Energetics and Structure of Hydroxynicotinic Acids. Crystal Structures

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Energetics and Structure of Hydroxynicotinic Acids. Crystal Structures of 2-, 4-, 6-Hydroxynicotinic and 5-Chloro-6-hydroxynicotinic Acids Rui C. Santos,† Rita M. B. B. M. Figueira,†,‡ M. Fa´tima M. Piedade,†,‡ Hermıńio P. Diogo,‡ and Manuel E. Minas da Piedade*,† Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, UniVersidade de Lisboa, 1649-016 Lisboa, Portugal, and Centro de Quı´mica Estrutural, Complexo Interdisciplinar, Instituto Superior Tećnico da UniVersidade Tećnica de Lisboa, 1049-001 Lisboa, Portugal ReceiVed: July 21, 2009; ReVised Manuscript ReceiVed: September 1, 2009

The relationship between energetics and structure in 2-, 4-, 5-, and 6-hydroxynicotinic and 5-chloro-6hydroxynicotinic acids (2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA, respectively) was investigated in the solid and gaseous phases by means of a variety of experimental and computational chemistry techniques. The molecular and crystal structures of the 2HNA, 4HNA, 6HNA, and 5Cl6HNA solid forms used in this study were determined by single crystal X-ray diffraction at 293 ( 2 K. The 2HNA, 4HNA, and 5Cl6HNA samples were monoclinic (space groups: P21/n for 2HNA and P21/c for 4HNA and 5Cl6HNA), and that of 6HNA was found to be triclinic (space group: P1j). The 2HNA sample investigated corresponds to a new polymorphic form of this compound. The 2HNA, 4HNA, 6HNA, and 5Cl6HNA molecules crystallize as oxo tautomers exhibiting N-H and CringdO bonds. This is also supported by the observation of bands typical of N-H and CringdO stretching frequencies in the corresponding FT-IR spectra. The absence of these bands in the spectrum of 5HNA indicates that a hydroxy tautomer with an unprotonated N heteroatom and a Cring-OH bond is likely to be present in this case. Results of theoretical calculations carried out at the G3MP2 and CBS-QB3 levels of theory suggest that in the ideal gas phase, at 298.15 K, 2HNA favors the oxo form, 4HNA prefers the hydroxy form, and no strong dominance of one of the two tautomers exists in the case of 6HNA and 5Cl6HNA. The standard molar enthalpies of formation of 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA in the crystalline state, at 298.15 K, ∆fHom(cr), were determined by micro combustion calorimetry. The corresponding enthalpies of sublimation, ∆subHom, were also derived from vapor pressure versus temperature measurements by the Knudsen effusion method. The obtained ∆fHom(cr) and ∆subHom values led to the enthalpies of formation of 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA in the gaseous phase. These were discussed together with the corresponding predictions by the B3LYP/cc-pVTZ, B3LYP/aug-cc-pVTZ, G3MP2, and CBS-QB3 methods on the basis of isodesmic or atomization reactions. The experimental “stability” order (more stable meaning a more negative ∆fHom(g) value) found was 5Cl6HNA > 2HNA > 6HNA > 4HNA > 5HNA, and it was accurately captured by the CBS-QB3 and G3MP2 methods, which give 5Cl6HNA > 2HNA ∼ 6HNA > 4HNA > 5HNA, irrespective of the use of isodesmic or atomization reactions. In contrast, only when well-balanced isodesmic reactions were considered did the DFT results agree with the experimental ones. The picture that emerged from the structural and energetic studies carried out in this work was also discussed in light of that typical of hydroxypyridines, which are generally regarded as the archetype systems for the study of the hydroxy T oxo tautomerization in N-heterocyclic compounds. Introduction Nicotinic acid (also known as niacin or vitamin B3) is one of eight water-soluble B vitamins.1 These B vitamins, often referred to as B complex vitamins, are essential in the breakdown of fats and proteins, helping the body to convert carbohydrates into glucose, which is “burned” to produce energy.1 The hydroxyl derivatives of nicotinic acid (2-, 4-, 5-, and 6-hydroxynicotinic acids) have also some biological activity and ample industrial applications, such as in the manufacture of pharmaceuticals, herbicides, and insecticides. 2-Hydroxynicotinic acid, for example, has been used as a hypoglycemic agent2-4 and as a metabolic inhibitor of nicotinamide adenine dinucleotide (NADH) in human blood platelets;5 4-hydroxynicotinic acid and * Corresponding author. E-mail: [email protected]. † Universidade de Lisboa. ‡ Universidade Tećnica de Lisboa.

some of its salts have been explored in the treatment of rheumatism and nasal congestion and hoarseness, typical of the common cold;6,7 and 6-hydroxynicotinic acid, perhaps the most widely used of all the isomers, is a key building block in the synthesis of many modern insecticides.8-14 This family of compounds also offers an attractive possibility to extend our systematic investigations of the structure-energetics relationship in hydroxybenzoyl compounds15-17 to analogous systems with a N-heterocyclic ring. Due to the presence of this ring, more complex patterns of inter- or intramolecular hydrogen bonds (H-bond) are expected to determine the structure and energetics of solid and gaseous hydroxynicotinic acid isomers when compared, for example, with their hydroxybenzoic acid counterparts.15,16 A further complicating aspect may be the existence of an equilibrium involving competing hydroxy and oxo tautomers, as illustrated in Scheme 1 for 6-hydroxynicotinic acid.18 This type of equilibrium, which according to simple

10.1021/jp906908n CCC: $40.75  2009 American Chemical Society Published on Web 09/28/2009

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resonance theory is plausible for all except the 5-hydroxynicotinic acid isomer, has been intensively investigated for 2- and 4-hydroxypyridine, both experimentally19-28 and theoretically,29-44 and proved to be significantly influenced by the molecular environment (i.e., the relative preference for the hydroxy or oxo tautomers is different in the solid and gaseous states, and in the case of solutions, it also depends on the nature of the solvent) and experimental conditions, such as the temperature. The strategy adopted before,15-17,45-47 which relies on a combination of experimental (e.g., X-ray diffraction, combustion calorimetry, differential scanning calorimetry, vapor pressure measurements) and computational chemistry results, was also followed in this work to study all the hydroxynicotinic acid isomers (2HNA, 4HNA, 5HNA, and 6HNA) and 5-chloro-6hydroxynicotinic acid (5Cl6HNA), which are represented in Figure 1 in their hydroxy forms. Materials and Methods General. Elemental analyses were carried out with a Fisons Instruments EA1108 apparatus. The infrared spectra were recorded in a Unicam Mattson 1000 Fourier-transform spectrophotometer, calibrated with polystyrene film, using KBr disks. The 1H NMR spectra were obtained at ambient temperature in an AMX-Bruker 300 MHz spectrometer. The X-ray powder diffractograms were recorded on a Philips PW1730 diffractometer operating in the θ-2θ mode, with automatic data acquisition (APD Philips v.35B). The apparatus had a vertical goniometer (PW1820), a proportional xenon detector (PW1711), and a graphite monocromator (PW1752). A Cu KR radiation source was used. The tube amperage was 30 mA, and the tube voltage was 40 kV. The diffractograms were recorded in the range 5° e 2θ e 40° in the continuous mode with a step size of 0.015° (2θ) and an acquisition time of 1.5 s/step. The samples were mounted on an aluminum sample holder. The indexation of the powder patterns was performed using the program Chekcell.48 The differential scanning calorimetry (DSC) experiments were performed with a Setaram DSC 121 apparatus. The samples with masses in the range of 5-14 mg were sealed under air in aluminum crucibles and were weighed with a precision of 0.1 µg in a Sartorius 4504 Mp8-1 ultramicro balance. Argon (Air Liquide N45), at a flow rate of 0.3 cm3 · s-1 was used as the

Figure 1. Hydroxy forms of 2-, 4-, 5-, and 6-hydroxynicotinic acids and 5-chloro-6-hydroxynicotinic acid (2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA, respectively).

Santos et al. purging gas. The temperature and heat flow scales of the instrument were calibrated as previously described49 by using the following standards: benzoic acid (BDH thermochemical standard; Tfus ) 395.52 K, ∆fusho ) 147.9 J · g-1), indium (Perkin-Elmer; mass fraction 0.99999; Tfus ) 429.78 K, ∆fusho ) 28.45 J · g-1), tin (Goodfellow SN006110; mass fraction 0.99995; Tfus ) 505.12 K, ∆fusho ) 59.6 J · g-1), lead (Goodfellow PB006100; mass fraction 0.99995; Tfus ) 600.65 K, ∆fusho ) 23.2 J · g-1), and zinc (Perkin-Elmer; mass fraction 0.99999; Tfus ) 692.65 K, ∆fusho ) 108.4 J · g-1). The heating rate was 2 K · min-1. For all samples, fusion was followed by thermal decomposition, and no phase transitions other than fusion were observed in the measuring curves recorded between 288 K and the fusion temperature. Materials. Solvents were dried as recommended by Perrin et al.50 and distilled and stored under an argon U atmosphere. 2-Hydroxynicotinic Acid. 2HNA (Aldrich; mass fraction 0.98) was twice recrystallized from distilled water at 363 K.51 The precipitated white solid was dried in vacuum at 1.3 Pa and 353 K for ∼2 h then ground with a mortar and a pestle and, finally, dried again at 1.3 Pa and 353 K over 24 h. Elemental analysis for C6H5O3N: expected C 51.80%, H 3.62%, N 10.07%; found C 51.83%, H 3.57%, N 9.99% (average of two determinations). FT-IR (KBr, main peaks): ν˜ /cm-1 ) 3229 (νN-H stretch), 2936 (νO-H stretch), 1741 (νCdO stretch, -COOH), 1630 (νCdO stretch, ring). The presence of water in the sample was also ruled out by the absence of the characteristic bands at 3408, 1644, and 700 cm-1.52 1H NMR (300 MHz, DMSO-d6/TMS): δ ) 8.37-8.39 (dd, CH, 1H), 7.93-7.95 (dd, CH, 1H), 6.67 (t, CH, 1H). The FT-IR and 1H NMR results are in agreement with those reported in a reference database.53 The powder pattern obtained at 295 ( 1 K was indexed as monoclinic, space group P21/n, with a ) 3.798 Å, b ) 7.354 Å, c ) 20.684 Å, and β ) 90.09°. These values are in good agreement with those obtained in this work by single crystal X-ray diffraction carried out at 293 ( 2 K (see below): P21/n, a ) 3.797 Å, b ) 7.354 Å, c ) 20.905 Å, and β ) 90.007°. The onset (Ton) and maximum (Tmax) temperatures of the fusion peak obtained by DSC at a scan rate β ) 2 K · min-1 were Ton ) 533.2 K and Tmax ) 535.4 K, which are within the range of the previously reported temperatures of fusion of 2HNA (533-535 K).51 4-Hydroxynicotinic Acid. The synthesis of 4HNA was adapted from that reported by Ross.54 A 2.81 g portion of a 4-chloronicotinic acid sample that had been previously prepared by a literature method55 and 57 cm3 of water were introduced in a three-neck, round-bottom flask equipped with a reflux condenser and connected to a vacuum/N2 line by a takeoff. The mixture was refluxed with magnetic stirring and under N2 atmosphere for 1 h. The obtained brownish solution was allowed to cool to room temperature, and its pH was subsequently adjusted to 7 by the addition of aqueous NaOH (0.5 mol · dm-3). The volume of the reaction mixture was reduced to half by the removal of water in vacuum at 323 K, and the precipitation of 4HNA was observed on cooling the concentrated solution to 253 K. The product was isolated by vacuum filtration; washed with ethyl ether; recrystallized from ethanol; and finally, sublimed at 11 Pa and 433 K. Elemental analysis for C6H5O3N: expected C 51.80%, H 3.62%, N 10.07%; found C 51.80%, H 3.70%, N 10.01% (average of two determinations). FT-IR (KBr, main peaks): ν˜ /cm-1 ) 3195 (νN-H stretch), 2857 (νO-H stretch), 1724 (νCdO stretch, -COOH), 1639 (νCdO stretch, ring). These results are in good agreement with those reported in a reference database.53

Structure and Energetics of Hydroxynicotinic Acids The presence of water in the sample was also ruled out by the absence of the characteristic bands at 3408, 1644, and 700 cm-1.52 1H NMR (300 MHz, DMSO-d6/TMS): δ ) 16.50 (s, NH, 1H), 12.87 (s, COOH, 1H), 8.60 (d, CH, 1H), 8.07 (d, CH, 1H), 6.72 (d, CH, 1H). The powder pattern obtained at 295 ( 1 K was indexed as monoclinic, space group P21/c, with a ) 3.807 Å, b ) 14.587 Å, c ) 10.682 Å, and β ) 94.24°. These values are in good agreement with those obtained in this work at 293 ( 2 K by single crystal X-ray diffraction (see below): P21/c, a ) 3.804 Å, b ) 14.582 Å, c ) 10.673 Å, and β ) 94.254°. DSC (fusion, β ) 2 K · min-1): Ton ) 528.8 K and Tmax ) 536.7 K. The indicated Ton is within the range of the published fusion temperatures of 4HNA, namely, 523.1556 and 533.15 K.54 5-Hydroxynicotinic Acid. The synthesis 5HNA was adapted from that reported by Ueno and Imoto.57 A 300 cm3 Parr 4561 pressure reactor was loaded with 20 g of 5-bromonicotinic acid (Aldrich; mass fraction 0.98), 16.7 g of potassium hydroxide pellets (Labsolve P. A.), 4 g of CuSO4 · 5H2O (Merck P. A.), and 4 g of sodium tartrate dihydrate (Na2C4H4O6 · 2H2O; J. M. G. Santos P. A.; used as a pH buffer). The mixture was left under mechanical stirring, at 448 K for 48 h. The reactor was opened, and the Cu+ ions present in the dark brown solution were precipitated as Cu2S by the addition of Na2S · 9H2O (Aldrich; mass fraction g0.98). The precipitate was removed by vacuum filtration, and concentrated hydrochloric acid was added to the solution until pH ) 1-2 was achieved. This operation was accompanied by the precipitation of crude 5HNA (as a dark brown solid) and abundant H2S release. To complete the precipitation, the mixture was kept at ∼275 K for 10 h. The solid product was separated from the mother liquor by vacuum filtration and extracted five times with 25 cm3 of distilled water at 363 K. The extracts were combined; concentrated by evaporation of the solvent in air at 353 K; cooled to room temperature; and finally, kept overnight at 253 K. The light yellow-orange precipitate was separated by vacuum filtration and dried over P2O5 in a desiccator for 24 h. The dried compound was finally subjected to two successive molecular sublimations at 446 and 434 K and at a pressure of 5 × 10-5 Pa using the Knudsen effusion apparatus mentioned below, with a coldfinger adapted to the vacuum chamber. The area, A; radii, r; and thickness, l, of the effusion hole were A ) 6.613 × 10-7 m2, r ) 4.588 × 10-4 m, and l ) 2.09 × 10-5 m. A white crystalline sample of 5HNA was collected in the coldfinger of the apparatus. Elemental analysis for C6H5O3N: expected C 51.80%, H 3.62%, N 10.07%; found C 51.74%, H 3.70%, N 9.91% (average of two determinations). FT-IR (KBr, main peaks): ν˜ /cm-1 ) 3279 (νO-H stretch), 1841 (νCdO stretch, -COOH). The presence of water in the sample was also ruled out by the absence of the characteristic bands at 3408, 1644, and 700 cm-1.52 1H NMR (300 MHz, DMSO-d6/TMS): δ ) 13.31 (s, COOH, 1H), 10.33 (s, OH, 1H), 8.53 (s, CH, 1H), 8.31 (d, CH, 1H), 7.58 (quin., CH, 1H). The powder pattern could not be indexed because no single crystal X-ray diffraction structure has been reported for 5HNA, and the attempts carried out in our laboratory to produce crystals suitable for such a determination failed up to now. The pattern obtained at 295 ( 1 K was as follows. 2θ (relative intensity in %): 14.660° (4.2), 15.105° (4.1), 17.520° (48.8), 17.630° (61.1), 17.720° (48.7), 19.085° (20.2), 20.770° (12.9), 20.890° (17.8), 20.985° (16.2), 23.100° (2.7), 23.280° (3.4), 23.780° (3.9), 23.885° (3.6), 25.005° (24.2), 25.465° (3.5), 26.100° (4.0), 26.295° (3.9), 26.765° (2.8), 27.710° (3.3), 28.385° (66.3), 28.475° (91.8), 28.540° (100.0), 28.620° (92.6),

J. Phys. Chem. B, Vol. 113, No. 43, 2009 14293 29.465° (5.2), 29.570° (5.3), 30.245° (2.5), 31.105° (3.2), 36.440° (1.3), 36.845° (4.5), 37.040° (5.2), 37.360° (3.4), 37.490° (2.7), 38.065° (16.3), 38.125° (17.6). DSC (fusion, β ) 2 K · min-1): Ton ) 571.1 K and Tmax ) 571.8 K. The indicated Ton is within the upper range of the published fusion temperatures of 5HNA; namely, 565.15-566.15 K57 and 572.15 K.58 6-Hydroxynicotinic Acid. 6HNA (Aldrich; mass fraction 0.98) was purified by two successive recrystallizations from distilled water at 363 K.51 The obtained white crystalline solid was first dried in vacuum at 1.3 Pa and 353 K. The crystals were then crushed with a mortar and a pestle and dried again for 24 h at 1.3 Pa and 353 K. Elemental analysis for C6H5O3N: expected C 51.80%, H 3.62%, N 10.07%; found C 51.45%, H 3.57%, N 9.91% (average of two determinations). FT-IR (KBr, main peaks): ν˜ /cm-1 ) 3231 (νN-H stretch), 2875 (νO-H stretch), 1708 (νCdO stretch, -COOH), 1639 (νCdO stretch, ring). The presence of water in the sample was also ruled out by the absence of the characteristic bands at 3408, 1644, and 700 cm-1.52 1H NMR (300 MHz, DMSO-d6/TMS): δ ) 7.96 (d, CH, 1H), 7.74-7.77 (dd, CH, 1H), 6.34 (d, CH, 1H). The FT-IR and 1H NMR results are in agreement with those reported in a reference database.53 The powder pattern obtained at 295 ( 1 K was indexed as triclinic, space group P1j, with a ) 6.974 Å, b ) 11.225 Å, c ) 16.303 Å, R ) 82.63°, β ) 78.29°, γ ) 75.19°. These results are in good agreement with those obtained in this work from single crystal X-ray diffraction experiments carried out at 293 ( 2 K (P1j, a ) 6.976 Å, b ) 11.231 Å, c ) 16.290 Å, R ) 82.553°, β ) 78.279°, γ ) 75.166°). DSC (fusion, β ) 2 K · min-1): Ton ) 583.3 K and Tmax ) 585.4 K. The indicated Ton is in agreement with the reported Tfus > 573.15 K.51 5-Chloro-6-hydroxynicotinic Acid. 5Cl6HNA (Aldrich; mass fraction 0.99) was recrystallized four times from ethanol at 345 K. The obtained white crystalline solid was first dried in vacuum at 1.3 Pa and 353 K. The crystals were then ground with a mortar and a pestle and further dried for 24 h at 1.3 Pa and 353 K. Elemental analysis for C6H4O3NCl: expected C 41.52%, H 2.32%, N 8.07%; found C 41.53%, H 2.26%, N 7.88% (average of two determinations). FT-IR (KBr, main peaks): ν˜ /cm-1 ) 3243 (νN-H stretch), 3000 (νO-H stretch), 1712 (νCdO stretch, -COOH), 1639 (νCdO stretch, ring). The presence of water in the sample was also ruled out by the absence of the characteristic bands at 3408, 1644, and 700 cm-1.52 1H NMR (300 MHz, DMSO-d6/TMS): δ ) 12.60 (s broad, NH + COOH, 2H), 7.97 (d, CH, 2H). These results are in agreement with those reported in a reference database.59 The powder pattern obtained at 295 ( 1 K was indexed as monoclinic, space group P21/c, with a ) 5.478 Å, b ) 10.545 Å, c ) 11.796 Å, β ) 97.76°. These results are in agreement with those obtained in this work from single crystal X-ray diffraction experiments carried out at 293 ( 2 K (P21/c, a ) 5.469 Å, b ) 10.529 Å, c ) 11.795 Å, β ) 97.72°). DSC (fusion, β ) 2 K · min-1): Ton ) 582.2 K and Tmax ) 585.6 K. The indicated Ton is higher by 4 K than the reported Tfus ) 578 K.60 Crystal Structure Determination. Single-crystal X-ray diffraction (XRD) was carried out on an Enraf-Nonius TurboCAD4 apparatus employing Cu KR radiation. Intensities were corrected for Lorentz polarization effects. No empirical absorption correction was applied. The data reduction was performed with the XCAD4 program.61 All structures were solved by direct methods and refined by full-matrix least-squares on F2 using SHELX97,62 included in WINGX, version 1.80.00.63 Non-hydrogen atoms were refined with anisotropic thermal

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TABLE 1: Crystal Data and Structure Refinement Parameters for the Nicotinic Acid Derivatives Studied 2HNA empirical formula formula weight T/K wavelength/Å crystal system space group a/Å b/Å c/Å R/° β/° γ/° V/Å3 Z Z’ Fcalcd/g · cm-3 µ/mm-1 F(000) θ limits/deg limiting indices reflections collected/ unique completeness to θ/% refinement method data/restraints/ parameters GOF on F2 final R indices [I > 2σ(I)] R indices (all data) extinction coefficient largest diff. peak and hole/e.Å-3

4HNA

C 6 H5 O3 N 139.11 293 ( 2 1.54180 monoclinic P21/n 3.7970(10) 7.354(2) 20.905(4)

C 6 H5 O3 N 139.11 293 ( 2 1.54180 monoclinic P21/c 3.804(3) 14.582(7) 10.673(6)

90.007(11)

94.254(18)

583.7(2) 4 1 1.583 1.115 288 4.23-71.82 -3 e h e 3 -7 e k e 0 -20 e l e 0 792/792 [R(int) ) 0.0000] 69.0 (θ ) 71.82) full-matrix least-squares on F2 792/0/112

6HNA

5Cl6HNA C6H4O3NCl 173.55 293 ( 2 1.54180 monoclinic P21/c 5.469(2) 10.529(2) 11.795(2)

590.4(6) 4 1 1.565 1.103 288 5.14-66.95 0ehe4 0 e k e 17 -12 e l e 12 999/999[R(int) ) 0.0000] 94.9 (θ ) 66.95) full-matrix least-squares on F2 999/0/112

C 6 H5 O3 N 139.11 293 ( 2 1.54180 triclinic P1j 6.976(2) 11.231(5) 16.290(6) 82.553 (20) 78.279(17) 75.166(15) 1204.0(8) 8 4 1.535 1.082 576 4.09-66.94 0ehe8 -12 e k e 13 -18 e l e 19 4218/4218 [R(int) ) 0.0000] 98.3 (θ ) 66.94) full-matrix least-squares on F2 4218/0/435

1.042 R1 ) 0.0510

1.034 R1 ) 0.0364

0.995 R1 ) 0.0654

1.063 R1 ) 0.0406

R1 ) 0.0581 0.063(8) 0.263 and -0.274

R1 ) 0.0476 0.015(2) 0.152 and -0.132

R1 ) 0.0970

R1 ) 0.0435 0.0113(18) 0.342 and -0.393

parameters. All hydrogen atoms were located in a Fourier map, and their positions and isotropic displacement parameters, Uiso(H), were refined freely, except for hydrogens H2B and H2D in the 6HNA compound. These were also found in a Fourier map, but their crystallographic parameters were constrained to ride on their parent atoms, with O-H distances of 0.82 Å and with Uiso(H) values set to 1.5Ueq(O). Graphical representations were prepared using Raster3D64 and Mercury 2.2.65 The intermolecular interactions were calculated with the PARST program.66 A summary of the crystal data, structure solution, and refinement parameters is given in Table 1. Combustion Calorimetry. The isoperibol micro rotatingbomb combustion calorimeter used in the determination of the standard molar enthalpies of formation of all the HNA isomers studied in this work and 5Cl6HNA has been described.67,68 The calorimeter was operated in the static-bomb mode in the study of 2-, 4-, 5-, and 6HNA and in the rotating-bomb mode for 5Cl6HNA. The energy equivalent of the apparatus, εo ) 1806.97 ( 0.34 J · K-1 (for 2HNA, 6HNA, and 5Cl6HNA), εo ) 1811.41 ( 0.56 J · K-1 (for 4HNA), and εo ) 1808.37 ( 0.19 J · K-1 (for 5HNA), was determined without bomb rotation from the combustion of benzoic acid (BDH thermochemical standard), whose standard specific energy of combustion under the certificate conditions was ∆cuo ) -26433 ( 2 J · g-1. In the case of 4HNA, 5HNA, and 5Cl6HNA, n-hexadecane (BDH; mass fraction 0.99) with a standard specific energy of combustion, ∆cuo ) -47131.02 ( 0.39 J · g-1, was used as a combustion aid. No combustion aid was necessary in the study of 2HNA and 6HNA. Typically, when the apparatus was

0.308 and -0.398

97.72(2) 673.0(4) 4 1 1.713 4.676 352 5.66-72.91 -6 e h e 0 0 e k e 13 -14 e l e 14 1485/1343 [R(int) ) 0.0452] 100.0 (θ ) 72.91) full-matrix least-squares on F2 1343/0/117

operated in the static-bomb mode, a pellet of the compound under study with a diameter of ∼4 mm was placed in a platinum crucible, and if necessary, a drop of n-hexadecane was added. The weightings of the compound, crucible, and n-hexadecane were performed with a precision of (0.1 µg in a Sartorius 4504 Mp8-1 ultramicro balance. The crucible with the sample was adjusted to the sample holder in the bomb head. A volume of 0.05 cm3 of distilled and deionized water from a Millipore system (conductivity e0.1 µS · cm-1) was added to the bomb body by means of Brand micropipet (Transferpette Digital; 50-250 µL; accuracy e(0.5%). The platinum-lined stainless steel bomb of 19.63 cm3 internal volume was assembled and purged twice by successively charging it with oxygen (Air Liquide N45; mass fraction >0.9995) at a pressure of 1.01 MPa and venting the overpressure. After purging, the bomb was charged with oxygen at a pressure of 3.04 MPa, and a few seconds was allowed for equilibration before closing the inlet valve. The bomb was placed in the calorimeter proper, inside the thermostatic jacket. The combustion of the sample was initiated by discharge of a 2200 µF capacitor from a potential of ∼40 V through a platinum wire (Johnson Matthey; mass fraction 0.9995, diameter 0.05 mm), which was connected between the two discharge electrodes. The duration of the initial, main, and final periods of the experiment was 30 min each. The completeness of the combustion was confirmed in each experiment by visually examining the bomb head and internal walls for the absence of soot deposits. The nitric acid formed in the calorimetric process from traces of atmospheric N2

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remaining inside the bomb after purging was determined using a Dionex 4000i ion chromatography apparatus.68 The procedure adopted in the rotating-bomb combustion experiments carried out on 5Cl6HNA was that previously used in the study of 4-chlorobenzoic acid.68 The most relevant departures from the static-bomb combustion method described above were as follows: Instead of distilled and deionized water, 1 cm3 of a 0.0618 mol · dm-3 As2O3 (BDH; mass fraction 0.998) aqueous solution was added to the bomb body from an Eppendorf micropipet (Varipette 4810, 500-2500 µL, accuracy e(0.6%). The presence of the arsenious oxide solution ensured that all Cl2 formed in the combustion was reduced to aqueous HCl.69-71 Since mixtures of Cl2 and HCl of variable composition are always formed in the combustion of chlorine organic compounds, this method enabled simplification of the analysis of the final state.69 The bomb rotation was automatically started 2 min after ignition and maintained for 15 min. The analysis of the As2O5(aq) formed in the reaction of As2O3(aq) with Cl2 during the combustion of 5Cl6HNA was performed by ion chromatography. Heat Capacity Measurements. The standard molar heat capacities of solid 2-, 4-, 5-, and 6HNA and 5Cl6HNA were determined as a function of the temperature by using the Setaram DSC 121 apparatus mentioned above and the experimental procedure previously described.49 The samples had masses in the range 91-147 mg. Each determination required two consecutive runs. In the blank run, the reference and the sample measuring tubes contained empty crucibles. The temperature of the metal block was increased from room temperature to the initial temperature of the experiment at a rate of 2 K · min-1. After 600 s at this temperature, the block was heated again at 2 K min-1, and the calorimetric signal deviated from the initial isotherm. The heating period stopped at a programmed temperature, and a decay of the calorimetric signal to the final baseline was observed. In the second experiment, the crucible previously contained in the sample measuring tube was filled with the compound under study, and the temperature program described above was repeated. The heat capacity of the sample was derived from the amplitude difference (∆φ) between the blank and the sample heat flow rates at each temperature as o Cp,m )

M ∆φ mβ

(1)

where m and M are the mass and molar mass of the sample, respectively, and β is the heating rate. Knudsen Effusion. The standard molar enthalpies of sublimation of the hydroxynicotinic acid derivatives investigated in this work were measured using the Knudsen effusion apparatus and the operating procedure previously reported.72-75 The temperature of the tubular furnace surrounding the brass block containing the effusion cell was controlled with an accuracy of better than (0.1 K by using a Eurotherm 902P thermostatic unit and a K-type thermocouple placed in contact with the inner wall of the furnace. The equilibrium temperature inside the cell was assumed to be equal to the temperature of the brass block. This temperature was measured with a precision of (0.1 K using a Tecnisis 100 Ω platinum resistance thermometer embedded in the block and connected in a four-wire configuration to a Keithley 2000 multimeter. The cell was initially charged with ∼200-300 mg of sample, and the mass loss in each run was determined to (10 µg using a Mettler AT201 balance.

Computational Details. Density functional theory (DFT),76 Gaussian-3 theory with second-order Møller-Plesset (G3MP2),77 and complete basis set-quadratic Becke3 (CBS-QB3)78,79 procedures were applied to predict thermochemical properties of the systems under examination. In the case of the DFT methods, full geometry optimizations and frequency predictions were carried out with the B3LYP80,81 hybrid functional using the cc-pVTZ82,83 or aug-cc-pVTZ83,84 basis set. The corresponding molecular energies were converted to standard enthalpies at 298.15 K by using zero point energy (ZPE) and thermal energy corrections calculated at the same level of theory. The obtained vibration frequencies and ZPEs were not scaled unless otherwise stated. The DFT, G3MP2, and CBS-QB3 calculations were performed with the Gaussian-03 package.85 Results and Discussion Structure. The Raster3D64 drawings and labeling schemes of the molecular structures of 2HNA, 4HNA, 6HNA, and 5Cl6HNA, obtained from single crystal X-ray diffraction analysis, are illustrated in Figure 2. The corresponding bond angles and distances are compared in Table 2 with those given for the equivalent configurations of the isolated molecules by the B3LYP/aug-cc-pVTZ method. The packing diagrams of 2HNA, 4HNA, 6HNA, and 5Cl6HNA are illustrated in Figures 3-6, and some pertinent intermolecular distances are listed in Table 3. Also included in Table 3 are the corresponding data at 90 K, published for a different polymorph of 2HNA,86 dubbed form I, and for the same 6HNA phase studied in this work.87 The new polymorphic form of 2HNA here reported is named form II. Figure 2 shows that the 2HNA, 4HNA, 6HNA, and 5Cl6HNA molecules adopt oxo structures in the crystalline state, as evidenced by the short exocyclic C1-O1, C3-O1, and C5-O1 bond distances in Table 2, typical of CringdO bonding:88 dC1-O1 ) 1.269 Å for 2HNA; dC3-O1 ) 1.279 Å for 4HNA; dC5-O1 ) 1.272, 1.249, 1.255, 1.287 Å for the four nonequivalent a, b, c, and d molecules in the unit cell of 6HNA (see Figure 5a), respectively; and dC5-O1 ) 1.250 Å for 5Cl6HNA. This conclusion is also corroborated by the observation of bands typical of N-H and Cring)O stretching frequencies in the corresponding FT-IR spectra (see Supporting Information): ν˜ N-H ) 3229 (2HNA), 3195 (4HNA), 3231 (6HNA), and 3243 cm-1 (5Cl6HNA); ν˜ Cring ) O ) 1630 (2HNA), 1639 (4HNA), 1639 (6HNA), and 1639 cm-1 (5Cl6HNA). The absence of these bands in the spectrum of 5HNA suggests that a hydroxy structure is preferred in this case, as expected from simple valence theory. The bond distances and angles for the most stable hydroxy configuration of 5HNA predicted by the B3LYP/ aug-cc-pVTZ method are also listed in Table 2 for comparison purposes. The corresponding labeling scheme is indicated in Figure 7. In the case of 2HNA and 4HNA, intramolecular H-bonds involving the exocyclic O1 oxygen and the OH fragment of the carboxylate group in a S(6) pattern are also present, with dO2H · · · O1 ) 1.651 Å (2HNA) and dO2H · · · O1 ) 1.619 Å (4HNA). As shown in the packing diagram of Figure 3a (see also Table 3), the crystalline structure of form II of 2HNA exhibits planar head-to-tail dimeric units, sustained by two equivalent N1-H · · · O1 H-bonds forming a R22(8) pattern, that along with the intramolecular S(6) O2-H · · · O1 H-bond forms a S(6)R22(8) motif. The H-bond interactions of the R22(8) pattern are strong, as indicated by the short NH · · · O distances dN1H · · · O1 ) 1.85 Å. The dimers are interconnected along the [-1-10] direction by two weaker H-bonds of the O2-H · · · O2 (dO2H · · · O2 ) 2.70 Å) and

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Figure 2. Raster3D64 drawing and labeling schemes of the (a) 2HNA, (b) 4HNA, (c) 6HNA, and (d) 5Cl6HNA molecules.

C5-H · · · O3 (dC5H · · · O3 ) 2.47 Å) types, generating onedimensional chains parallel to each other along the a axis (Figure 3b). Adjacent chains are rotated relative to each other with a dihedral angle of ∼49°. Although the interplanar separation between these chains along the a axis is relatively small (3.377 Å for C2 · · · C7, Figure 3b), the strength of the contact is also weak, considering the difference, ∆, between the H · · · O distance and the sum of the van der Waals radii65 of H and O (∆ ) -0.02 Å, Table 3) an indication of the strength of contact interactions. As mentioned above, the structure of a different polymorph of 2HNA (form I) has been previously determined at 90 K.86 This polymorph also crystallizes in the monoclinic crystal system and space group P21/n (Z ) 4), with the molecule in the oxo form, but the unit cell parameters (a ) 3.640 Å, b ) 11.584 Å, c ) 13.565 Å, and β ) 94.64°, V ) 570.1 Å3) are significantly different from those of the structure obtained in this work at 293 K (Table 2). The crystal packing is also different: no planar head-to-tail dimeric units are present, and the structure exhibits one-dimensional chains along the [110] direction that are formed by a S(6)C(6) hydrogen bonding motif. This motif is sustained by intramolecular O-H · · · O (dOH · · · O1 ) 1.721 Å) and N-H · · · O (dNH · · · O1 ) 1.95 Å) H-bond interactions. The chains pack parallel to each other, with a separation distance of 3.277 Å along the a axis, and they are interconnected along the b axis by weak C-H · · · O interactions (dCH · · · O ) 2.592 Å). The crystalline structure of 4HNA (Figure 4a) exhibits infinite linear chains C(6) along the c axis, held by strong N1-H · · · O1 H-bonds (dN1H · · · O1 ) 1.85 Å, Table 3). These intermolecular H-bonds, together with intramolecular H-bonds of O2-H · · · O1 type (dO2H · · · O1 ) 1.62 Å), generate a S(6)C(6) motif. The linear

chains C(6) are linked along the b axis by two equivalent C1-H · · · O3 H-bonds (dC1H · · · O3 ) 2.27 Å), forming a R22(10) motif, and a C4-H · · · O3 H-bond (dC4H · · · O3 ) 2.49 Å), generating essentially noninteracting layers separated by 3.368 Å (Figure 4b). The four symmetry-independent molecules contained in the unit cell of 6HNA originate a tetramer sustained by four H-bonds (Figure 5a): two N1-H · · · O1 interactions generating an R22(8) pattern (dN1bH · · · O1c ) 1.86 Å and dN1cH · · · O1b ) 1.82 Å), and two others of the O2-H · · · O1 type (dO2cH · · · O1d ) 1.66 Å and dO2aH · · · O1b ) 1.69 Å) forming different D(2) motifs. The tetramers generate a two-dimensional layer in the ab plane sustained by N1-H · · · O1, O2-H · · · O1, and C1-H · · · O3 H-bonds (see Table 3). These layers are essentially noninteracting, since they are stacked along the c axis at a distance of 3.44 Å (Figure 5b). The structure of 6HNA obtained in this work at 293 K corresponds to the same triclinic phase (space group P1j; Z ) 8) with unit cell parameters a ) 6.813 Å, b ) 11.134 Å, c ) 16.278 Å, R ) 82.557°, β ) 78.106°, and γ ) 76.251° previously investigated at 90 K.87 The packing features observed at 90 K are similar to those typical of the 293 K structure. The unit cell volumes found here (V ) 1204.0 Å3, Table 2) and in the low temperature determination (V ) 1169.4 Å3), are consistent with the expected volume contraction on cooling from 293 to 90 K. The packing diagram of 5Cl6HNA (Figure 6a) exhibits infinite linear chains C(8) formed by a O2-H · · · O1 H-bond (dO2H · · · O1 ) 1.83 Å). These chains are linked by two equivalent N1-H · · · O1 interactions (dN1H · · · O1 ) 2.06 Å) that form an R22(8) pattern. The C(8) and R22(8) motifs, reinforced by a C1-H · · · O3 H-bond (dC1H · · · O3 ) 2.23 Å), generate two-dimensional undulated layers in the (102) plane, and the three-dimensional



TABLE 2: Experimental and/or Calculateda Bond Distances (in Å) and Bond Angles (in degrees) for 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA. Intramolecular Hydrogen Bond Contacts (in Å) for 2HNA and 4HNA

a

See Figures 2 and 7 for labeling schemes. The theoretically predicted structures correspond to the conformations of the oxo tautomers found in the solid state, except for 5HNA, whose molecular structure was not experimentally determined, but which is suggested to crystallize in a hydroxy conformation by FT-IR. b The sequence of bond distances and angles refer to the four molecules (a, b, c, and d) in the asymmetric unit of 6HNA (see Figure 5a).

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Figure 3. Crystal structure of 2-hydroxynicotinic acid, form II, (a) projected in the bc plane and (b) along the c axis.

structure of 5Cl6HNA is built by repeating these layers along the (010) plane (Figure 6b). The B3LYP/aug-cc-pVTZ model accurately captures the structural features of the 2HNA, 4HNA, 6HNA, and 5Cl6HNA molecules. The differences between the experimental and calculated C-C, N-C, or O-C bond distances are smaller than 0.03 Å. As expected, the larger deviations are observed for distances between atoms that are involved in H-bonds in the solid state but not in the gaseous state. Thus, for example, the experimental O2-C6 bond distances in 6HNA and 5Cl6HNA are shorter than the computed ones by 0.047 and 0.036 Å, respectively; the experimental distances O1-C1 in 2HNA, O1-C3 in 4HNA, and O1-C5 in 6HNA and 5Cl6HNA, are longer than their calculated counterparts, by 0.025-0.043 Å (Table 2). The theoretical calculations also correctly predict the bond distances between the heavy atoms involved in the intramolecular H-bonds of 2HNA and 4HNA, C6-O2 and O1-O2, respectively. Similar conclusions are reached if the bond angles are considered. It should also be noted that, although an overall better agreement with the experimental results is

reached when the aug-cc-pVTZ basis set is selected, the accuracy gain relative to the smaller cc-pVTZ basis is marginal: the maximum differences in the bond distances and angles predicted by the B3LYP/aug-cc-pVTZ and B3LYP/cc-pVTZ methods are 0.001 Å and 0.1°, respectively. Energetics. The 2005 IUPAC recommended standard atomic masses were used in the calculation of all molar quantities.89 The standard specific internal energies of combustion, ∆cu°, at 298.15 K obtained in the calorimetric experiments were derived from

∆cµ° ) [∆UIBP + ∆UΣ + ∆Uign + ∆Urot + ∆U(HNO3) + ∆U(As2O5) - ∆U(aux)] /m (2) were m is the mass of sample; ∆UIBP is the internal energy change associated with the bomb process under isothermal conditions, at 298.15 K; ∆UΣ represents the sum of all corrections necessary to reduce ∆UIBP to the standard state (Washburn corrections);90-93 ∆Uign is the electrical energy

Structure and Energetics of Hydroxynicotinic Acids supplied for ignition of the sample; ∆Urot is the energy dissipated by the rotation of the bomb; ∆U(HNO3) and ∆U(As2O5), are the energy changes associated with the formation of nitric acid and arsenic pentoxide, respectively; and ∆U(aux) is the contribution of the n-hexadecane used as combustion aid to the energy of the isothermal bomb process. The obtained ∆cuo values and the corresponding standard molar enthalpies of combustion at 298.15 K were: o (2HNA) ) ∆cuo (2HNA) ) -17931.36 ( 6.98 J · g-1, ∆cHm -1 o -2492.6 ( 2.2 kJ · mol , ∆cu (4HNA) ) -17945.88 ( 5.53 o (4HNA) ) -2494.6 ( 2.2 kJ · mol-1, ∆cuo J · g-1, ∆cHm o (5HNA) ) -18258.47 ( 16.44 J · g-1, ∆cHm (5HNA) ) -1 o -2538.1 ( 4.6 kJ · mol , ∆cu (6HNA) ) -17866.39 ( 7.18 o (6HNA) ) -2483.5 ( 2.2 kJ · mol-1, ∆cuo J · g-1, ∆cHm (5Cl6HNA) ) -13498.68 ( 3.43 J · g-1, and ∆cHom (5Cl6HNA) ) -2339.7 ( 1.5 kJ · mol-1. According to normal thermochemical practice, the uncertainties quoted for ∆cuo are the standard error of the mean of the individual results given as o represent twice the Supporting Information; those of ∆cHm overall standard error of the mean,94 including the contributions from the calibration with benzoic acid and also, when

J. Phys. Chem. B, Vol. 113, No. 43, 2009 14299 applicable, from the combustion of n-hexadecane and the oxidation of As2O3 by Cl2.92 For 2-, 4-, 5-, and 6HNA, the above results refer to the reaction

C6H5O3N(cr) + 23/4O2(g) ) 6CO2(g) + 5/2H2O(1) + 1/2N2(g) (3) and for 5Cl6HNA to the process

C6H4O3NCl(cr) + 21/4O2(g) + 1197/2H2O(1) ) 6CO2(g) + HCl · 600H2O(1) + 1/2N2(g)

(4)

They lead to the corresponding standard molar enthalpies of o (CO2, g) ) -393.51 ( 0.13 formation in Table 4 by using ∆fHm -1 95 o kJ · mol , ∆fHm(H2O, l) ) -285.830 ( 0.042 kJ · mol-1,95 and o (HCl · 600H2O, l) ) -166.619 ( 0.080 kJ · mol-1.96 The ∆fHm o (5HNA, cr) value in Table 4 should be regarded as prelimi∆fHm nary, since it corresponds to the mean of 24 results exhibiting an abnormally large dispersion. In fact, the enthalpies of formation

Figure 4. Crystal structure of 4-hydroxynicotinic acid (a) projected on the bc plane and (b) along the b axis.

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Figure 5. Crystal structure of 6-hydroxynicotinic acid (a) projected on the bc plane and (b) viewed down the c axis.

of 5HNA in the crystalline state that can be derived from the individual ∆cuo (5HNA) results given as Supporting Information span a range of 48 kJ · mol-1 (from -565 kJ · mol-1 to -517 kJ · mol-1), and the precision of the combustion results could not be improved by the use of a combustion aid. The standard molar enthalpies of sublimation of 2-, 4-, 5-, and 6HNA, and 5Cl6HNA, were obtained from vapor pressure, p, against temperature measurements by the Knudsen effusion method. The values of p were calculated from97,98

p)

m 2πRT At M

(

) ( 8r 8r+ 3l )( 2λ +2λ0.48r ) 1/2

(5)

where m is the mass loss during the time, t; A, l, and r are the area, the thickness, and the radius of the effusion hole, respectively; M is the molar mass of the compound under study; R is the gas constant; T is the absolute temperature; and λ is the mean free path given by99

λ)

kT √2πσ2p

(6)

Here, k represents the Boltzmann constant, and σ, the collision diameter. The collision diameters were estimated as 600 (2HNA),

601 (4HNA), 602 (5HNA), 603 (6HNA), and 626 pm (5Cl6HNA) from the van der Waals volume of each molecule calculated with the GEPOL93 program,100 on the basis of the molecular structures of the most stable conformations calculated in this work for each compound by the B3LYP/cc-pVTZ method. The van der Waals radii of carbon (170 pm), hydrogen (120 pm), nitrogen (155 pm), and oxygen (152 pm) given by Bondi were selected for this calculation.101 The area, A; radii, r; and thickness, l, of the effusion holes used in the measurements were A ) 4.404 × 10-7 m2, r ) 3.744 × 10-4 m, l ) 2.09 × 10-5 m (2HNA, 6HNA, and 5Cl6HNA); A ) 3.991 × 10-7 m2, r ) 3.564 × 10-4 m, l ) 2.09 × 10-5 m (4HNA); and A ) 6.613 × 10-7 m2, r ) 4.588 × 10-4 m, l ) 2.09 × 10-5 m (5HNA). Since the mean free path in eq 5 is pressure-dependent, an iterative method was needed to obtain the vapor pressure of the compound through eqs 5 and 6. As a first approximation, p was calculated by ignoring the λ-dependent term in eq 5. The obtained result was subsequently used to derive λ from eq 6. The calculated mean free path was introduced in eq 5, and a second p value was calculated. The iteration was continued until the difference between successive values of p was smaller than 10-8 Pa. The vapor pressure against temperature data was fitted to the equation102

ln p ) a -

b T

(7)



Figure 6. Crystal structure of 5-chloro-6-hydroxynicotinic acid (a) viewed down the a axis and (b) projected in the (102) plane.

where the slope, b, is related to the enthalpy of sublimation at the average of the highest and lowest temperatures of the range covered o in each series of experiments, Tm, by ∆subHm (Tm) ) bR. The obtained results are given in Table 5. The uncertainties assigned o to a and b correspond to standard errors, and that of ∆subHm (Tm) includes Student’s factor for 95% confidence level (2HNA and 5Cl6HNA, t ) 2.365 for eight independent measurements; 4HNA, t ) 2.306 for nine independent measurements; 5HNA and 6HNA, t ) 2.447 for seven independent measurements).103 Correction of o o the obtained ∆subHm (Tm) values to 298.15 K led to the ∆subHm results listed in Table 4. The correction was made through the equation o o ∆subHm (298.15K) ) ∆subHm (T) + o o (g) - Cp,m (cr)] dT ∫T298.15K [Cp,m

(8)

o o where Cp,m (cr) and Cp,m (g) are the standard molar heat capacities of the compounds in the crystalline and gaseous states, respectively. The calculations were based on the temperature dependence of the heat capacities of the compounds in the solid state, determined by DSC, and in the gaseous state, calculated by statistical mechanics104 by using vibration frequencies obtained by the B3LYP/cc-pVTZ o (cr/g) values (in method and scaled by 0.965.105 The Cp,m -1 -1 J · K · mol ) were fitted to equation

o Cp,m (cr/g) ) aT + b

(9)

whose coefficients and ranges of application are given in Table 6. The ∆fHom(cr) and ∆subHom at 298.15 K determined in this work led to the enthalpies of formation of 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA in the gaseous state indicated in Table 4. Table 7 shows the corresponding values predicted by the

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TABLE 3: Selected Intra- and Intermolecular Distances and Angles for 2HNA, 4HNA, 6HNA, and 5Cl6HNA N · · · O, O · · · O, or C · · · O distance/Å interaction

293 K

intra O2-H · · · O1 N1-H1 · · · O1 C5-H5 · · · O3 O2-H · · · O2

90 K

293 K

N-H · · · O, O-H · · · O, or C-H · · · O angle/°

90 K

293 K

2HNA (form II) 1.65(4) 1.85(3) 2.47(3) 2.70(4)

2.559(2) 2.815(3) 3.401(3) 3.019(3)

intra O2-H · · · O1 N1-H1 · · · O1 C4-H2 · · · O3

H · · · O distance/Å

2.504(2)b 2.810(2)b 3.309b

90 K

∆/Åa 293 K

90 K

-1.07 -0.87 -0.25 -0.02

161(4) 176(3) 155(3) 101(3)

2HNA (form I)b 1.72b 1.95b 2.592b

-0.999 -0.766 -0.128

154b 164b 132.5b

4HNA intra O2-H · · · O1 N1-H1 · · · O1 C1-H1 · · · O3 C4-H4 · · · O3

2.523(2) 2.741(2) 3.196(2) 3.315(2)

N1-H1 · · · O1

2.823(3) 2.781(3) 2.796(3) 2.764(3) 2.576(3) 2.615(3) 2.576(3) 2.615(3) 3.247(4) 3.222(4) 3.210(4) 3.236(4)

O2-H2 · · · O1

C1-H1 · · · O3

N1-H1 · · · O1 O2-H2 · · · O1 C1-H1 · · · O3

1.62(3) 1.85(2) 2.27(2) 2.49(2) 2.813(2)c 2.772(2)c 2.761(2)c 2.800(2)c 2.568(2)c 2.592(2)c 2.568(2)c 2.597(2)c 3.207c 3.218c 3.233c 3.236c

2.914(2) 2.732(3) 3.099(3)

6HNA 1.96c 1.90c 1.88c 1.93c 1.74c 1.76c 1.74c 1.76c 2.35c 2.35c 2.36c 2.35c

168(3) 178(3) 173(3) 171(3) 171(4) 161(6) 173(2) 161(6) 164(3) 156(3) 151(3) 160(3)

5Cl6HNA 2.06(3) 1.83(4) 2.23(3)

170(3) 174(4) 154(2)

1.86(3) 1.82(3) 1.83(3) 1.78(3) 1.66(4) 1.69(7) 1.76(2) 1.69(7) 2.34(3) 2.37(3) 2.26(3) 2.32(3)

-1.101 -0.872 -0.449 -0.226

159(3) 156(2) 164(2) 144(2)

-0.862 -0.872 -0.883 -0.940 -1.062 -1.027 -1.062 -1.027 -0.378 -0.226 -0.454 -0.397

163c 173c 175c 169c 171c 171c 171c 171c 149c 151c 153c 154c

-0.759 -0.822 -0.836 -0.789 -0.984 -0.959 -0.959 -0.955 -0.365 -0.348 -0.361 -0.366

-0.658 -0.891 -0.498

Difference between the H · · · O distance in column 5 (293 K) or 6 (90 K) and the sum of the van der Waals radii of H and O. b Ref 86. Ref 87. a

c

TABLE 5: Coefficients of Eq 7 and Corresponding Standard Molar Enthalpies of Sublimation (in kJ · mol-1) at the Average of the Highest and Lowest Temperatures of the Range Covered in the Experiments, ∆subHom(Tm)

Figure 7. Labeling scheme of the most stable configuration of 5HNA calculated at the B3LYP/aug-cc-pVTZ level of theory.

TABLE 4: Standard Molar Enthalpies of Formation and Sublimation of 2-, 4-, 5- and 6-Hydroxynicotinic Acids and 5-Chloro-6-hydroxynicotinic Acid at 298.15 Ka compound

o -∆fHm (cr)

o ∆subHm

o -∆fHm (g)

2HNA 4HNA 5HNA 6HNA 5Cl6HNA

583.1 ( 2.3 581.1 ( 2.4 537.6 ( 4.7 592.1 ( 2.4 616.8 ( 1.7

128.3 ( 5.1 148.1 ( 3.7 149.8 ( 7.1 146.4 ( 4.6 151.3 ( 2.8

454.8 ( 5.6 433.0 ( 4.4 387.8 ( 8.5 445.7 ( 5.2 465.5 ( 3.3

a

Data in kJ · mol-1.

B3LYP/cc-pVTZ, B3LYP/aug-cc-pVTZ, G3MP2, and CBSQB3 methods for the most stable conformations of the hydroxy and oxo forms of each isomer and their differences relative to o o (exp) - ∆fHm (calc). the experimental values, ∆fHm The results in Table 7 were based on the theoretically computed enthalpies of the atomization reaction 10 and on the enthalpies of the isodesmic106 reactions 11-20, which are compared in Table 8 with the corresponding experimental values (it should be noted that reactions 11-20 can be considered

2HNA 4HNA 5HNA 6HNA 5Cl6HNA

a

b

Tm/K

o ∆subHm (Tm)

33.24 ( 0.57 38.05 ( 0.43 38.37 ( 0.77 36.01 ( 0.47 37.35 ( 0.28

15 083.9 ( 252.8 17 387.2 ( 188.3 17 696.9 ( 341.8 17 201.5 ( 223.4 17 928.5 ( 133.6

447.0 440.8 447.1 474.9 472.5

125.4 ( 5.0 144.6 ( 3.6 147.1 ( 7.0 143.0 ( 4.5 149.1 ( 2.6

TABLE 6: Coefficients of Eq 9 for the Solid and Gaseous States 2HNA 4HNA 5HNA 6HNA 5Cl6HNA

s g s g s g s g s g

T/K

a

b

293-468 200-500 288-450 200-500 288-474 200-500 288-483 200-500 297-473 200-500

0.416 24 0.364 50 0.462 46 0.365 18 0.434 00 0.356 25 0.440 02 0.359 17 0.334 46 0.352 42

25.507 25.154 14.157 25.834 23.501 34.367 19.288 31.167 67.837 48.220

isodesmic only if 2HNA, 4HNA, 6HNA, and 5Cl6HNA are in o their hydroxy forms). These were obtained from the ∆fHm (g) o data in Table 4 in conjunction with ∆fHm(C, g) ) 716.67 ( 0.46,107 ∆fHom(H, g) ) 217.999 ( 0.006,107 ∆fHom(O, g) ) 249.17 o o (N, g) ) 472.68 ( 0.10,107 ∆fHm (Cl, g) ) ( 0.10,107 ∆fHm o 107 ∆fHm(C6H6, g) ) 82.6 ( 0.7,108 121.302 ( 0.006, o o ∆fHm (C5H5N, g) ) 140.4 ( 0.7,108 ∆fHm (C6H5COOH, g) ) o 108 -294.0 ( 2.2, ∆fHm(C6H4NCOOH, g) ) -233.2 ( 1.4,109


J. Phys. Chem. B, Vol. 113, No. 43, 2009 14303 o terms refer to the standard molar enthalpies of where the Hm the CaHbOcNdCle molecule and of the C, H, O, N, and Cl atoms in the gaseous state, at 298.15 K, computed at the B3LYP/cc-pVTZ, B3LYP/aug-cc-pVTZ, G3MP2, or CBSQB3 levels of theory (see Supporting Information). The enthalpy of formation of gaseous CaHbOcNdCle at 298.15 K was then derived from

o o ∆fHm (CaHbOcNdCle, g) ) -∆fHm (reaction 10) + o o (C, g) + b∆fHm (H, g) + a∆fHm o c∆fHm (O,

o o g) + d∆fHm (N, g) + e∆fHm (Cl, g)

(22)

∆fHmo(2-HOC6H4COOH, g) ) -497.3 ( 1.4,16 ∆fHmo(3o (4HOC6H4COOH, g) ) -475.6 ( 2.3,16 and ∆fHm HOC6H4COOH, g) ) -480.2 ( 1.5 kJ · mol-1.16 In the case of reactions 19 and 20, the estimated value ∆fHmo(3-Cl-4HOC6H3COOH, 1 g) ) -500.6 ( 5.0 kJ · mol-1 was also used. This corresponds to conformation 1 of 3-Cl-4-HOC6H3COOH, which is predicted to be less stable than conformation 2, ∆fHom(3Cl-4-HOC6H3COOH, 2 g) ) -514.0 ( 5.0 kJ · mol-1, but has the OH group with the same orientation relative to Cl present in 5Cl6HNA. Selecting conformation 1 allows removal of the contribution of a stabilizing OH · · · Cl interaction that is present o (3-Cl-4in 2 but not in 5Cl6HNA. The estimates of ∆fHm o HOC6H3COOH, 1 g) and ∆fHm(3-Cl-4-HOC6H3COOH, 2 g) indicated above are the mean values of the ∆fHom results obtained from the corresponding atomization enthalpies and from the enthalpies of a series of isodesmic reactions calculated at the CBS-QB3 and G3MP2 levels of theory (see Supporting Information for details).

The enthalpies of formation of the CaHbOcNdCle compounds obtained from the theoretically calculated enthalpies of reaction 10 (Table 8) were derived as follows: First, the enthalpy of the atomization process was calculated at 298.15 K from ∆rHom(reaction 10) ) aHom(C, g) + bHom(H, g) + cHom(O, g) + dHom(N, g) + eHom(Cl, g) - Hom(CaHbOcNdCle, g)

(21)

o (reaction 10) and the experiby using the calculated ∆rHm mental values of the standard molar enthalpies of formation of C(g), H(g), O(g), N(g), and Cl(g) at 298.15 K, indicated above. It can be concluded from Table 7 that when the calculations are based on the atomization reaction 10, the B3LYP/cco (g) that are more pVTZ method systematically yields ∆fHm positive than the experimental values. The maximum (∆max ) 70 kJ · mol-1) and average (∆aver ) 49 kJ · mol-1) absolute deviations are substantial, and they worsen (∆max ) 79 kJ · mol-1; ∆aver ) 58 kJ · mol-1) with the use of the larger aug-cc-pVTZ basis. This poor performance of the selected o (g) values from DFT models in the prediction of ∆fHm atomization enthalpies is not unexpected,76,110-112 and the increase of ∆aver when the cc-pVTZ basis is replaced by the larger aug-cc-pVTZ has also been previously noted.112 Considerable improvements are observed when the CBS-QB3 (∆max ) 28 kJ · mol-1, ∆aver ) 15 kJ · mol-1) and the G3MP2 (∆max ) 18 kJ · mol-1, ∆aver ) 6 kJ · mol-1) methods are used. The latter leads to a better agreement with the experimental values than the former, not only because the corresponding deviations are generally smaller, but also because their reduction is more significant when the data for 5HNA are not taken into account (as mentioned above, the enthalpy of formation of gaseous 5HNA should be taken as preliminary due to the difficulties associated with the determination of the corresponding enthalpy of formation in the crystalline state). o (5HNA, g), the following deviations are Ignoring ∆fHm obtained: ∆max ) 8 kJ · mol-1, ∆aver ) 5 kJ · mol-1 for the G3MP2 and ∆max ) 21 kJ · mol-1, ∆aver ) 13 kJ · mol-1 for the CBS-QB3 methods. In contrast, for the DFT models, ∆max remains the same, but ∆aver slightly increases when the data for 5HNA are disregarded: ∆aver ) 51 kJ · mol-1 for the B3LYP/cc-pVTZ and ∆aver ) 59 kJ · mol-1 for the B3LYP/ aug-cc-pVTZ methods. The results of the DFT models match, however, those of the G3MP2 and CBS-QB3 methods when well-balanced isodesmic reactions 11-20, with the hydroxy tautomer as reagent, are considered. The discrepancy increases if 2HNA, 4HNA, 6HNA, and 5Cl6HNA are assumed to be on their oxo tautomers, thus invalidating the isodesmic nature of those reactions. The relative stabilities of gaseous 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA, deduced from the experimental o (g) data in Table 4, are compared in Figure 8 with the ∆ fH m corresponding predictions by the B3LYP/cc-pVTZ, B3LYP/ aug-cc-pVTZ, G3MP2, and CBS-QB3 methods for the most stable conformations of the hydroxy or oxo forms (Table 7). The theoretical data refer to the atomization reaction 10. 2-Hydroxynicotinic acid was taken as reference for the

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TABLE 7: Theoretically Predicted Enthalpies of Formation at 298.15 K

a

o o The values in parentheses correspond to the differences between the experimental and calculated values, ∆fHm (exp) - ∆fHm (calc).

comparison, and the terms ∆∆fHom were computed as ∆∆fHom ) ∆fHom(g) - ∆fHom(2HNA, g), where ∆fHom(g) represents the enthalpy of formation of 4HNA, 5HNA, 6HNA, or 5Cl6HNA. In general, the experimental stability order 5Cl6HNA > 2HNA > 6HNA > 4HNA > 5HNA (more stable meaning o ) is accurately captured by the CBS-QB3 and smaller ∆∆fHm G3MP2 methods, which give 5Cl6HNA > 2HNA ∼ 6HNA > 4HNA > 5HNA. The DFT models predict 2HNA > 6HNA > 5Cl6HNA > 4HNA > 5HNA, thus leading to a misplacement of 5Cl6HNA in the series. The orders of stability predicted by the two DFT models agree, however, with the experimental sequence and those given by the CBS-QB3 and G3MP2 methods when the ∆fHom(g) are derived from reactions 11-20. It should also be noted that, as illustrated in Figure 8, the theoretically based stability orders are equally valid for the hydroxy or oxo forms. The enthalpies and Gibbs energies associated with the tautomeric equilibrium hydroxy T oxo in gaseous 2HNA, 4HNA, 6HNA, and 5Cl6HNA, calculated at various levels of theory are summarized in Table 9. The values of ∆rHom and ∆rGom o o were derived from the Hm and Gm results obtained for the

tautomers given as Supporting Information. Also included in Table 9 are the molar fractions of each tautomer present in equilibrium, which were calculated from

e-∆rGm/RT o

xoxo )

1 + e-∆rGm/RT o

xhydroxy ) 1 - xoxo

(23)

(24)

o o ∼ ∆rGm , in It can be concluded from Table 9 that ∆rHm agreement with the expected small entropic difference between the two tautomers. For a given compound, systematic differences o o or ∆rGm predicted by each model are between the values of ∆rHm o in Figure 9, approximately observed. This is illustrated for ∆rHm which shows that the CBS-QB3 method yields results that are consistently more negative by 0.4-1.2 kJ · mol-1 than those of the G3MP2 model and more positive by 4.3-7.1 and 4.4-7.5 kJ · mol-1, respectively, than those of the B3LYP/cc-pVTZ and B3LYP/aug-cc-pVTZ methods. These systematic differences are



TABLE 8: Theoretically Predicted Enthalpies of Reaction at 298.15 K

o o a The values in parentheses correspond to the differences between the experimental and calculated values, ∆fHm (exp) - ∆fHm (calc). b This value is not exclusively based on experimental data, since an estimated enthalpy of formation of 3-Cl-4-HOC6H3COOH was used in the calculation (see text).

reflected in the equilibrium fractions of each tautomer given by the different models. All methods predict that in the gas phase, 2HNA predominantly exists in the oxo form (xoxo > 0.9), whereas for 4HNA, the hydroxy tautomer is dominant (xhydroxy > 0.9). The DFT methods also indicate that the vapors of 6HNA and 5Cl6HNA are composed of mainly the oxo form (xoxo > 0.9) but no such prevalence is suggested by the G3MP2 and CBS-QB3 models, which lead to xoxo ∼ 0.4 for 6HNA and xoxo ∼ 0.6 for 5Cl6HNA. It is interesting to compare the picture emerging here for the structural preferences of hydroxynicotinic acid derivatives in the solid and gaseous states with those typical of hydroxypyridines (2HP, 3HP, and 4HP), which are generally considered to be the archetype systems for the study of the hydroxy T oxo tautomerization in N-heterocyclic compounds.18 The behavior of hydroxynicotinic acid derivatives seems to parallel that of the hydroxypyridines in the solid state, but not entirely in the gaseous state. Thus, 2HP is found to crystallize in the oxo form,113-116 analogously

to 2HNA, 6HNA, and 5Cl6HNA, which are similar in terms of the relative positions of the N and OH groups. The same is also true for crystalline 4HP,117 which favors the oxo form such as 4HNA. Finally, 3HP crystallizes in the hydroxy form114,118,119 in the same way as 5HNA. The vapors of 3HP and 5HNA should also consist of the corresponding hydroxy tautomers. However, as noted above, the results of all computational methods used here point to a strong preference of gaseous 4HNA for the hydroxy tautomer and suggest that the oxo form is clearly dominant for 2HNA (Table 9 and Figure 9). In contrast, the available experimental evidence (Table 10) indicates a strong preference of both 2HP and 4HP for the hydroxy tautomer in the gas phase, although the tendency for the formation of the oxo form is clearly larger for 2HP than for 4HP, thus paralleling the behavior of the 2HNA-4HNA pair.20,22-27 The results of G3MP2 and CBS-QB3 calculations given in Table 10 (see Supporting Information for details) lead to a similar conclusion.

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Figure 8. Experimental (center) and theoretically computed (hydroxy forms at left and oxo forms at right) orders of stability of 2HNA, 4HNA, o o 5HNA, 6HNA, and 5Cl6HNA in terms of ∆∆fHm (see text). The uncertainties of the experimental ∆∆fHm values are indicated by error bars.

Despite the discrepancies between the absolute values of xhydroxy and xoxo obtained by the DFT models and the higher level G3MP2 and CBS-QB3 methods, all the computational methods predict the tendency for the formation of the oxo tautomer in the vapors of 6HNA and 5Cl6HNA to be larger than for 4HNA but smaller than for 2HNA.

Finally, an interesting aspect of the energetics of group additivity associated with Cl substitution can be evidenced by comparing the difference between the enthalpies of formation of gaseous TABLE 9: Theoretically Predicted Standard Molar Enthalpies and Gibbs Energies (Data in kJ · mol-1) for the Hydroxy T Oxo Equilibrium, at 298.15 K, for Gaseous 2HNA, 4HNA, 6HNA, and 5Cl6HNA, and Corresponding Fractions (x) of the Two Tautomers method B3LYP/cc-pVTZ B3LYP/aug-cc-pVTZ G3MP2 CBS-QB3

o ∆r H m

o ∆ rG m

xhydroxy

xoxo

2HNA -11.2 -11.5 -11.1 -11.3 -5.6 -5.9 -6.8 -6.9

0.010 0.010 0.085 0.058

0.990 0.990 0.915 0.942

B3LYP/cc-pVTZ B3LYP/aug-cc-pVTZ G3MP2 CBS-QB3

4HNA 7.5 6.7 13.9 12.7

7.4 6.7 13.5 12.4

0.952 0.937 0.996 0.993

0.048 0.063 0.004 0.007


6HNA -6.5 -6.1 1.4 1.0

-6.8 -6.3 0.9 0.7

0.060 0.073 0.590 0.570

0.940 0.927 0.410 0.430


5Cl6HNA -7.8 -7.2 -0.1 -0.7

-8.0 -7.4 -0.5 -1.0

0.038 0.048 0.450 0.400

0.962 0.952 0.550 0.600

o Figure 9. Enthalpic differences, ∆rHm , between the most stable conformers of the hydroxy and oxo tautomers of 2HNA, 4HNA, 6HNA, and 5Cl6HNA (the molecular structures are given in Table 7 and Figure 2) calculated at various levels of theory: (A) B3LYP/cc-pVTZ, (B) B3LYP/aug-cc-pVTZ, (C) G3MP2, and (D) CBS-QB3.

o 6HNA and 5Cl6HNA in Table 4, ∆ ) ∆fHm (5Cl6HNA, g) -1 o ∆fHm(6HNA, g) ) -19.8 ( 6.2 kJ · mol , with the analogous values for the following pairs of molecules:

o These were calculated from ∆fHm (C6H6, g) ) 82.6 ( 0.7,108 o o 108 ∆fHm(C6H5Cl, g) ) 52.0 ( 1.3, ∆fHm (C5H5N, g) ) 140.4 ( 108 o o (C6H5COOH, 0.7, ∆fHm(C5H4NCl, g) ) 107.6 ( 1.7,120 ∆fHm 108 o g) ) -294.0 ( 2.2, and ∆fHm(3Cl-C6H4COOH, g) ) -322.6



TABLE 10: Theoretically Predicted and Experimental Standard Molar Enthalpies and Gibbs Energies (Data in kJ · mol-1) for the Hydroxy T Oxo Equilibrium in Gaseous 2HP and 4HP at the Temperature T (K) and Corresponding Fractions (x) of the Two Tautomers method

T

o -∆rHm

o -∆rGm

2HP 5.4 5.4 3.3-4.2b 2.9-3.9c 3.8-4.9d 2.5e 3.0 ( 0.6f 3.1-3.2f 3.2 ( 0.4g 1.9 ( 0.2h 3.9-4.3h

298.15 G3MP2a CBS-QB3a 298.15 experimental 433-573b 393-623c 323-723d 403e 428-533f 356g 423-444h

6.0 5.9 2.5 ( 2.3 1.4 ( 0.4c 2.6 ( 0.2d

G3MP2 298.15 CBS-QB3 298.15 experimental 433.5 363

15.4 15.4

4HP 14.6 14.8 0.97c >0.95i

0.003 0.003

Energetics and Structure of Hydroxynicotinic Acids. Crystal Structures

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