Energetics and structure of nicotinic acid (Niacin)

Article abstract of DOI:10.1021/jp101490b

The standard molar enthalpies of formation and sublimation of crystalline (monoclinic, space group P2₁/c) nicotinic acid (NA), at 298.15 K, were determined as δ_fHm°(NA, cr) = -344.7 ± 1.2 kJ·mol^-1 and δ_subHm°(NA) = 112.1 ± 0.5 kJ·mol^-1 by using combustion calorimetry, drop-sublimation Calvet microcalorimetry, and the Knudsen effusion method. The experimental determinations were all based on a sample of NIST Standard Reference Material 2151, which was characterized in terms of chemical purity, phase purity, and morphology. From the above results, δ_fHm° (NA, g) = -232.6 ± 1.3 kJ·mol^-1 could be derived. On the basis of this value and on published experimental data, the enthalpy of the isodesmic reaction nicotinic acid(g) + benzene(g) ? benzoic acid(g) + pyridine(g) was calculated as -3.6 ± 2.7 kJ·mol^-1 and compared with the corresponding predictions by the B3LYP/cc-pVTZ (-3.6 kJ·mol^-1), B3LYP/aug-cc-pVTZ (-3.7 kJ·mol ^-1), B3LYP/6-311++G(d,p) (-4.2 kJ·mol^-1), G3MP2 (-4.3 kJ·mol^-1), and CBS-QB3 (-4.0 kJ·mol^-1) quantum chemistry models. The excellent agreement between the experimental and theoretical results supports the reliability of the δ_fHm° (NA, cr), δ_subHm°(NA), and δ_fHm°(NA, g) recommended in this work. These data can therefore be used as benchmarks for discussing the energetics of nicotinic acid in the gaseous and crystalline states and, in particular, to evaluate differences imparted to solid forms by the production and processing methods. Such differences are perhaps at the root of the significant inconsistencies found between the published enthalpies of sublimation of this important active pharmaceutical ingredient and thermochemical standard. The molecular packing in the crystalline phase studied in this work was also discussed and its influence on the molecular structure of nicotinic acid was analyzed by comparing bond distances and angles published for the solid state with those predicted by the B3LYP/cc-pVTZ method. No advantage in terms of accuracy of the structural predictions was found by the use of the larger aug-cc-pVTZ or 6-311++G(d,p) basis sets.

Full text of DOI:10.1021/jp101490b

J. Phys. Chem. B 2010, 114, 5475–5485
5475
Energetics and Structure of Nicotinic Acid (Niacin)
Elsa M. Gonc¸alves,† Carlos E. S. Bernardes,†,‡ Herm´ınio P. Diogo,‡ and
Manuel E. Minas da Piedade*,†
Departamento de Qu´ımica e Bioqu´ımica, Faculdade de Cieˆncias, UniVersidade de Lisboa,
1649-016 Lisboa, Portugal, and Centro de Qu´ımica Estrutural, Complexo Interdisciplinar, Instituto Superior
Te´cnico da UniVersidade Te´cnica de Lisboa, 1049-001 Lisboa, Portugal
ReceiVed: February 18, 2010; ReVised Manuscript ReceiVed: March 18, 2010
The standard molar enthalpies of formation and sublimation of crystalline (monoclinic, space group P21/c)
nicotinic acid (NA), at 298.15 K, were determined as ∆fH°(NA, cr) ) -344.7 ( 1.2 kJ ·mol-1 and ∆subH°(NA)
m
m
) 112.1 ( 0.5 kJ · mol-1 by using combustion calorimetry, drop-sublimation Calvet microcalorimetry, and
the Knudsen effusion method. The experimental determinations were all based on a sample of NIST Standard
Reference Material 2151, which was characterized in terms of chemical purity, phase purity, and morphology.
From the above results, ∆fH°(NA, g) ) -232.6 ( 1.3 kJ · mol-1 could be derived. On the basis of this value
m
and on published experimental data, the enthalpy of the isodesmic reaction nicotinic acid(g) + benzene(g) f
benzoic acid(g) + pyridine(g) was calculated as -3.6 ( 2.7 kJ · mol-1 and compared with the corresponding
predictions by the B3LYP/cc-pVTZ (-3.6 kJ · mol-1), B3LYP/aug-cc-pVTZ (-3.7 kJ · mol-1), B3LYP/6-
311++G(d,p) (-4.2 kJ ·mol-1), G3MP2 (-4.3 kJ ·mol-1), and CBS-QB3 (-4.0 kJ ·mol-1) quantum chemistry
models. The excellent agreement between the experimental and theoretical results supports the reliability of
the ∆fH°(NA, cr), ∆subH°(NA), and ∆fH°(NA, g) recommended in this work. These data can therefore be
m
m
m
used as benchmarks for discussing the energetics of nicotinic acid in the gaseous and crystalline states and,
in particular, to evaluate differences imparted to solid forms by the production and processing methods. Such
differences are perhaps at the root of the significant inconsistencies found between the published enthalpies
of sublimation of this important active pharmaceutical ingredient and thermochemical standard. The molecular
packing in the crystalline phase studied in this work was also discussed and its influence on the molecular
structure of nicotinic acid was analyzed by comparing bond distances and angles published for the solid state
with those predicted by the B3LYP/cc-pVTZ method. No advantage in terms of accuracy of the structural
predictions was found by the use of the larger aug-cc-pVTZ or 6-311++G(d,p) basis sets.
Introduction
the dissolution rate of the drug, ultimately affecting its
therapeutic window.9-11
Nicotinic acid (NA, CAS number [59-67-6]), pyridine-3-
carboxylic acid, also known as niacin or vitamin B3, is a water-
soluble vitamin, that is credited to have been synthesized for
the first time by Huber, in 1867.1 It is an indispensable nutrient
for humans and animals, and has been widely used as an additive
in food, forage, and cosmetics.2,3 It has also found important
pharmacological applications, particularly in the treatment of
hypercholesterolemia and atherosclerosis.4,5 The world demand
for nicotinic acid and its derivatives has been steadily rising
from 8500 t per year in the 1980s to 22000 t in the 1990s and,
more recently, 35000-40000 t.6-8
We have long been interested in the study of the relationship
between the structure and energetics of individual molecules,12
and more recently on how intermolecular forces determine their
packing in the solid state, the lattice energy of the crystals,13-15
or the relative stability of different polymorphs that may coexist
under the same temperature and pressure conditions.16 The
importance of NA
Nicotinic acid is often employed as a solid, and it is well-
known that the physical properties of organic molecular solids
may be affected by the methods of production and processing,
with a possible impact on the end-use applications. For example,
the manufacturing of solid dosage forms normally involves the
purification of the active pharmaceutical ingredient (API) by
crystallization from solution, followed by grinding and compac-
tion. Any of these processes can influence the crystallinity, size,
morphology, and energetics (lattice and surface energies) of the
API particles, and even the nature of the obtained phase if
different polymorphs are possible. These aspects dictate, in turn,
both as an API and as a standard reference material for the
measurement of enthalpies of combustion17 makes it an attractive
candidate for these types of studies, in particular, since it is not
clear from the literature how strongly changes in crystallinity,
morphology, particle size distribution, etc., associated with the
methods of preparation and processing may influence the
thermodynamic stability of a given sample. Thus, for example,
while a preformulation study carried out by thermogravimetry
showed no significant effect of compaction and grinding on the
kinetics of nicotinic acid sublimation,18 the values of the standard
* To whom correspondence should be addressed. E-mail: memp@fc.ul.pt.
† Universidade de Lisboa.
‡ Instituto Superior Te´cnico da Universidade Te´cnica de Lisboa.
10.1021/jp101490b  2010 American Chemical Society
Published on Web 04/08/2010

5476 J. Phys. Chem. B, Vol. 114, No. 16, 2010
Gonc¸alves et al.
molar enthalpies of sublimation at 298.15 K, ∆subH°(NA),
and quadrupole analyzer were maintained at 553, 503, and 423
K, respectively. A solvent delay of 4 min was selected. Electron
ionization mass spectra in the range 35-550 m/z were recorded
in the full-scan mode, with 70 eV electron energy and an
ionization current of 34.6 µA. Data recording and instrument
control were performed by using the MSD ChemStation
software from Agilent (G1701CA; version C.00.00). The identity
of the analyzed compound was assigned by comparison of the
mass-spectrometric results with the data in Wiley’s reference
spectral databank (G1035B, Rev D.02.00), and its purity was
calculated from the normalized peak areas, without using
correction factors to establish abundances. X-ray powder
diffraction analyses were carried out on a Philips PW1730
diffractometer, with automatic data acquisition (APD Philips
v.35B), operating in the θ-2θ mode. 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 40 kV. The diffractograms were recorded at
∼293 K in the range 10° e 2θ e 40°. Data were collected 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 Checkcell.31 Scanning
electron microscopy (SEM) images of Au/Pd-sputtered samples
were recorded in high vacuum, using a FEI ESEM Quanta 400
FEG apparatus, with a resolution of 2 nm. The electron beam
voltage was set to 10 kV.
m
published over a period of 18 years span a range of ∼20
kJ·mol-1.19-22 In contrast, the three independent determinations
of the standard molar enthalpy of formation of crystalline
nicotinic acid, ∆fH°(NA, cr), reported over a period of 24 years
m
diverge by no more than (0.5 kJ ·mol-1 21,23,24
.
It is worth
mentioning that a fourth and recent measurement led to a
∆fH°(NA, cr) value differing by 288 kJ ·mol-1 from the average
m
of all the previous ones.25 This must not be considered, however,
because the discrepancy was later found by the authors to be
due to problems with the calorimetric apparatus and the result
was discarded.26
Inconsistencies in ∆fH°(NA, cr) and ∆subH°(NA), arising
m
from sample variability, necessarily affect ∆fH°m(NA, g), which
m
is derived as a sum of the first two quantities. Analysis of the
original literature revealed that only in one case21 were both
∆fH°(NA, cr) and ∆subH°(NA) measured in the same laboratory,
m
m
and presumably with the same sample. We therefore felt that,
before embarking on further studies of the relationship between
the structure and energetics of nicotinic acid, the two basic
thermodynamic properties ∆fH°(NA, cr) and ∆subH°(NA),
m
m
which reflect the lattice energy, should be obtained using a single
and well-characterized sample and put on a firmer basis.
This work describes the redetermination of the standard molar
enthalpies of formation and sublimation of nicotinic acid by
using combustion calorimetry, drop-sublimation Calvet micro-
calorimetry, and the Knudsen effusion method. The experimental
determinations were all based on a sample of NIST SRM 2151,
which was characterized in terms of chemical purity, phase
purity, and morphology. Density functional theory (DFT),27
Gaussian-3 theory with second-order Møller-Plesset
(G3MP2),28 and complete basis set - quadratic Becke3
(CBS-QB3)29,30 calculations were also applied to help in the
assessment of the internal consistency of the obtained experi-
mental results. Finally, the crystal packing of the nicotinic acid
form studied in this work and its influence on the molecular
structure were also analyzed using the predictions of the DFT
models for an isolated molecule in the gas phase as a reference.
Materials. A nicotinic acid sample from NIST (standard
reference material 2151),32 without further purification, was used
in all thermodynamic measurements. Elemental analysis for
C6H5O2N: expected C 58.54%, H 4.10%, N 11.38%; found C
58.26%, H 3.91%, N 11.15% (average of two determinations).
DRIFT (KBr, main peaks): ν˜/cm-1 ) 3085, 3072 (νCsH); 2821,
2445, 1948 (νN· · ·H· · ·O); 1709 (νCdO, sCOOH); 1596, 1583
(νCdC, νCdN, ring); 1495 (δOsH· · ·N, in plane); 1418 (νCdC, νCdN
,
ring); 1324 (δOsH, in plane); 1303 (νCsO, sCOOH); 1186, 1139,
1115 (ꢀCsH, in plane), 1089 (δOsH· · ·N, out of plane); 1041, 1033
(ν ring breathing); 955 (δCsH· · ·O, out of plane); 831; 811, 751,
Materials and Methods
695 (γCsH, out of plane); 682 (δCOO, sCOOH); 642, 498 (δring
,
in plane deformation). The assignments were based on those
given by Taylor,33 Goher and Dra´tovsky´,34 and Hudson et al.35
1H NMR (400 MHz, DMSO-d6/TMS), δ/ppm ) 13.456 (s,
sOH, 1H), 9.078 (d, sCH, 1H), 8.797 (dd, sCH, 1H), 8.273
(dt, sCH, 1H), 7.552 (m, sCH, 1H). 13C NMR (100 MHz,
General. Elemental analyses were carried out on a Fisons
Instruments EA1108 apparatus. Diffuse reflectance infrared
Fourier-transform (DRIFT) spectroscopy measurements were
performed in the range 400-4000 cm-1 using a Nicolet 6700
spectrometer. The resolution was 2 cm-1, and the samples were
∼5% (w/w) nicotinic acid in KBr. The 1H NMR and 13C NMR
spectra were obtained in DMSO-d6, (Aldrich 99.9% containing
0.03% v/v TMS) at ambient temperature, on a Bruker Ultrashield
400 MHz spectrometer. GC-MS experiments were performed
on an Agilent 6890 gas chromatograph equipped with an Agilent
7683 automatic liquid sampler coupled to an Agilent 5973 N
quadrupole mass selective detector. An HP-5 column (5%
diphenyl/95% dimethylpolysiloxane; 28.7 m × 0.25 µm I.D.,
250 µm film thickness) was used. The sample was dissolved in
methanol (Fisher Scientific, HPLC grade, 99.99%), and the
injection volume was 1 µL. The carrier gas was helium
maintained at a constant pressure of 1.19 bar and with a flow
rate of 1.3 mL ·min-1. A programmed temperature vaporization
injector with a septumless sampling head having a baffled liner
(Gerstel) operating in the splitless mode was employed. The
inlet temperature was set to 523 K, and the oven temperature
was programmed as follows: 353 K for 1 min, ramp at 5
K·min-1 to 373 K, and finally ramp to 573 at 15 K·min-1, for
a total 18.33 min running time. The transfer line, ion source,
DMSO-d6/TMS), δ/ppm
) 166.31 (sCOOH), 153.35
(sCHCHNs), 150.25 [sNCHC(COOH)], 137.00 [sCHCH-
C(COOH)], 126.57 [sC(COOH)], 123.85 (sCHCHNs). The
observed 1H and 13C NMR spectra are in good agreement with
those reported in a reference database.36 No impurities were
detected by GC-MS. The absence of water in the sample was
corroborated by the lack of the typical HsOsH bending
frequency at 1644 cm-1 in the DRIFT spectra. DRIFT analysis
in KBr also showed no chemical differences between the original
material and a sample dried for 24 h at 358 K, as recommended
for the use of NIST SRM 2151 in combustion calorimetry.32
Differential Scanning Calorimetry (DSC). The determina-
tion of the temperatures and enthalpies of fusion and solid-solid
phase transition by differential scanning calorimetry was made
on a DSC 7 from Perkin-Elmer. The experiments were
performed at a heating rate of 10 K ·min-1 in the temperature
range 298-523 K. The temperature and heat flow scales of the
instrument were previously calibrated at the same heating rate
by using indium (Perkin-Elmer; mass fraction 0.99999; Tfus
)

Energetics and Structure of Nicotinic Acid
J. Phys. Chem. B, Vol. 114, No. 16, 2010 5477
429.75 K, ∆fush° ) 28.45 J ·g-1). The nicotinic acid samples,
with masses in the range 1.9-7.1 mg, were sealed in air, inside
aluminum crucibles, and weighed with a precision of 1 µg in a
Mettler M5 microbalance. Nitrogen (Air Liquide N45), at a flow
rate of 0.5 cm3 ·s-1, was used as the purging gas.
pellet of the compound. The nitric acid formed from
combustion of the sample and traces of atmospheric N2
remaining inside the bomb after purging was determined by
titrating the final bomb solution with aqueous sodium
hydroxide (Merck titrisol, 0.01 mol · dm-3), using methyl red
as an indicator. No carbon residues, indicating incomplete
combustion, were found inside the bomb at the end of the
experiments. The energy equivalent of the calorimeter, ε° )
18562.59 ( 1.84 J · K-1, was obtained from the combustion
of a benzoic acid sample (BA; NIST SRM 39j), whose massic
energy of combustion under the certificate conditions was
A temperature-modulated TA Instruments Inc. 2920 MTDSC
apparatus, operated as a conventional DSC, was also used to
analyze the sample in a wider temperature range (193-523 K).
This analysis was mainly conducted to rule out the presence of
a possible glass transition indicating the sample to be partially
amorphous. In this case, ∼1.9 mg of compound was weighed
with a precision of 0.1 µg in a Mettler UMT2 ultramicrobalance
and sealed under air in an aluminum pan. Helium (Air Liquide
N55), at a flow rate of 0.5 cm3 ·s-1, was used as the purging
gas. The temperature and heat flow scales of the instrument
were calibrated as previously described.37 The heating rate was
∆cu(BA,cert) ) -26434 ( 3 J · g-1
.
Enthalpy of Sublimation Measurements. The enthalpy of
sublimation of nicotinic acid was determined from vapor-
pressure measurements by the Knudsen effusion method39-41
and by Calvet microcalorimetry.42,43
10 K ·min-1
.
The Knudsen effusion setup was a modified version of that
previously described.39-41 The main change consisted in the
adaptation of a new cylindrical brass block, which can accom-
modate up to three bronze cells with different holes, to the
bottom of the vacuum chamber. The block was surrounded by
a tubular furnace whose temperature was controlled to better
than (0.1 K by a Eurotherm 902P thermostatic unit driven by
a K type thermocouple embedded in the block. The equilibrium
temperature inside each cell was assumed to be identical to the
temperature of the brass block. This temperature was measured
with a precision of (0.1 K with a Tecnisis 100 Ω platinum
resistance thermometer embedded in the block and connected
in a four wire configuration to a Keithley 2000 multimeter. The
platinum resistance sensors for temperature measurement and
control were calibrated against a standard platinum resistance
thermometer, which had been calibrated at an accredited facility
in accordance to the International Temperature Scale ITS-90.
Each of the three cells was initially charged with ∼500 mg of
sample, and the corresponding mass loss during a run was
determined to (0.01 mg with a Mettler AT201 balance. The
effusion holes were drilled in a 2.090 × 10-5 m thick copper
foil (Cu 99%, Goodfellow Metals) soldered to the cell lids, and
had areas of 2.089 × 10-7 m2 (cell 1), 2.640 × 10-7 m2 (cell
2), and 4.283 × 10-7 m2 (cell 3), respectively. Before insertion
into the brass block, the bottom and sides of the Knudsen cells
were covered with a thin film of Apiezon N. This ensured a
better thermal contact between the cell and the temperature
controlled metal block. Evacuation of the system was started
after the cells were thermally equilibrated with the block for
45-60 min, under a nitrogen atmosphere. Typically, a pressure
of 1 × 10-3 Pa was reached in less than 3 min and a final
constant pressure of 8 × 10-5 Pa was obtained in about 20 min.
The experiment was ended by stopping the pumping and filling
the vacuum chamber with nitrogen. DRIFT analysis in KBr
showed no chemical differences between the original compound
and samples collected from the surface and bulk of the material
present inside each cell at the end of the measurements (see
the Supporting Information). This was also corroborated by the
corresponding elemental analysis on the bulk material (average
of two determinations): C 58.64%, H 4.04%, N 11.39% (cell
1); C 58.88%, H 4.04%, N 10.92% (cell 2); C 58.41%, H 4.07%,
N 11.35% (cell 3).
Combustion Calorimetry. The standard massic energy of
combustion of nicotinic acid was measured using an isoperibol
stirred liquid combustion macrocalorimeter previously de-
scribed.38 The general procedure was as follows. A platinum
crucible with a mass of ∼9.3 g was weighed with a precision
of (0.01 mg in a Mettler AT201 balance. The crucible was
loaded with a pellet of nicotinic acid (∼0.78-0.93 g) and
weighed again. The difference between the two weightings gave
the mass of the pellet. The crucible containing the compound
was adjusted to the sample holder in the bomb head, and the
platinum ignition wire (Johnson Matthey; mass fraction: 0.9995;
diameter 0.05 mm) was connected between the two discharge
electrodes. A cotton thread fuse of empirical formula CH1.887
-
O0.902 was weighed to (0.1 µg in a Mettler Toledo UMT2
balance. One end of the fuse was tied to the ignition wire, and
the other was brought into contact with the pellet. A volume of
1.0 cm3 of distilled and deionized water from a Millipore system
(conductivity, <0.1 µS·cm-1) was added to the bomb body by
means of a volumetric pipet. The stainless-steel bomb (Parr
1108) of 340 cm3 internal volume was assembled and purged
twice by successively charging it with oxygen 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
minutes were allowed for equilibration before closing the inlet
valve. The bomb was placed into the calorimeter proper, which
was subsequently filled (on average) with 3751.99 g of distilled
water, dispensed from a 4 dm3 round-bottom flask. The mass
of water was determined by weighing the flask to (0.01 g, in
a Mettler PM6100 balance, before and after transfer of the
content into the calorimeter. The calorimeter proper was closed
and placed into the thermostatic jacket, whose temperature was
maintained at ∼301 K with a precision of (10-4 K by means
of a Tronac PTC 41 temperature controller. The temperature-time
data acquisition was started, and the calorimetric experiment
began once the baseline progress ensured that heat transfer
between the vessel and the jacket conformed to Newton’s law
(exponential T vs t variation).12 The temperature measurements
were carried out with a resolution better than 3 × 10-5 K, by
using a YSI 46047 thermistor of 6.0 kΩ nominal resistance at
298.15 K, connected in a four wire configuration to a Hewlett-
Packard HP 34420A digital multimeter. The duration of the fore,
main, and after periods was 30 min each. The combustion of
the sample was initiated at the end of the fore period by
discharge of a 2990 µF capacitor, from a potential of 40 V,
through the platinum wire. The discharge current heated the
wire, and when the temperature was increased sufficiently, the
thread fuse ignited, and the combustion propagated to the
Two series of Calvet microcalorimetry experiments separated
by 1 year were performed. In the first series, the temperature
of the calorimeter was set to 376.5 K. A sample with a mass in
the range 2.8-11.0 mg was placed into a small glass capillary
and weighed with a precision of 1 µg in a Mettler M5 balance.
The capillary was equilibrated for ∼15 min at 298 K, inside a

5478 J. Phys. Chem. B, Vol. 114, No. 16, 2010
Gonc¸alves et al.
of a bounding rectangle for the measured object) of Ar ) 1.46
( 0.35. The indicated uncertainties represent standard errors
of the mean.
The powder pattern obtained at 298 ( 2 K was indexed as
monoclinic, space group P21/c, with a ) 7.181 Å, b ) 11.679
Å, c ) 7.233 Å, and ꢀ ) 113.49°. These results are in excellent
agreement with those of previously reported single crystal X-ray
diffraction experiments carried out at 293 K: P21/c, a ) 7.186(2)
Å, b ) 11.688(3) Å, c ) 7.231(2) Å, ꢀ ) 113.55(6)°.53,54 The
single crystal X-ray diffraction data show that, in this phase,
the molecules of nicotinic acid adopt conformation 1,53,54 which
is predicted by the B3LYP/6-311++G(d,p), B3LYP/cc-pVTZ,
B3LYP/aug-cc-pVTZ, G3MP2, and CBS-QB3 calculations
carried out in this work to be lower in Gibbs energy by ∼1
kJ·mol-1 than conformation 2 (see below).
Figure 1. SEM micrograph of the nicotinic acid sample (NIST SRM
2151) used in the thermochemical experiments.
furnace positioned above the entrance of the sample cell, and
subsequently dropped into the calorimeter under N2 atmosphere.
After dropping, an endothermic peak due to the heating of the
sample from 298 to 376.5 K was first observed. When the signal
returned to the baseline, the sample and reference cells were
simultaneously evacuated to 0.13 Pa and the measuring curve
associated with the sublimation of the compound was acquired.
The corresponding enthalpy of sublimation was subsequently
derived from the area of that curve, A, the area of the pumping
background contribution, Ab, and the energy equivalent of the
apparatus, ε. The value of Ab was determined from independent
runs where only gaseous nitrogen was pumped out of the
calorimetric cells and ε was obtained by electrical calibration.42
The same procedure was followed in the second series of
experiments, which were carried out at 374.8 K and with masses
of sample in the range 1.9-5.0 mg. No decomposition or
unsublimed residues were found inside the capillaries or
calorimetric cell at the end of the experiments. Small residues,
which could not be analyzed, were systematically found,
however, in two series of measurements performed at 353.7
and 357.6 K, and these were discarded.
To the best of our knowledge, the structure of nicotinic acid
in the gas phase has not been determined (e.g., from electron
diffraction measurements). The bond distances and angles
reported for the solid state53,54 are compared in Table 1 with
those predicted for the equivalent configuration of the isolated
molecule at the B3LYP/cc-pVTZ level of theory. The calculated
data for conformation 2 were also included in the table. It can
be concluded from Table 2 that the B3LYP/cc-pVTZ model
accurately reproduces most structural features of the nicotinic
acid molecule given by the X-ray diffraction analysis. Hence,
for example, the differences between the experimental and
calculated C-C and N-C bond distances in the pyridine ring
are smaller than 0.8%. Not unexpectedly, the largest deviation
found (∆ ) -3.52%) refers to the C6-O1 bond, where O1
acts as the donor atom in a O-H· · ·N hydrogen bond in the
solid state but not in the gaseous state. A similar conclusion
can be drawn if the bond angles are considered: the larger
deviations are observed for the angles involving the N1 atom
or the COOH group which are implicated in hydrogen bond
formation in the solid state. It should also be mentioned that
no benefit in terms of the accuracy of the structural predictions
wasfoundbytheuseofthelargeraug-cc-pVTZor6-311++G(d,p)
basis sets (see the Supporting Information).
Packing diagrams of the nicotinic acid form studied in this
work, obtained from reported single crystal X-ray diffraction
data at 293 K53,54 by using the Mercury 2.2 program,55 are
illustrated in Figures 2 and 3. As shown in Figure 2, the unit
cell contains two antiparallel dimeric units (labeled A and B),
related by a center of symmetry. These units are arranged in
infinite zigzag chains C(6) along the b axis (Figure 3a), sustained
by strong O-H· · ·N hydrogen bonds (dOH· · ·N ) 1.843 Å, dO· · ·N
) 2.660 Å) and reinforced by weaker C-H· · ·O contacts
(dCH· · ·O ) 2.550 Å). The two layers of chains are situated at a
distance of 3.54 Å and do not interact among themselves, except
by some possible degree of π-π stacking along the c axis. They
show however C-H· · ·O contacts with adjacent chains situated
above and below in approximately parallel planes (Figure 3b).
Computational Details. Density functional theory (DFT),27
Gaussian-3 theory with second-order Møller-Plesset (G3MP2),28
and complete basis set - quadratic Becke3 (CBS-QB3)29,30
procedures were applied to predict thermochemical properties
of the systems under examination. In the case of the DFT
methods, full geometry optimizations and frequency predic-
tions were carried out with the B3LYP44,45 hybrid functional
usingthe6-311++G(d,p),46,47 cc-pVTZ,48,49 andaug-cc-pVTZ49,50
basis sets. 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 frequen-
cies and ZPEs were not scaled, unless otherwise stated. The
DFT, G3MP2, and CBS-QB3 calculations were performed
with the Gaussian-03 package.51
Results and Discussion
Structure. The SEM micrograph in Figure 1 shows that from
a morphological point of view the sample was composed of
smooth-faced prismatic particles. Image analysis carried out on
103 particles using the Olympus CellD 2.6 software, led to a
Feret’s mean diameter (the mean value of the distance between
pairs of parallel tangents to the projected outline of the particle,
like in a measurement with a caliper)52 of dF ) 3.68 ( 1.38
µm and an aspect ratio (the maximum ratio of width and height

Energetics and Structure of Nicotinic Acid
J. Phys. Chem. B, Vol. 114, No. 16, 2010 5479
TABLE 1: Experimentala and Calculatedb Bond Distances (in Å) and Bond Angles (in Degrees) for Nicotinic Acid
a References 53 and 54. b This work, see structures 1 and 2 for labeling schemes. c ∆ represents the difference between the experimental
bond distance or angle and the corresponding value calculated for conformation 1 (that is also adopted in the crystalline state) by the B3LYP/
cc-pVTZ method.
TABLE 2: Results of the Combustion Calorimetric Experiments on Nicotinic Acid
m(NA)/g
m(cotton)/g
∆m(H2O)/g
104 ·n(HNO3)/mol
εi/J·K-1
0.93275
0.0024156
0.15
6.69
15.53
0.89473
0.0023012
0.28
7.06
15.48
0.91223
0.0036117
0.18
7.84
15.51
0.88510
0.0022986
-0.54
7.07
15.47
0.84879
0.0019878
0.17
5.67
15.43
0.78127
0.0022186
0.43
5.86
15.35
εf/J·K-1
Ti/K
15.98
15.88
15.88
15.86
15.87
15.72
298.1753
299.4294
0.1345
0.51
298.2332
299.4306
0.1236
0.58
298.2228
299.4776
0.1585
0.33
298.2269
299.4237
0.1343
0.35
298.3111
299.4821
0.1529
0.37
298.1821
299.2744
0.1547
0.55
Tf/K
∆Tc/K
∆ignU/J
-∆IBPU/J
20800.77
19950.27
20368.10
19736.89
18915.15
17420.17
∆ΣU/J
19.25
39.94
40.02
18.36
42.15
38.12
18.73
46.80
59.83
18.14
42.21
38.08
17.38
33.85
32.93
15.86
34.98
36.75
∆U(HNO3)/J
-∆U(cotton)/J
∆U(NA)/J
20701.56
22194.11
19851.64
22187.30
20242.74
22190.39
19638.46
22187.84
18830.99
22185.69
17332.58
22185.13
-∆cu°(NA, cr)/J ·g-1
These contacts labeled a and b (for a, dCH· · ·O ) 2.576 Å; for b,
dCH· · ·O ) 2.608 Å) together with the analogous interaction that
reinforces the C(6) chains (here designated by c) are part of
three centered bifurcated C-H· · ·O hydrogen bonds involving
the carbonyl oxygen of the COOH group as the common
acceptor (Figure 3c). As illustrated in Figure 3b, when viewed
along the b axis, alternate layers of A and B type chains can be
observed. These reflect the 3D propagation of the dimeric motifs
found inside the unit cell (Figure 2) throughout the lattice. Two
different and short interplanar distances (1.48 and 2.06 Å) can
be distinguished in Figure 3b. The longest (2.06 Å) separates a
pair of planes containing C(6) chains of the same type (either
AA or BB). The shortest (1.48 Å) corresponds to planes holding
chains of different types (AB).
Figure 2. Unit cell of the monoclinic (space group P21/c) nicotinic
acid form studied in this work, with indication of the a, b, and c axis.
The different orientations of the dimeric units inside the cell are denoted
by A and B, respectively.

5480 J. Phys. Chem. B, Vol. 114, No. 16, 2010
Gonc¸alves et al.
Figure 3. (a) Two layers of infinite C(6) chains viewed along the c axis. (b) View along the b axis, displaying the two types of interchain CH · · ·O
contacts a ) 2.576 Å and b ) 2.608 Å and the distances between planes containing chains with A or B type sequences of nicotinic acid molecules
as defined in Figure 2. (c) Three centered bifurcated C-H· · ·O hydrogen bond motif that sustains the interactions between chains in adjacent planes
and reinforces the O-H· · ·N hydrogen bond within a chain.
Energetics. The 2005 IUPAC recommended standard atomic
masses were used in the calculation of all molar quantities.56
The onset (Ton) and maximum (Tmax) temperatures of the
fusion peak obtained by DSC were Ton ) 507.3 ( 1.4 K and
Tmax ) 509.9 ( 0.8 K, respectively, and the corresponding
enthalpy of fusion, ∆fusHm ) 27.8 ( 0.2 kJ·mol-1. Fusion was
preceded by a reversible phase transition for which Ton ) 452.9
( 0.5 K, Tmax ) 456.1 ( 0.4 K, and ∆trsHm ) 0.83 ( 0.10
kJ·mol-1. The uncertainties indicated for Ton, Tmax, ∆trsHm, and
∆fusHm correspond to twice the standard error of the mean of
seven determinations. The values of Ton and Tmax corresponding
to the fusion event observed in this work are within the interval
508.7-509.8 K attributed to pure nicotinic acid in a compre-
hensive study of its temperature of fusion.57 The corresponding
∆fusHm ) 27.8 ( 0.2 kJ ·mol-1 also ranks among the highest
values published for the enthalpy of fusion of nicotinic
acid.21,58-61 This indicates the sample to be significantly crystal-
line, in agreement with the X-ray powder diffraction and SEM
evidence, and also with the fact that no glass transition was
detected in a DSC analysis carried out in the range 193-523 K
at a heating rate of 10 K ·min-1. It should be noted that the
reported temperatures and enthalpies of fusion of nicotinic acid
vary in a considerably wide range: Tfus ) 507.0 ( 0.8,59 509.1,60
509.16 ( 0.01,21 509.2 ( 0.6,57 509.5 ( 0.5,62 509.8 ( 0.7,59
510,61,63 512.0,18 and 515.5 K;64 ∆fusHm ) 12.4,58 13.01 ( 0.32,21
crystallinity and particle size of the sample. For example, in
differential thermal analysis experiments carried out at 5
K·min-1, Moussaoui et al.59 observed that grinding a sample
of nicotinic acid led to decreases of ∼3 K and ∼6 kJ·mol-1 in
Tfus and ∆fusHm, respectively. In the same experiments, Ttrs
increased by 1.2 K and ∆trsHm decreased by 0.26 kJ · mol-1
.
Furthermore, DSC runs carried out at 10 K ·min-1 by Rehman
et al.58 showed that an improvement of the crystallinity of the
sample could translate into a change of ∆fusHm from ∼12 to
∼25 kJ ·mol-1
.
The results of the combustion calorimetric experiments are
given in Table 2, where m(NA) and m(cotton) are the masses
of nicotinic acid and cotton thread fuse, respectively; ∆m(H2O)
is the difference between the mass of water inside the
calorimeter proper during the main experiment and that used
on average in the calibration (3751.99 g); n(HNO3) is the amount
of substance of nitric acid formed in the bomb process; εi and
εf are the energy equivalents of the bomb contents in the initial
and final states of the bomb process, respectively; Ti and Tf
represent the initial and final temperatures of the experiment;
∆Tc is the contribution to the observed temperature rise of the
calorimeter proper due to the heat exchanged with the sur-
roundings and the heat dissipated by the temperature sensor;
∆ignU is the electrical energy supplied for ignition of the sample,
which was calculated from
20.8 ( 0.4,59 24.6,58 26.7 ( 0.4,59 27.57,60 and 30 kJ ·mol-1 61
.
The same applies to the phase transition: Ttrs ) 451.4,60 452.0
(Vi2 - Vf2)C
( 0.6,59 453.2 ( 0.5,59 457,63,64 and 457.7 K;18 ∆trsHm ) 0.78
( 0.01,59 0.52 ( 0.01,59 and 0.81 kJ ·mol-1 60
.
This probably
∆ignU )
(1)
2
reflects the fact that they seem to be notably influenced by the

Energetics and Structure of Nicotinic Acid
J. Phys. Chem. B, Vol. 114, No. 16, 2010 5481
where Vi and Vf are the potential of the condenser of capacitance
C ) 2990 µF before and after its discharge through the platinum
ignition wire, respectively; ∆IBPU is the internal energy change
associated with the bomb process under isothermal conditions,
at 298.15 K; ∆ΣU represents the sum of all corrections necessary
to reduce ∆IBPU to the standard state (Washburn corrections),
which were derived as recommended for organic compounds
containing C, H, O, and N,12,65,66 by using the following heat
capacity, density, and -(∂u/∂p)T data for crystalline nicotinic
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 ) 8.314472 J ·K-1 ·mol-1 is the gas constant, T is the absolute
temperature, and λ is the mean free path given by74
kT
λ )
(6)
2
√
2πσ p
acid: c° ) 1.21 J ·g-1 60 F ) 1.469 g ·cm-3 53
, , -(∂u/∂p)T ) 6.91
p
× 10-8 J·g-1 Pa-1;67 ∆U(HNO3) is the energy change associated
with the formation of nitric acid which was based on -59.7
kJ · mol-1 for the molar internal energy of formation of
HNO3(aq) of concentration 0.1 mol · dm-3 from 5/4O2(g),
Here, k represents the Boltzmann constant and σ the collision
diameter. The collision diameter of nicotinic acid was estimated
as 585 pm from the van der Waals volume of the molecule
calculated with the GEPOL93 program,75 based on the molecular
structure reported by Kutoglu and Scheringer.53 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.76 Since the mean free path in eq 6 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 were fitted to eq 7 (Figure 4):77
1
1/2N2(g), and /2H2O (l);68 ∆U(cotton) is the energy associated
with the combustion of the cotton fuse of standard specific
energy of combustion ∆cu°(cotton) ) -16565.9 ( 8.6 J ·g-1 38
;
∆U(NA) is the contribution of nicotinic acid for the energy of
the isothermal bomb process; and, finally, ∆cu°(NA, cr) is the
corresponding standard specific internal energy of combustion.
The values of Ti, Tf, and ∆Tc were calculated by using a
computer program based on the Regnault-Pfaundler method,12,69
and ∆IBPU was derived from12
∆
IBPU ) [ε° + ∆m(H2O)c°(H2O, l)](Ti - Tf + ∆Tc) +
p
εi(Ti - 298.15) + εf(298.15 - Tf + ∆Tc) + ∆ignU (2)
where c°(H2O, l) ) 4.179 J ·g-1 68
.
p
b
T
The standard specific energies of combustion of nicotinic acid
ln p ) a -
(7)
in Table 2 refer to the reaction
where the slope b is related to the enthalpy of sublimation at
the average of the highest and lowest temperatures of the range
5
C6H5O2N(cr) + 25/4O2(g) ) 6CO2(g) + /2H2O(l) +
1/2N2(g) (3)
covered in each series of experiments, Tm, by ∆subH°(NA, Tm)
m
) bR. The obtained results, which refer to Tm ) 366.5 K, were
the following: for cell 1, a ) 35.43 ( 0.72, b ) 13152.4 (
and were obtained from
1
264.2, and ∆subH°(NA, 366.5 K) ) 109.4 ( 4.6 kJ ·mol-1; for
m
cell 2, a ) 35.74 ( 0.63, b ) 13295.8 ( 229.2, and ∆subH°(NA,
m
366.5 K) ) 110.6 ( 3.9 kJ ·mol-1; for cell 3, a ) 34.88 (
∆cu°(NA, cr) )
[∆IBPU + ∆ΣU - ∆U(HNO3) -
∆U(cotton)] (4)
0.59, b ) 12982.2 ( 214.7, and ∆subH°(NA, 366.5 K) ) 107.9
m(NA)
m
( 3.7 kJ·mol-1. The uncertainties assigned to a and b are the
corresponding standard errors, and that for ∆subH°(NA, 366.5
m
K) includes Student’s factor for 95% confidence level78 (cell 1,
t ) 2.093 for 20 independent measurements; cells 2 and 3, t )
2.064 for 25 independent measurements). Correction of the
They lead to the mean value ∆cu°(NA, cr) ) -22188.41 (
1.37 J ·g-1, at 298.15 K, from which ∆cU°(NA, cr) ) -2731.60
m
( 0.88 kJ ·mol-1 and ∆cH°(NA, cr) ) -2730.98 ( 0.88
m
kJ·mol-1 can be derived. The uncertainties indicated for
∆cu°(NA, cr) represent the standard error of the mean of the
six individual measurements, and those of ∆cU°(NA, cr) and
m
∆cH°(NA, cr) correspond to twice the overall standard error of
m
the mean, including the contributions from the calibration with
benzoic acid.70 From the value of ∆cH°(NA, cr) indicated above,
m
∆fH°(CO2, g) ) -393.51 ( 0.13 kJ ·mol-1 71
,
and ∆fH°(H2O,
m
m
l) ) -285.830 ( 0.042 kJ·mol-1 71
,
it is possible to conclude
that ∆fH°(NA, cr) ) -344.7 ( 1.2 kJ ·mol-1
.
m
The enthalpy of sublimation of nicotinic acid was obtained
from vapor-pressure vs temperature measurements by the
Knudsen effusion method and also by drop-sublimation Calvet
microcalorimetry (detailed results are given as Supporting
Information). In the Knudsen effusion experiments, the values
of p were calculated from72,73
Figure 4. Vapor pressure of nicotinic acid as a function of the
temperature: (0) cell 1 (A ) 2.089 × 10-7 m2, r ) 2.579 × 10-4 m,
l ) 2.09 × 10-5 m); (O) cell 2 (A ) 2.640 × 10-7 m2, r ) 2.899 ×
10-4 m, l ) 2.09 × 10-5 m); (4) cell 3 (A ) 4.283 × 10-7 m2, r )
3.692 × 10-4 m, l ) 2.09 × 10-5 m).
1/2
m 2πRT
8r + 3l
8r
2λ
p )
(5)
(
)
(
)(
)
At
M
2λ + 0.48r

5482 J. Phys. Chem. B, Vol. 114, No. 16, 2010
Gonc¸alves et al.
TABLE 4: Experimental and Theoretical Enthalpies of
TABLE 3: Standard Molar Enthalpies of Combustion,
Formation, and Sublimation of Nicotinic Acid at 298.15 K
Reaction 11
(Data in kJ ·mol-1
)
-∆rH°(11)/kJ·mol-1
m
-∆cH°(NA, cr) -∆fH°(NA, cr)
∆
subH°(NA) -∆fH°(NA, g)
m
m
m
m
B3LYP/cc-pVTZ
3.6
2730.98 ( 0.88a
2730.63 ( 0.69b
2730.81 ( 0.76c
2731.10 ( 2.19d
344.7 ( 1.2a
345.0 ( 1.1b
344.8 ( 1.1c
344.5 ( 2.3d
112.1 ( 0.5a
232.6 ( 1.3
B3LYP/aug-cc-pVTZ
B3LYP/6-311++G(d,p)
G3MP2
3.7
4.2
4.3
103.8 ( 1.2d
123.4 ( 1.2e
124.4 ( 0.6f
117.4 ( 0.9g
240.7 ( 2.6
CBS-QB3
4.0
experimental
3.6 ( 2.7
auxiliary data (e.g., molar mass, heat capacity).19-21,24,67 Also
indicated in Table 3 are the standard molar enthalpies of
a This work. b Reference 67. c Reference 24. d Reference 21.
e Reference 19. f Reference 20; weighted mean of five independent
determinations (see text). g Reference 22; this value refers to a high
temperature nicotinic acid phase (see text).
formation of gaseous nicotinic acid, ∆fH°(NA, g), calculated
m
from the corresponding ∆fH°(NA, cr) and ∆subH°(NA). It can
m
m
be concluded from Table 3 that the enthalpy of formation of
nicotinic acid in the crystalline state obtained in this work is in
excellent agreement with all of the previously reported values.
obtained ∆subH°(NA, 366.5 K) values to 298.15 K led to
m
∆
subH°(NA) ) 112.4 ( 4.6 kJ ·mol-1 (cell 1), ∆subH°(NA) )
m
m
113.6 ( 3.9 kJ ·mol-1 (cell 2), and ∆subH°(NA) ) 110.9 ( 3.7
To the best of our knowledge, four determinations of the
enthalpy of sublimation of nicotinic acid appeared in the
literature up to now. Drop-sublimation Calvet microcalorimetry
experiments carried out by Bickerton et al.,19 at 420 K, led to
m
kJ·mol-1 (cell 3). The correction was made through the equation
subH°(NA) ) 123.4 ( 1.2 kJ ·mol-1 at 298.15 K. This value
∆
subH°m(NA, 298.15 K) ) ∆subH°m(NA, T) +
298.15K [C°p,m(NA, g) - Cp°,m(NA, cr)] dT (8)
∆
m
diverges by +11.3 kJ ·mol-1 from that obtained in this work.
No reassessment based on the same auxiliary data used here
was possible, since the primary data corresponding to 420 K
were not published. The results of Calvet microcalorimetry
measurements performed by Sabbah and Ider21 on a sample
∫
T
where C° (NA, cr) and C° (NA, g) are the standard molar heat
p,m
p,m
capacities of the compound in the crystalline and gaseous states,
respectively. For the crystalline state, the calculations were based
on the equation60
subliming from a Knudsen cell at 362.2 K give ∆subH°(NA,
m
362.2 K) ) 101.1 ( 1.2 kJ ·mol-1, where the indicated
uncertainty corresponds to twice the standard error of seven
independent results. Correction of this value to 298.15 K through
C°p,m(NA, cr)/J ·K-1 ·mol-1 ) 115.77043 + 59.91381x +
eqs 8-10 leads to ∆subH°(NA) ) 103.8 ( 1.2 kJ·mol-1, which
m
7.53269x2 + 1.2433x3 - 2.39857x4 + 7.21254x5 +
differs by -8.3 kJ·mol-1 from the result recommended in this
work. From the five independent experiments carried out by
Ribeiro da Silva et al.20 using the Knudsen effusion method
coupled with quartz crystal balance detection, it is possible to
4.134x6 (9)
where x ) (T - 223.5)/144.5 and T is the absolute temperature.
Equation 9 is valid in the temperature range 79-368 K. The
heat capacity of gaseous nicotinic acid was taken as
derive ∆subH°(NA) ) 126.2 ( 1.6 kJ ·mol-1 at 351.6 K, 116.3
m
( 3.5 kJ ·mol-1 at 353.8 K, 117.8 ( 4.8 kJ ·mol-1 at 355.8 K,
123.8 ( 1.6 kJ ·mol-1 at 358.2 K, and 120.9 ( 0.7 kJ ·mol-1 at
360.6 K. The indicated uncertainties are those reported by the
authors. The corresponding values at 298.15 K, calculated
through eqs 8-10, are 128.4 ( 1.6, 118.6 ( 3.5, 120.2 ( 4.8,
126.3 ( 1.6, and 123.6 ( 0.7 kJ ·mol-1. These lead to a
Cp°,m(NA, g)/J ·K-1 ·mol-1 ) 6.28434 + 0.385604T -
8.53356 × 10-5T2 (10)
weighted mean ∆subH°(NA) ) 124.4 ( 0.6 kJ·mol-1, which
m
Equation 10 originated from a least-squares fitting to the
differs by +12.3 kJ ·mol-1 from the value recommended in this
work. Finally, Menon et al.22 used “Langmuir’s” equation to
obtain the vapor pressure of nicotinic acid in the range
473.15-483.15 K from thermogravimetry measurements. Three
methods of analysis were used. A least-squares fit to the results
of the apparently more reliable comparative method led to
C° (NA, g) data calculated by statistical mechanics,79 using
p,m
vibration frequencies obtained by the B3LYP/cc-pVTZ method
and scaled by 0.965.80
The first and second series of drop-sublimation Calvet
microcalorimetry experiments led to ∆subH°(NA, 376.5 K)
m
) 108.79 ( 0.93 kJ · mol-1 and ∆subH°(NA, 374.8 K) )
∆
subH°(NA, 478.2 K) ) 99.1 ( 0.9 kJ ·mol-1. The reference
m
m
108.43 ( 0.64 kJ · mol-1, respectively, where the uncertainty
quoted represents twice the overall standard error of five
independent results including the contribution from the
electrical calibration. Correction of these values to 298.15
temperature corresponds to the mean value of the interval
covered in the experiments, and the assigned uncertainty is the
standard error of the slope b of eq 7 multiplied by Student’s
factor for 95% confidence level (t ) 2.228 for 11 independent
K, using eqs 8-10, leads to ∆subH°(NA) ) 112.4 ( 0.9
measurements).78 Conversion of ∆subH°(NA, 478.2 K) to 298.15
m
m
kJ · mol-1 and ∆subH°(NA) ) 111.9 ( 0.6 kJ · mol-1 in good
K, using eqs 8-10, yields ∆subH°(NA) ) 117.4 ( 0.9 kJ ·mol-1.
m
m
agreement with the corresponding values obtained by the
It should be noted that this value refers to experiments carried
out in a temperature range significantly above the onset of the
solid-solid phase transition observed for nicotinic acid by DSC
(Ton ) 452.9 ( 0.5 K, see above). It is, therefore, not strictly
comparable to all the other standard molar enthalpies of
sublimation in Table 3, since it probably corresponds to a
different nicotinic acid solid phase.
Knudsen effusion method. The weighted mean70 of the five
results from both techniques, at 298.15 K, ∆subH°(NA) )
m
112.1 ( 0.5 kJ · mol-1, was selected in this work.
The values of ∆cH°(NA, cr), ∆fH°(NA, cr), and ∆subH°(NA)
here determined are compared in Table 3 with those recalculated,
when possible, from published results by using identical
m
m
m

Energetics and Structure of Nicotinic Acid
J. Phys. Chem. B, Vol. 114, No. 16, 2010 5483
The nature of the discrepancies between the ∆subH°(NA)
agreement with all of the other determinations. A similar
m
value recommended here and those obtained from published
data (all originating from very credible thermochemistry labo-
ratories) eluded a clear-cut identification. For example, in none
of the published work was the crystallinity and phase purity of
the samples analyzed by X-ray powder diffraction. Nevertheless,
the enthalpy of the only solid-solid phase transition reported
for nicotinic acid up to now amounts to less than 1 kJ ·mol-1
(see above) and it seems, therefore, unlikely that differences in
phase purity would translate into changes of up to 12 kJ ·mol-1
discussion could not be transposed to the higher ∆subH°(NA)
m
values of Bickerton et al.19 and Ribeiro da Silva et al.20 (Table
3), since, in these cases, the enthalpies of fusion and combustion
of the samples used in the sublimation experiments were not
reported. To help in the assessment of the internal consistency
of our data, we therefore resorted to an isodesmic reaction
scheme and to computational chemistry.
The values of ∆fH°(NA, cr) and ∆subH°(NA) recommended
m
m
in this work (Table 3) lead to ∆fH°(NA, g) ) -232.6 ( 1.3
m
in ∆subH°(NA). These could, in principle, be traced back to the
kJ·mol-1, which together with ∆fH°(C6H6, g) ) 82.6 ( 0.7
m
m
crystallinity of the samples. Indeed, as mentioned above, a
decrease in the crystallinity of solid nicotinic acid was found
by Rehman et al.58 to lower the corresponding enthalpy of fusion
by up to 13 kJ ·mol-1 and a similar effect should be expected
kJ·mol-1 81
,
∆fH°(C5H5N, g) ) 140.4 ( 0.7 kJ·mol-1 81
,
and
m
∆fH°(C6H5COOH, g) ) -294.0 ( 2.2 kJ ·mol-1 81 allows the
m
calculation of the enthalpy of the isodesmic reaction 11 as
∆rH°(11) ) -3.6 ( 2.7 kJ ·mol-1
.
m
for ∆subH°(NA). In line with this reasoning, the enthalpies of
m
fusion (13.01 ( 0.32 kJ ·mol-1) and sublimation (103.8 ( 1.2
kJ·mol-1) of nicotinic acid reported by Sabbah and Ider21 are
both considerably smaller than the corresponding values recom-
mended in this work (Table 3), thus suggesting that they refer
to a material of substantial amorphous character. However, this
should also lead to a less negative standard molar enthalpy of
formation in the crystalline state and, as shown in Table 3, the
This value is compared in Table 4 with the corresponding
predictions by various theoretical models, which were computed
from the data in Table 5. It should be noted that the standard
∆fH°(NA, cr) value reported by Sabbah and Ider is in good
m
TABLE 5: Electronic Energies (Eel), Zero Point Energies (ZPE), Thermal Corrections (Ev + Er + Et), Standard Enthalpies
(H°),a Standard Gibbs Energies (G°), and Boltzmann Weights (pi),b at 298.15 K, Calculated with the B3LYP/cc-pVTZ, B3LYP/
aug-cc-pVTZ, B3LYP/6-311++G(d,p), G3MP2, and CBS-QB3 Methods (Data in Hartree)c
a H°(298.15 K) ) Eel + ZPE + Ev + Er + Et + RT, where Ev, Er, and Et represent the vibrational, rotational, and translational contributions.
b Calculated from eqs 12 or 13 (see text). c 1 hartree ) 2625.499963 kJ ·mol-1
.

5484 J. Phys. Chem. B, Vol. 114, No. 16, 2010
Gonc¸alves et al.
molar enthalpy of nicotinic acid used in the theoretical calcula-
and C.E.S.B. (SFRH/BPD/43346/2008). Thanks are also due
to Nuno Neng at the laboratory of Dr. Jose´ M. Nogueira (FCUL,
Portugal) for the performance of the GC-MS analysis, to Janine
Schwiertz at the group of Prof. Matthias Epple (University of
Duisburg-Essen, Germany) for the recording of the SEM images,
to Prof. Maria das Dores Ribeiro da Silva (FCUP, Portugal)
for helpful comments, and to Prof. Zhi-Cheng Tan (Dalian
Institute of Chemical Physics, China) for kindly providing
unpublished details about the determination of the enthalpy of
formation of nicotinic acid included in Reference 25.
tions of ∆rH°(11) includes contributions from the conformations
m
1 and 2 mentioned above (e.g., Table 5). The corresponding
weights, p1 and p2, respectively, were obtained from
1
p1 )
(12)
(13)
-∆G°2/RT
1 + e
p2 ) 1 - p1
Supporting Information Available: Figure S1 with the
results of the GC-MS analysis of the nicotinic acid sample used
by assuming that the two conformations were in equilibrium
and that this equilibrium was governed by Boltzmann’s distribu-
tion. In eq 12, T is the absolute temperature, R is the gas
1
in this work; Figures S2 and S3 with the H and 13C NMR
spectra, respectively; Table S1 with the details of the powder
X-ray diffraction characterization; Tables S2 and S3 with the
bond distances and bond angles for conformations 1 and 2 of
nicotinic acid calculated at the B3LYP/6-311++G(d,p) and
B3LYP/aug-cc-pVTZ levels of theory; Table S4 containing the
experimental vapor pressures of nicotinic acid obtained by the
Knudsen effusion method; Figures S4-S6 and Table S5 with
the results of the DRIFT analysis carried out on the nicotinic
acid sample, before and after the Knudsen effusion experiments;
Tables S6 and S7 with the details of the drop-sublimation Calvet
microcalorimetry experiments. This material is available free
of charge via the Internet at http://pubs.acs.org.
constant, and ∆G° represents the difference in Gibbs energy
2
between conformation 2 (highest G°) and conformation 1
(lowest G°).
As shown in Table 4, the experimentally and theoretically
obtained ∆rH°(11) results are all in excellent agreement. This
m
supports the reliability of the standard molar enthalpies of
formation and sublimation of nicotinic acid recommended in
this work (Table 3) and indicates a very good thermodynamic
consistency with the other experimental data used in the
calculation of ∆rH°(11). Hence, the ∆fH°(NA, cr), ∆subH°(NA),
m
m
m
and ∆fH°(NA, g) values here reported can be used as reliable
m
anchor points for discussing the energetics of nicotinic acid.
It should finally be emphasized that the energetics of
crystalline materials is sensitive to a multitude of structural
effects that are normally difficult to control in practice and can
significantly influence the outcome of the measurements when
high accuracy and precision are aimed. Thus, for example, the
results of calorimetric experiments or vapor pressure determina-
tions may be influenced by the possible existence of different
crystalline forms (polymorphs) or amorphous domains coexist-
ing under the same temperature and pressure conditions.
Techniques such as X-ray diffraction and DSC are very helpful
in signaling the presence of mixtures of polymorphs and
amorphous phases and should not be left out of the sample
characterization process. An additional concern is lattice
imperfections (e.g., vacancies, screw dislocations), which can
develop during crystallization and may change in nature and
number, as a result of the stresses and strains typical of
processing operations, such as drying, grinding, compression,
or temperature annealing. In some cases, the measurement of
specific properties appears to be more sensitive to sample
variability than others. This seems to occur for nicotinic acid
where the reported standard molar enthalpies of sublimation
show a far larger discrepancy than the corresponding enthalpies
of formation in the crystalline state (Table 3). The reproducibility
of the solid state is therefore an important issue when accurate
data are sought, and the availability of well characterized
materials that can be used as references for intercomparison
studies necessary. Last but not the least, the discrepancies in
∆fH°(cr) and ∆subH° ultimately affect the determination of
References and Notes
(1) Elvehjem, C. A.; Teply, L. J. Chem. ReV. 1943, 33, 185–208.
(2) Blum, R. Vitamins. In Ullmann’s Encyclopedia of Industrial
Chemistry, 5th ed.; Elvers, B., Hawkins, S., Eds.; VCH: Weinheim,
Germany, 1996; Vol. A27, p 581.
(3) Block, J. Vitamins. In Kirk-Othmer Encyclopedia of Chemical
Technology, 5th ed.; Seidel, S., Ed.; Wiley: Hoboken, NJ, 1996; Vol. 25,
p 797.
(4) Carlson, L. A. J. Intern. Med. 2005, 258, 94–114.
(5) Gille, A.; Bodor, E. T.; Ahmed, K.; Offermarms, S. Annu. ReV.
Pharmacol. Toxicol. 2008, 48, 79–106.
(6) Shimizu, S. Vitamins and Related Compounds: Microbial Produc-
tion. In Biotechnology: A Multi-Vol. ComprehensiVe Treatise, 2nd com-
pletely rev. ed.; Rehm, H.-J., Reed, G., Puhler, A., Stadler, P. J. W., Eds.;
VCH: Weinheim, Germany, 2001; Vol. 10, p 320.
(7) Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry, 4th ed.;
Wiley-VCH: Weinheim, Germany, 2003.
(8) Cantarella, M.; Cantarella, L.; Gallifuoco, A.; Intellini, R.; Kaplan,
O.; Spera, A.; Mart´ınkova´, L. Enzyme Microb. Technol. 2008, 42, 222–
229.
(9) Brittain, H. G. Polymorphism in Pharmaceutical Solids; Marcel
Dekker: New York, 1999.
(10) Bernstein, J. Polymorphism in Molecular Crystals; Oxford Uni-
versity Press: Oxford, U.K., 2002.
(11) Hilfiker, R. Polymorphism in the Pharmaceutical Industry; Wiley-
VCH: Weinheim, Germany, 2006.
(12) Martinho Simo˜es, J. A.; Minas da Piedade, M. E. Molecular
Energetics; Oxford University Press: New York, 2008.
(13) Canongia Lopes, J. N.; Cabral do Couto, P.; Minas da Piedade,
M. E. J. Phys. Chem. A 2006, 110, 13850–13856.
(14) Lousada, C. M.; Pinto, S. S.; Canongia Lopes, J. N.; Piedade,
M. F. M.; Diogo, H. P.; Minas da Piedade, M. E. J. Phys. Chem. A 2008,
112, 2977–2987.
(15) Picciochi, R.; Lopes, J. N. C.; Diogo, H. P.; Minas da Piedade,
M. E. J. Phys. Chem. A 2008, 112, 10429–10434.
(16) Bernardes, C. E. S.; Piedade, M. F. M.; Minas da Piedade, M. E.
Cryst. Growth Des. 2008, 8, 2419–2430.
(17) Marsh, K. N. Recommended Reference Materials for the Realization
of Physicochemical Properties; IUPAC-Blackwell Scientific Publications:
Oxford, U.K., 1987.
(18) Vora, P.; Menon, D.; Samtani, M.; Dollimore, D.; Alexander, K.
Instrum. Sci. Technol. 2001, 29, 231–245.
m
m
∆fH°(g), which is frequently used to discuss bonding energetics
m
and to assess the predictions of empirical estimation schemes
or computational chemistry methods. In this case, the effect of
sample variability may be mitigated if the same material is used
to obtain both ∆fH°(cr) and ∆subH°.
m
m
(19) Bickerton, J.; Pilcher, G.; Altakhin, G. J. Chem. Thermodyn. 1984,
16, 373–378.
(20) Ribeiro da Silva, M. D. M. C.; Gonc¸alves, J. M.; Acree, W. E., Jr.
J. Chem. Thermodyn. 2000, 32, 1071–1073.
(21) Sabbah, R.; Ider, S. Can. J. Chem. 1999, 77, 249–257.
Acknowledgment. This work was supported by Fundac¸a˜o
para a Cieˆncia e a Tecnologia, Portugal (Project PTDC/QUI-
QUI/098216/2008). Ph.D. and Post Doctoral grants from FCT
are gratefully acknowledged by E.M.G. (SFRH/BD/28458/2006)

Energetics and Structure of Nicotinic Acid
J. Phys. Chem. B, Vol. 114, No. 16, 2010 5485
(22) Menon, D.; Dollimore, D.; Alexander, K. S. Thermochim. Acta
2002, 392-393, 237–241.
(23) Jessup, R. S. J. Res. Natl. Bur. Stand. (U. S.) 1942, 29, 247–270.
(24) Sato-Toshima, T.; Kamaguchi, A.; Nishiyama, K.; Sakiyama, M.;
Seki, S. Bull. Chem. Soc. Jpn. 1983, 56, 51–54.
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(52) Jillavenkatesa, A.; Dapkunas, S. J.; Lum, L.-S. H. Particle Size
Characterization; National Institute of Standards and Technology: Gaith-
ersburg, MD, 2001.
(25) Di, Y. Y.; Shi, Q.; Tan, Z. C.; Sun, L. X. Acta Chim. Sinica 2007,
65, 1940–1946.
(26) Tan, Z. C. Private communication.
(27) Koch, W.; Holthausen, M. C. A. Chemist’s Guide to Density
Functional Theory, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2002.
(28) Curtiss, L. A.; Redfern, P. C.; Raghavachari, K.; Rassolov, V.;
Pople, J. A. J. Chem. Phys. 1999, 110, 4703–4709.
(29) Montgomery, J. A., Jr.; Frisch, M. J.; Ochterski, J. W.; Petersson,
G. A. J. Chem. Phys. 1999, 110, 2822–2827.
(30) Montgomery, J. A., Jr.; Frisch, M. J.; Ochterski, J. W.; Petersson,
G. A. J. Chem. Phys. 2000, 112, 6532–6542.
(31) Laugier, J.; Bochu, B. Chekcell; http://www.ccp14.ac.uk/tutorial/
lmgp/chekcell.htm.
(32) NIST Certificate for Standard Reference Material 2151.
(33) Taylor, L. D. J. Org. Chem. 1962, 27, 4064–4065.
(34) Goher, M. A. S.; Dra´tovsky´, M. Collect. Czech. Chem. Commun.
1975, 40, 26–35.
(35) Hudson, M. R.; Allis, D. G.; Hudson, B. S. Chem. Phys. Lett. 2009,
473, 81–87.
(36) Saito, T.; Hayamizu, K.; Yanagisawa, M.; Yamamoto, O.; Wasada,
N.; Someno, K.; Kinugasa, S.; Tanabe, K.; Tamura, T.; Hiraishi, J. Spectral
Database for Organic Compounds (SDBS); http://riodb01.ibase.aist.go.jp/
sdbs/.
(37) Moura Ramos, J. J.; Taveira-Marques, R.; Diogo, H. P. J. Pharm.
Sci. 2004, 93, 1503–1507.
(38) Pinto, S. S.; Diogo, H. P.; Minas da Piedade, M. E. J. Chem.
Thermodyn. 2003, 35, 177–188.
(39) Calado, J. C. G.; Dias, A. R.; Minas da Piedade, M. E.; Martinho
Simo˜es, J. A. ReV. Port. Quim. 1980, 22, 53–62.
(40) Diogo, H. P.; Minas da Piedade, M. E.; Fernandes, A. C.; Martinho
Simo˜es, J. A.; Ribeiro da Silva, M. A. V.; Monte, M. J. S. Thermochim.
Acta 1993, 228, 15–22.
(41) Diogo, H. P.; Minas da Piedade, M. E.; Gonc¸alves, J. M.; Monte,
M. J. S.; Ribeiro da Silva, M. A. V. Eur. J. Inorg. Chem. 2001, 228, 257–
262.
(42) Kiyobayashi, T.; Minas da Piedade, M. E. J. Chem. Thermodyn.
2001, 33, 11–21.
(43) Bernardes, C. E. S.; Santos, L. M. N. B. F.; Minas da Piedade,
M. E. Meas. Sci. Technol. 2006, 17, 1405–1408.
(44) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(45) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789.
(46) Mclean, A. D.; Chandler, G. S. J. Chem. Phys. 1980, 72, 5639–
5648.
(47) Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys. 1984, 80,
3265–3269.
(48) Dunning, T. H. J. Chem. Phys. 1989, 90, 1007–1023.
(49) Dunning, T. H.; Peterson, K. A.; Wilson, A. K. J. Chem. Phys.
2001, 114, 9244–9253.
(53) Kutoglu, A.; Scheringer, C. Acta Crystallogr. 1983, C39, 232–
234.
(54) Allen, F. H. Acta Crystallogr. 2002, B58, 380–388.
(55) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields,
G. P.; Taylor, R.; Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006,
39, 453–457.
(56) Wieser, M. E. Pure Appl. Chem. 2006, 78, 2051–2066.
(57) Gording, R.; Flexser, L. A. J. Am. Pharm. Assoc. 1940, 5, 230–
231.
(58) Rehman, M.; Shekunov, B. Y.; York, P.; Colthorpe, P. J. Pharm.
Sci. 2001, 90, 1570–1582.
(59) El Moussaoui, A.; Chauvet, A.; Masse, J. J. Therm. Anal. 1993,
39, 619–632.
(60) Wang, S. X.; Tan, Z. C.; Di, Y. Y.; Xu, F.; Wang, M. H.; Sun,
L. X.; Zhang, T. J. Therm. Anal. Calorim. 2004, 76, 335–342.
(61) Allan, J. R.; Geddes, W. C.; Hindle, C. S.; Orr, A. E. Thermochim.
Acta 1989, 153, 249–256.
(62) Spa¨th, E.; Spitzer, H. Ber. Dtsch. Chem. Ges. 1926, 59B, 1477–
1486.
(63) Malaviolle, R.; Demaury, G.; Chauvet, A.; Terol, A.; Masse, J.
Thermochim. Acta 1987, 121, 283–294.
(64) Jingyan, S.; Jie, L.; Yun, D.; Ling, H.; Xi, Y.; Zhiyong, W.; Yuwen,
L.; Cunxin, W. J. Therm. Anal. Calorim. 2008, 93, 403–409.
(65) Hubbard, W. N.; Scott, D. W.; Waddington, G. In Experimental
Thermochemistry; Rossini, F. D., Ed.; Interscience: New York, 1956; Vol.
1, Chapter 5.
(66) Månsson, M.; Hubbard, W. N. In Experimental Chemical Ther-
modynamics; Sunner, S., Månsson, M., Eds.; Pergamon Press: London, 1979;
Vol. 1, Chapter 5.
(67) Johnson, W. H. J. Res. Natl. Bur. Stand. (U. S.) 1975, 79A, 425–
429.
(68) Wagman, D. D.; Evans, W. H.; Parker, V. B.; Schumm, R. H.;
Halow, I.; Bailey, S. M.; Churney, K. L.; Nuttall, R. L. J. Phys. Chem.
Ref. Data 1982, 11, suppl. no. 2.
(69) Santos, L. M. N. B. F.; Silva, M. T.; Schro¨der, B.; Gomes, L. J.
Therm. Anal. Calorim. 2007, 89, 175–180.
(70) Olofsson, G. Assignment of Uncertainties; In Experimental Chemi-
cal Thermodynamics; Sunner, S., Månsson, M., Eds.; Pergamon Press:
London, 1979; Vol. 1, Chapter 6.
(71) Cox, J. D.; Wagman, D. D.; Medvedev, V. A. CODATA Key Values
for Thermodynamics; Hemisphere: New York, 1989.
(72) Edwards, J. W.; Kington, G. L. Trans. Faraday Soc. 1962, 58,
1323–1333.
(73) Andrews, J. T. S.; Westrum, E. F., Jr.; Bjerrum, N. J. Organomet.
Chem. 1969, 17, 293–302.
(74) Atkins, P. W.; de Paula, J. Physical Chemistry, 7th ed.; Oxford
University Press: Oxford, U.K., 2002; p 822.
(50) Kendall, R. A.; Dunning, T. H.; Harrison, R. J. J. Chem. Phys.
1992, 96, 6796–6806.
(75) Pascual-Ahuir, J. L.; Silla, E.; Tunon, I. GEPOL93; http://
www.ccl.net/cca/software/SOURCES/FORTRAN/molecular_surface/gepol93/.
(76) Bondi, A. J. Phys. Chem. 1964, 68, 441–451.
(77) Denbigh, K. The Principles of Chemical Equilibrium, 4th ed.;
Cambridge University Press: Cambridge, U.K., 1981.
(78) Korn, G. A.; Korn, T. M. Mathematical Handbook for Scientists
and Engineers; McGraw-Hill: New York, 1968.
(79) Irikura, K. K.; Frurip, D. J. Computational Thermochemistry.
Prediction and Estimation of Molecular Thermodynamics; ACS Symposium
Series No. 677; American Chemical Society: Washington, DC, 1998.
(80) Computational Chemistry Comparison and Benchmark DataBase.
NIST Standard Reference Database 101 (Release 12); National Institute of
Standards and Technology: Gaithersburg, MD, 2005.
(81) Pedley, J. B. Thermochemical Data and Structures of Organic
Compounds; TRC: College Station, TX, 1994; Vol. 1.
(51) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
JP101490B