Thermogravimetric analysis and crystal structure of tri-3-pyridylmethanol monohydrate
Kouzou Matsumoto Institute of Natural Sciences, Senshu University1 Hiroyuki Kurata Organization for Fundamental Education,
Fukui University of Technology
Daisuke Takajo Research Center for Thermal and Entropic Science, Osaka University
Abstract. The composition of the crystal of tri-3-pyridylmethanol monohydrate (1·H2O) has been determined by the elemental analysis, thermogravimetric analysis (TGA), and X-ray crystallographic analysis. In the crystal of 1·H2O, the oxygen atom of water forms the hydrogen bond with O–H proton of 1, whereas both two hydrogen atoms of water form the hydrogen bonds with the nitrogen atom of 1.
Tri-3-pyridylmethanol (1) is one of the promising precursors to tetra-3-pyridylmethane. Wibaut et al. synthesized 1 by the reaction of 3-lithiopyridine, generated in situ from 3-bromopyridine by the treatment with n-butyllithium, with ethyl nicotinate or di-3-pyridylketone in 1950’s (Scheme 1). They found that 1 dissolved in alkali as well as in acid and determined the acid dissociation constant of 1. In their intensive investigation of 1, they encountered the difficulty in obtaining the crystal of 1 without moisture. Although they reported that the result of the elemental analysis for 1 was “anomalous”, the data of the elemental analysis was not presented. This contrasted the fact that tri-2- and tri-4-pyridylmethanol were obtained as crystalline substance without moisture and their elemental analyses were not anomalous. Several conformers of 1 based on the rotation of 3-pyridyl groups within a small energy range may prevent 1 from crystallizing. On the other hand, the water molecules may form the hydrogen bonds with 1 to crystallize as hydrate. We have disclosed that the composition of the hydrated crystal of 1 is 1·H2O by the elemental analysis, thermogravimetric analysis (TGA), and X-ray crystallographic analysis. Furthermore, the hydrogen bonds between 1 and water molecule in 1·H2O have also been revealed by X-ray crystallographic analysis.
Scheme 1. Synthesis of tri-3-pyridylmethanol (1).
We synthesized 1 from the reaction of 3-lithiopyridine with 0.5 equivalent of ethyl nicotinate as the reported procedure.[1a] A solution of 3-bromopyridine (25 g, 0.158 mol) in dry ether (70 mL) was added to a solution of 1.43M n-butyllithium in hexane (110 mL, 0.157 mol) in dry ether (110 mL) with stirring over 80 minutes below –60 ºC under nitrogen atmosphere. The reaction was exothermic and the temperature of the reaction mixture was raised about 5 ºC. The resulting yellow suspension was stirred for further an hour below –65 ºC, a solution of ethyl nicotinate (11.9 g, 78.7 mmol) in dry ether (50 mL) was added over 50 minutes below –60 ºC. The reaction was also exothermic. The resulting light brown suspension was stirred for further an hour below –65 ºC, and then stirred overnight at ambient temperature. The reaction mixture was cooled with ice-water bath, 2M HCl (120 mL) was added carefully over 30 minutes below 10 ºC. The aqueous layer was separated with a 500 mL separatory funnel, the organic layer was extracted with 1M HCl (50 mL) two times. The combined aqueous layers were alkalized with K2CO3 (12.2 g, 88 mmol) and KOH (4.6 g, 82 mmol) and extracted with chloroform (100 mL) three times. The combined organic layers were dried over anhydrous Na2SO4. After the filtration and concentration, the residue was dissolved in 100 mL of CH2Cl2 and purified by column chromatography on alumina (column diameter 40 mm, alumina 150 g, eluting with 100 mL of CH2Cl2, 200 mL of CH2Cl2 : CH3CO2C2H5 = 1 : 1 (v/v), then 1 L of CH2Cl2 : CH3CO2C2H5 : CH3OH = 20 : 10 : 1 (v/v)). The product was mainly eluted by CH2Cl2 : CH3CO2C2H5 : CH3OH = 20 : 10 : 1 (v/v). The fractions in which the product was mainly contained were combined and concentrated. The crude product was dissolved in 3 mL of ethanol-water (1 : 5 (v/v)) and ethyl acetate (3 mL). The crystal of 1·H2O appeared by the addition of seed crystals. Ethyl acetate (7 mL) was added for washing and the crystals were collected by filtration. The obtained crystals were washed with the small amount of ethyl acetate and dried under air. Iterative crystallization gave total amount of 7.0 g of the product (yield 33%).
Figure 1. DSC trace of 1·H2O. Conditions: heating rate; 10 ºC min–1, sample weight; 4.52 mg.
The composition of 1·H2O was firstly supported by the elemental analysis. This composition was further supported by the thermogravimetric analysis (TGA) of 1·H2O (Figure 2). About 7.0% (= 100(6.761 – 6.286) / 6.761) weight loss was observed, which was caused by the removal of the hydrated water molecules from the crystals. This result also supported the composition of 1·H2O, because the weight loss by the removal of water from 1·H2O was calculated to be 6.4% (= 100(281.32 – 263.31) / 281.32).
Figure 2. Mass/time curve of 1·H2O. The temperature was hold at 150 ºC after the heating from 30 ºC to 150 ºC with the heating rate of 100 ºC min–1. The initial and final sample weight were 6.761 and 6.286 mg, respectively.
Figure 3. Hydrogen bonds between 1 and water in the crystal of 1·H2O. Red dotted lines represent the hydrogen bonds.
Figure 4. Bond lengths (Å with standard deviation) of 1 in the crystal of 1·H2O. The aromatic C–N bond lengths are shown in blue.
In summary, we have intensely investigated the properties of the crystalline substance 1·H2O by DSC measurement, TGA, and X-ray crystallographic analysis. The hydrogen bonds between 1 and water is unambiguously observed in 1·H2O by X-ray analysis, which help the orientation of pyridyl groups of 1 to crystalize. Wibaut et al. synthesized seven tripyridylmethanol isomers and found that di-3-pyridyl-4-pyridylmethanol was not obtained in crystal as the case
of 1. This suggests that a molecule having several 3-pyridyl groups hardly crystallize. In this standpoint, we will synthesize tetra-3-pyridylmethane and investigate its thermal properties.
This paper was funded by a Senshu University research grant in 2020 and is based on the results of a project entitled “Synthesis and structure in the solid state of tetra-3-pyridylmethane and tetrapyrazinylmethane”.
 (a) J. P. Wibaut, A. P. de Jonge, H. G. P. Van der Voort, P. Ph. H. L. Otto, Recl. Trav. Chim. Pays-Bas Belg., 1951,
70, 1054–1066; (b) J. P. Wibaut, P. Ph. H. L. Otto, Recl. Trav. Chim. Pays-Bas Belg., 1958, 77, 1048–1063.
 Amorphous solid was obtained by the drying under vacuum because of the removal of water.
 Physical data for 1·H2O: Colorless crystals; mp 83–84 °C (benzene (not distilled and containing water)); Rf value 0.20 (CH2Cl2 : CH3CO2C2H5 : CH3OH = 20 : 10 : 1 (v/v), on alumina); MS (EI) m/z (rel intensity) 263 (M+, 16), 185 ([M – C5H4N]+, 100); UV/Vis (in CH2Cl2) max / nm (log ) 269sh (3.86), 262 (3.96), 257 (3.95); IR (KBr disk, cm1) 3136 (brs, OH); 1H NMR (400 MHz, CDCl3) / ppm 8.42–8.40 (m, 6H, Py-2,6H), 7.58 (dt, J = 8.0, 2.0 Hz, 3H, Py-4H), 7.23 (dd, J = 8.0, 4.8 Hz, 3H, Py-5H), 6.82 (brs, 1H, OH); 13C NMR (100 MHz, CDCl3) / ppm 148.69, 148.56, 141.18, 135.49, 123.17, 77.66; Anal Calcd for C16H13N3OH2O: C; 68.31, H; 5.37, N; 14.94. Found: C; 68.15, H; 5.42, N; 14.88.
 Crystal data for 1·H2O: C16H15N3O2, Mr = 281.31, monoclinic, C2/c (No. 15), a = 11.4613(6), b = 11.6124(6), c = 22.0298(11) Å, = 90.175(3)°, V = 2909.1(3) Å3, Z = 8, Dcalcd = 1.285 g cm3, T = 200 K, total reflection collected = 25710, unique reflection = 2654 (Rint = 0.040), final R factor = 0.055 (Rw = 0.146 for all data) for 2372 reflections (I > 2(I)), GOF = 1.12. The structure was solved by direct method and refined by full-matrix least squares by using the SHELXL-97 program. The O–H proton of 1 (H1) and the hydrogen atoms of water molecule (H2 and H2A) were located in a difference Fourie map and refined freely. The C–H hydrogen atoms were positioned geometrically and allowed to ride on their parent atoms, with C–H = 0.95 Å and Uiso(H) = 1.2Ueq(C) for aromatic H atoms. CCDC-2036432 contains the supplementary crystallographic data. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk/data_request/cif.