deg) 50.00 49.98 49.98 50.00 50.00 50.04 F(000) 352 512 356 176 712 256

No. of Reflns. Measured 9227 5283 11032 5273 12453 5252

No. Unique Reflns. 9227 1923 2847 1370 2900 1930

No.of Reflns. Used 6163 1649 2294 1141 2088 1252

No. of Parameters 236 174 299 226 227 207

GOF on F2 1.170 1.050 1.130 1.178 1.078 1.059

R1 0.0562 0.0475 0.0382 0.0451 0.0399 0.0789

wR2 0.1721 0.1264 0.1087 0.1040 0.1051 0.1962

Final diff. fourier map (e- . Å-3) max, min

S10

25EA 26EE 26EA 34EE 34EA

Formula C12 H13 N2, C7 H5 O4 C12 H12 N2, 2(C7 H5 O4) C12 H14 N2 2(C7 H5 O4) C12 H10 N2, C7 H6 O4 C12 H12 N2, C7 H6 O4 CCDC Number CCDC297523 CCDC297525 CCDC297524 CCDC615223 CCDC297526 Formula Wt. 338.35 490.46 492.47 336.34 338.35

Crystal habit Blocks Blocks Blocks Blocks Blocks

Crystal color Colorless Colorless Colorless Colorless Colorless Crystal system Monoclinic Monoclinic Monoclinic Monoclinic Triclinic

Space group P21/n P21/c P21/c P21/c P a (Å) 8.015(10) 8.298(1) 8.325(1) 17.082(3) 9.174(2) b (Å) 18.131(2) 6.879(1) 6.947(1) 10.786(2) 12.815(3) c (Å) 11.088(10) 20.191(2) 19.916(2) 24.632(3) 14.399(3) α (deg) 90.00 90.00 90.00 90.00 86.24(2) β (deg) 90.50(10) 98.30(8) 97.84(8) 133.721(7) 86.33(1) γ (deg) 90.00 90.00 90.00 90.00 77.38(2) V (Å 3) 1611.0(2) 1140.5(3) 1141.1(3) 3279.9(9) 1646.2(6) Z 4 2 2 8 4 Dcalc (g cm -3 ) 1.395 1.428 1.433 1.362 1.365 T(K) 298(2) 298(2) 298(2) 298(2) 298(2) Mo kα 0.71073 0.71073 0.71073 0.71073 0.71073 μ(mm-1) 0.099 0.107 0.107 0.097 0.097 2 range (deg) 50.00 50.00 50.00 50.02 50.00 F(000) 712 512 516 1408 712

No. of Reflns. Measured 10085 7575 8464 16166 22376

No. Unique Reflns. 2827 1994 2006 5764 5779

No.of Reflns. used 1288 1280 1272 2641 4643

No. of Parameters 226 168 172 467 452

GOF on F2 0.825 1.048 1.039 0.838 1.096

R1 0.0410 0.0431 0.0444 0.0533 0.0515

wR2 0.0904 0.0955 0.0998 0.0939 0.1506

Final diff. fourier map (e- . Å-3) max, min

S11 Table S2. Hydrogen bond information

23EE_II 23EA 24EE 24EA 25EE 25EA

O–H…O 2.01 2.81 151 1.72 2.66 164 O–H… N 1.76 2.71 169 1.78 2.59 169 2.03 2.73 144 1.88 2.68 164 1.74 2.55 172 1.77 2.66 165 N–H…O 1.60 2.59 169 1.58 2.59 173 2.56 3.25 125 1.54 2.61 173 2.53 3.29 127 1.58 2.57 175 2.56 3.20 122 C–H…N 2.89 3.77 170 2.82 3.62 141 C–H… O 2.47 3.22 134 2.51 3.28 139 2.67 3.53 149 2.77 3.73 174 2.42 3.40 156 2.48 3.39 179 2.55 3.46 170 2.61 3.34 134 2.65 3.52 149 2.81 3.49 131 2.55 3.25 128 2.95 3.72 153 2.43 3.39 167 2.52 3.33 137 2.57 3.51 165 2.71 3.55 146 2.79 3.67 158 2.91 3.72 166 2.43 3.24 147 2.66 3.58 170 2.78 3.52 137 2.79 3.44 126 2.93 3.83 156 2.50 3.22 132 2.61 3.53 161 2.62 3.46 156 2.71 3.56 152 2.36 3.42 177 2.53 3.51 167 2.58 3.28 129 2.63 3.32 132 2.71 3.58 170 2.73 3.57 158 2.85 3.71 143 2.97 3.94 171

26EE 26EA 34EE 34EA 35EE 35EA

O–H…O 1.79 2.69 165 1.80 2.77 177 1.86 2.66 177 1.83 2.65 179 1.85 2.67 178 1.81 2.63 177 O–H…N 1.79 2.59 164 1.79 2.61 175 1.85 2.79 165 1.90 2.66 148 1.78 2.58 164 1.78 2.59 166 1.94 2.66 146 2.02 2.76 151 1.63 2.60 176 1.83 2.70 175 1.98 2.82 169 1.72 2.54 175 1.73 2.55 175 1.77 2.68 163 1.90 2.67 157 N–H…O 1.75 2.61 175 2.66 3.25 127 1.54 2.61 176 2.53 3.25 124 C–H… N 2.71 3.63 170 C–H… O 2.36 3.21 151 2.51 3.14 125 2.53 3.29 139 2.65 3.26 124 2.66 3.54 153 2.84 3.70 153 2.33 3.22 151 2.49 3.16 123 2.49 3.34 142 2.55 3.27 129 2.67 3.46 139 2.77 3.68 152 2.81 3.60 140 2.60 3.35 138 2.60 3.27 130 2.61 3.37 139 2.66 3.34 131 2.72 3.50 142 2.87 3.43 120 2.91 3.59 131 2.94 3.80 154 2.99 3.85 154 2.53 3.45 171 2.58 3.25 129 2.62 3.26 127 2.64 3.29 128 2.72 3.45 136 2.75 3.39 127 2.76 3.68 174 2.77 3.43 126 2.81 3.72 166 2.82 3.67 152 2.85 3.62 141 2.37 3.32 173 2.60 3.43 148 2.67 3.33 128 2.67 3.58 167 2.69 3.55 153 2.71 3.34 126 2.73 3.42 131 2.73 3.46 136 2.78 3.69 165 2.79 3.64 153 2.83 3.74 156 2.84 3.63 143 2.88 3.80 170

S12 Table S3. Geometric isomers of dihydroxybenzoic acid.

Acid isomers† Hydrate/Solvate Polymorphs CACDAM CACDAM01 2,3-Dihydroxybenzoic acid QIVTUK‡ QIVTUK01‡ (Monohydrate) UNAYOY (DMSO) ZZZEEU ZZZEEU01 ZZZEEU08 2,4-Dihydroxybenzoic acid BESKAL BESKAL01 2,5-Dihydroxybenzoic acid LEZJEF (Monohydrate) LEZJAB LEZJAB01 2,6-Dihydroxybenzoic acid BIJDON03‡ BIJDON04‡ BIJDON05‡ (Monohydate) EDUWUW (Acetonitrile) 3,4-Dihydroxybenzoic acid OKEJOE (DMSO, Water) OKEJUK (Chloroacetonitrile, water) OKEKAR (Ethyl acetate, water)

OKEKEV (Acetone, water) OKEKOF (2-Butanol, water) OKELAS (DMF, Water) WUYPOW WUYPOW01 3,5-Dihydroxybenzoic acid OH OH COOH OH OH COOH OH O H COOH OH O H COOH OH OH COOH OH O H COOH

S13 OKELUM (1-Propanol, water) OKEMAT (Hemihydrate) WUYPAI (Acetylacetone, water) WUYPEM (1,4-Dioxane) WUYPIQ (Tetrahydrofuran) †

CSD Version 5.35; ‡Polymorphic forms

Table S4. Relative electronic energies, enthalpies, and free energies (kJ mol‒1) of the lowest energy structures of all six DHB isomers.

Eo(elec) Ho Go 24DHB 0.0 0.0 0.0 26DHB 3.1 1.8 2.9 23DHB 5.5 4.6 4.9 25DHB 18.1 17.1 16.3 34DHB 27.9 27.3 23.5 35DHB 35.9 35.8 31.9

The electronic energies are at the B3LYP/6-311++G(2df,p)//B3LYP/6-31+G** level, while the thermodynamic corrections are at the B3LYP/6-31+G** level.

Table S3 is adapted from F. H. Yassin and D. S. Marynick, Mol. Phys., 2005, 103, 183.

Table S5. pKa value analysis*

pKa ΔpKa(bpyee) ΔpKa(bpyea) 23DHB 2.96 2.45 3.17 24DHB 3.32 2.09 4.04 25DHB 3.01 2.40 3.12 26DHB 1.30 4.11 4.83 34DHB 4.45 0.96 1.68 35DHB 3.96 1.45 2.17 bpyee 5.41 bpyea 6.13

S14

Interaction contributions to the derived Hirshfeld surfaces.

(a)

(b)

Fig. S2. Contributions of particular interactions to HS area for (a) bispirydyl (b) DHBA molecule

S15

Fig. 3a. O…H DHBA vs cohesive energy/one molecule

Fig. 3b. O…H BPEA/E vs cohesive energy/one molecule

R² = 0,6237 -550 -450 -350 -250 -150 -50 50 30 35 40 45 R² = 0,8806 -600 -500 -400 -300 -200 -100 0 10 15 20 25 30 35

S16 Table S6. Dimer interaction energies in kJ/mol.

23EA -409.3 -163.9 -180.9 -238.3 -245.2 -247.9 23EE_I -60.0 -43.3 -18.1 -23.8 23EE_II -571 -483(23) -486(17) -402(16) -394 (19) -386(24) 24EA -60.4 (7) -48.7 (14) -19.2 (13) -26.2 (6) -8.3(11) -13.1 (8) 24EE -56.4(12) -39.1 (4) -18.5 -15.1 (6) -19.8 (10) -22.2 (7)

S17 25EA -420.8 (8) -167.9 (6) -238.8 (10) -174.3 (11) -268.4 (12) 25EE -580.1 (13) -487.0 (12) -458.3 (11) -410.3 (10) 53.6 (6) 178.9 (4) 26EA -517.9 (11) -488.2 (8) -367.0 (13) -409.0 (10) -349.9 (9) 26EE -543.4 (10) -485.1 (11) -403.0 (8) -436.9 (12) -388.6 (13) 34EA

S18 -53.5 (6) -41.7 (4) -21.6 (22) -26.3 (23) -41.2 (11) -50.2 (20) -35.6 (16) 34EE -50.6 (13) -42.2 (21) -23.9 (18) -28.1 (23) -42.6 (9) -40.5 (6) -57.4 (12) -36.9 (21) 35EA -58.0(10) -45.6(18) -24.2(15) -38.3(7) -39.4(8) -59.5(16) -46.5(13) -17.6(17) -17.0(14) -17.3(20)

S19 35EE