molecules

Article
Dimerization of Acetic Acid in the Gas Phase—NMR
Experiments and Quantum-Chemical Calculations
Ondřej Socha 1,2 and Martin Dračínský 1, *
1 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2,
166 10 Prague, Czech Republic; [email protected]
2 Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 166 10 Prague, Czech Republic
* Correspondence: [email protected]; Tel./Fax: +42-02-2018-3139

Academic Editors: Wiktor Zierkiewicz and Steve Scheiner




Received: 31 March 2020; Accepted: 30 April 2020; Published: 4 May 2020

Abstract: Due to the nature of the carboxylic group, acetic acid can serve as both a donor and acceptor of
a hydrogen bond. Gaseous acetic acid is known to form cyclic dimers with two strong hydrogen bonds.
However, trimeric and various oligomeric structures have also been hypothesized to exist in both the
gas and liquid phases of acetic acid. In this work, a combination of gas-phase NMR experiments and
advanced computational approaches were employed in order to validate the basic dimerization model
of gaseous acetic acid. The gas-phase experiments performed in a glass tube revealed interactions of
acetic acid with the glass surface. On the other hand, variable-temperature and variable-pressure
NMR parameters obtained for acetic acid in a polymer insert provided thermodynamic parameters
that were in excellent agreement with the MP2 (the second order Møller–Plesset perturbation theory)
and CCSD(T) (coupled cluster with single, double and perturbative triple excitation) calculations
based on the basic dimerization model. A slight disparity between the theoretical dimerization model
and the experimental data was revealed only at low temperatures. This observation might indicate
the presence of other, entropically disfavored, supramolecular structures at low temperatures.

Keywords: NMR spectroscopy; quantum-chemical calculations; phase transitions; carboxylic acids;

hydrogen bonding

1. Introduction
Noncovalent interactions play a significant role in many chemical and biological processes.
For instance, molecular recognition, protein folding, and crystal packing are phenomena where these
interactions shape the structure, properties, and function of molecules and materials. Hydrogen bonding
is the most important noncovalent interaction. Hydrogen bonds are typically an order of magnitude
weaker than covalent bonds, and yet they determine, for example, the secondary structure of large
biopolymers such as DNA or proteins.
Carboxylic acids possess a functional group that can simultaneously serve as a hydrogen-bond
donor and acceptor. Therefore, carboxylic acids can form a number of supramolecular structures,
and they are often used as model systems to gain an insight into the hydrogen-bonding interaction [1].
Acetic acid, which is an archetypal carboxylic acid, serves as an excellent example to demonstrate this.
Crystalline acetic acid is comprised of linear chains of hydrogen-bonded molecules [2]. In the gas
phase, on the other hand, the presence of centrosymmetric cyclic dimers of acetic acid has been confirmed
by several experimental studies [3–6]. Each of the dimers contains two equivalent strong O–H···O=C
hydrogen bonds. The dimerization enthalpy and entropy have been estimated to be about −15 kcal/mol
and −37 cal/K·mol, respectively, by several experiments, such as IR experiments and vapor-density or
thermal-conductivity measurements [7]. However, NMR spectroscopy experiments of gaseous acetic
acid have estimated the dimerization enthalpy and entropy as about −18 kcal/mol and −42 cal/K·mol,

Molecules 2020, 25, 2150; doi:10.3390/molecules25092150 www.mdpi.com/journal/molecules

Molecules 2020, 25, 2150 2 of 16

respectively [8]. There is no clear consensus about the prevailing supramolecular structure in liquid
acetic acid [9]. While neutron diffraction [10] and time-domain Raman spectroscopy [11,12] experiments
have suggested that liquid acetic acid primarily consists of cyclic dimers, other experiments, such as
large-angle X-ray scattering [13] and IR [14] and Raman [15] spectroscopy, have suggested that the
main structural patterns in liquid acetic acid are linear chains similar to those found in the solid.
Furthermore, other studies have indicated that acetic acid monomers and cyclic trimers coexist with
the dimers and chains in the liquid phase [16,17].
Acetic acid and its supramolecular complexes have also been investigated in many theoretical
studies [18–22]. Thanks to its small size, acetic acid can be used for benchmarking different computational
approaches including various density-functional-theory (DFT) functionals or post-Hartree–Fock
methods [23–25]. Even expensive methods, such as coupled clusters (CC) and quadratic configuration
interaction, are feasible [26]. Besides the estimation of binding energies, quantum-chemical calculations
have been utilized for predictions of NMR, IR, and Raman spectroscopic parameters [27,28].
In this work, we combined NMR experiments with advanced computational approaches to better
understand the hydrogen-bonding interactions of acetic acid. The experimental part of this study
aimed to precisely measure the thermodynamic parameters of acetic acid dimerization using gas-phase
NMR spectrometry and to explain the previously observed discrepancies of NMR-derived dimerization
enthalpy and entropy with those obtained by other experiments. The goal of the computational
part was to accurately calculate the dimerization Gibbs energy and proton chemical shifts of the
monomeric and dimeric forms of acetic acid in the gas phase. Several DFT and post-Hartree–Fock
methods were employed for energy and NMR computations. In addition, we utilized path-integral
molecular dynamics (PIMD) simulations to obtain an insight into nuclear quantum effects such as
nuclear delocalization and proton tunneling in the acetic acid dimer. A comparison of theoretical and
experimental thermodynamic and spectroscopic parameters was used to discuss the accuracy of the
computational methods, as well as to provide a validation of the basic dimerization model of gaseous
acetic acid.

2. Models and Methods

2.1. Theoretical Model

A simple dimerization model was assumed:

2M ↔ D (1)

where M and D stand for the monomer and dimer of acetic acid, respectively. The equilibrium constant
K is then defined in terms of partial pressures:
pD
K= . (2)
p2M

According to the Dalton law of partial pressures, the total pressure ptot can be obtained using
the formula:
ptot = pM + 2pD . (3)

The observed chemical shift δ is calculated as a weighted average of monomeric and dimeric
shifts δM and δD , respectively:
pM
δ= (δM − δD ) + δD (4)
ptot
where the partial pressure of the monomeric form pM is derived using the above equations, which leads
to the expression:
p
1 + 8Kptot − 1
pM = (5)
4K
Molecules 2020, 25, 2150 3 of 16

The equilibrium constant K is directly related to the change of enthalpy ∆H and entropy ∆S of
dimerization through the van’t Hoff equation:

∆H − T∆S
 
K = exp − (6)
RT

A detailed derivation of the above formulae is available in the Supplementary Materials.

2.2. NMR Experiments

The experimental setup consisted of an evacuated torch-sealed glass insert ( 4 mm; L = 40 mm)
or a fluorinated ethylene propylene copolymer (FEP) insert sealed with a polytetrafluoroethylene
(PTFE) stopper filled with acetic acid vapors. The glass insert was evacuated and heated above
150 ◦ C to remove any residual moisture prior to the acetic acid injection (still under reduced pressure).
The insert was fitted into a regular 5 mm NMR tube. The restricted length of the insert confined
the sample within the NMR detection coil in the probe and limited heat transfer to the surrounding
space. This assembly enabled a regular 20 Hz rotation for B0 (the spectrometer magnetic field)
inhomogeneity averaging. Automatic gradient shimming procedures were inapplicable due to the
high diffusivity and low concentration of the vapors, and there was no lock signal. These conditions
led to slightly broadened signals despite the effort to manually adjust the magnetic-field homogeneity.
This, however, introduced only a negligible error to the chemical-shift measurement. No chemical-shift
reference was added to the sample, and only the differences ∆δ = δOH − δMe are reported, where δOH
and δMe are the proton chemical shifts of the OH and CH3 groups, respectively. We did not use any
internal chemical-shift standard because the magnetic susceptibility of liquid acetic acid is substantially
different from that of acetic acid vapors. Therefore, the resonance frequency of a standard would also
have differed in the solution and in the vapor, and we would have observed two different signals of
the standard (solution and gas phase). Furthermore, tetramethylsilane (TMS), the most common NMR
standard, is very volatile, and it would probably not have persisted in the acetic acid solution under
reduced pressure.
The measurements were performed on a 500 MHz Bruker Avance II NMR spectrometer
(Bruker BioSpin, Germany) equipped with a TBO probe, allowing for measurement in a wide
temperature range from −150 to 150 ◦ C. The temperature was regulated using a sensor and a heater
inside the probe at a constant air flow rate of 535 l/h. The temperature sensor was calibrated using
ethylene glycol prior to the experiment.
Temperature series of the 1 H–NMR spectra of acetic acid in the glass insert were measured from
150 to 30 ◦ C, with a 5 ◦ C step and a 15 min equilibration period between each step. The spectra were
acquired with 1024 transients, 9012 points in the time domain, a spectral width of 18 ppm, a repetition
time of 0.3 s, and an acquisition time of approximately 14 min per temperature point. In total, three
such datasets with different sample concentrations were measured. The spectra in the FEP inserts were
acquired as pseudo-2D time series with the acquisition time of 2.5 min per spectrum, 128 transients,
12,288 points of free induction decay (FID), a spectral width of 25 ppm, and a repetition time of 0.6 s.
Measurements were performed at four different temperatures (25, 60, 80, and 100 ◦ C).
Water content in the samples was estimated by the following procedure. Acetic acid used for
sample preparation in our experiments was delivered from the manufacturer in 1.5 mL glass ampules.
Water content was determined using standard liquid NMR measurement based on the following
information: Pure acetic acid solidifies from the solution (acetic acid–water) at temperatures under the
melting temperature of acetic acid. However, a mixture of remaining acetic acid and water stays liquid
above –27 ◦ C, which is the eutectic point of the mixture. An NMR tube filled with 0.5 mL of acetic acid
was cooled down below the freezing point of acetic acid. In Figure S1, two NMR spectra at –6 ◦ C are
shown. One spectrum directly corresponds to the acetic acid from the ampule, and the other one is
with the addition of 7 mol% of water. It is clear from the comparison of these two spectra that there
Molecules 2020, 25, 2150 4 of 16

was more than ten times less water in the original sample. Therefore, we concluded that the water
content in the acetic acid used in our experiments was far below 1 mol%.

2.2.1. Pressure Estimation

In the gas-phase measurement, the actual pressure in the NMR tube must be known for the
calculation of thermodynamic quantities. It was not a straightforward task to obtain an accurate
pressure value because the sample was either in a torch-sealed tube or in a leaky polymeric insert,
which means that any pressure setting was lost during or after the tube sealing. Therefore, the pressure
was estimated from the condensation temperature T0 . Generally, when condensation occurs, a second
set of NMR signals starts to appear in the spectrum. In the case of acetic acid and other diamagnetic
liquids, these signals are shifted to lower Larmor frequencies than the signals from the gas phase as
a result of the negative magnetic susceptibility of the bulk material. It is thus easy to distinguish between
gas- and liquid-state signals. At this point, the pressure p0 can be determined based on the temperature
T0 and the a priori knowledge of the temperature dependence of given liquid-vapor pressure. The vapor
pressure is tabulated for many materials in terms of Antoine equation coefficients [29,30]; see the
Supplementary Materials. In the case of airtight glass inserts under the assumption of ideal gas
behavior, the pressure only depends on the temperature according to the expression:
p0
ptot (T ) = (7)
T0

Measurements in the FEP inserts were performed at constant temperature. The FEP inserts were
not airtight, and the acetic acid vapors continuously leaked from the insert for several hours or days,
depending on the temperature. After the evaporation of the liquid, the partial pressure of the acetic
acid showed an exponential decay during the time t, which was best observed on the integral intensities
I(t) of the methyl-group NMR signal. The pressure at a given time (snapshot) was calculated using
the formula:
I (t)
ptot (t) = p0 (8)
I (t ) t=t
0

where the time t0 is tied to the beginning of the pressure decay.

2.2.2. Data Processing

Temperature and pressure series of the spectra were acquired and processed using the TopSpin 3.5
software (Bruker). An exponential apodization of 5 Hz was applied to improve the signal-to-noise ratio,
and the baseline was corrected using a 5th-order polynomial. Data were zero-filled to 3,2768 points.
Chemical shifts and line widths were obtained through fitting Lorentzian line shapes into the datasets.
The temperature or pressure dependencies of chemical shifts were subsequently fitted using Expression
(2), yielding the thermodynamic parameters ∆H and ∆S. Datasets from glass-insert measurement were
treated separately; the optimized parameters of ∆H, ∆S, and chemical-shift differences (δOH − δMe ) of
the monomer ∆δM and dimer ∆δD are available in the Supplementary Materials. The global fitting
procedure was employed for FEP measurement. The parameters ∆H and ∆S were shared between
datasets, while ∆δD and pcorr were independently optimized for each dataset. The parameter pcorr was
subtracted from the pressure in order to take into account the small baseline distortion that leads to
incorrect pressure behavior lim ptot (t) , 0:
t→∞

I (t)
ptot (t) = p0 − pcorr (9)
I (t ) t=t
0

The value of pcorr was always below 0.005 atm.

Molecules 2020, 25, 2150 5 of 16

The chemical shift of the monomer ∆δM was fixed at the value of 3.76 ppm, which was obtained
through extrapolation to zero pressure from the measurement at 150 ◦ C. To improve the convergence
of the optimization procedure, the Savitzky–Golay smoothing filter of the 3rd order with a 21-point
window was applied to the pressure data ptot (t). Further window widening had only a negligible effect
on the optimized parameters. There were between 600 and 1200 pressure points in each dataset.
The uncertainty of the optimized parameters was estimated from the p0 pressure uncertainty.
Two contributions to p0 uncertainty were considered: systematic contribution (10% of p0 ) and
dataset-specific contribution (5% of p0 ). Both originated from the uncertainty of the point where the
liquid evaporated, see below. Though these contributions could be merged into one, they tend to
behave differently in terms of error propagation. The systematic error seems to have had only a minor
influence on the uncertainties of the optimized thermodynamic parameters. The main source of the
error was thus a slight inconsistency in p0 determination between individual data sets. Standard
deviations of the fitted parameters were estimated using the Monte Carlo method. In 1000 iterations,
the predictors p0 were re-sampled from normal distributions with variance parameters reflecting the
above uncertainties. The set of re-optimized parameters was statistically analyzed, yielding standard
deviations of all optimized parameters and ∆H and ∆S covariance. All fitted parameters including
their uncertainties are in the Supplementary Materials.

2.3. Computational Methods

Energy calculations, geometry optimization, and the computation of NMR parameters were carried
out utilizing the Gaussian16 software package [31]. For all of these calculations, the “frozen-core”
approximation was employed. The B3LYP [32,33] calculations used an “ultrafine” integration grid, and the
effect of semiempirical Grimme’s dispersion correction (GD3) [34] on the structure and the binding
energy of acetic acid was evaluated. Energy computations were performed with Dunning’s augmented
correlation-consistent double-ζ (Aug-cc-pVDZ) to quintuple-ζ (Aug-cc-pV5Z) basis sets [35,36]. The basis
set superposition error (BSSE) was estimated using the counterpoise method (CP) [37]. C2 symmetry was
imposed for all calculations of the acetic acid dimer.
All geometry optimizations were carried out with “tight” convergence criteria, and the optimized
structures possessed no imaginary vibrational frequencies, with one exception. In the case of the dimer
structure optimized using the second order Møller–Plesset perturbation theory (MP2) [38] with the
Aug-cc-pVQZ basis set, the harmonic analysis could not be done because of excessive computational
requirements. However, this structure was pre-optimized at the MP2/Aug-cc-pVTZ level, yielding no
imaginary frequencies.
The input geometries for all MP2 and coupled cluster with single, double, and perturbative
triple excitation (CCSD(T)) [39–42] energy and/or NMR computations were optimized at the
MP2/Aug-cc-pVQZ level. To further improve the precision of MP2-calculated energies, the correlation
energy Ecorr was extrapolated to the complete basis set (CBS) limit using Helgaker’s formula [43]:

A
EX CBS
corr = Ecorr + (10)
X3

where X = 2,3,4,5 is the “cardinal number” of the basis set used to calculate the respective energy EX and
A is the system-dependent free parameter. As can be seen in Figure S8, the double-ζ basis set yielded
inconsistent results; therefore, these values were excluded from the extrapolation. The Hartree–Fock
(HF) energy calculated with Aug-cc-pV5Z was then added to ECBS corr in order to obtain the MP2/CBS
binding energy ECBS
MP2
. More detailed values are in Table S3 in the Supplementary Materials. A different
approach to CBS extrapolation was employed in the case of CCSD(T). Due to prohibitively demanding
requirements of the CCSD(T) method, only a single-point energy calculation with the Aug-cc-pVTZ
basis set was possible. However, it has been observed that the difference between the MP2 and CCSD(T)
Molecules 2020, 25, 2150 6 of 16

calculated energy is only slightly dependent on the basis set. Formula (4), which has been proposed to
exploit this fact [44], was employed here:
 
∆ECBS
CCSD(T )
= ∆ECBS
MP2 + ∆ECCSD ( T ) − ∆EMP2 (11)
smaller basis set

For all MP2 and CCSD(T) calculations, the entropy change ∆S and the thermal contributions to
the enthalpy change ∆Hthermal of dimerization were calculated at the MP2/Aug-cc-pVTZ level. These
values were subsequently added to the MP2- and CCSD(T)-calculated single-point energy values ∆E
according to the equation:

∆H = ∆E + (∆HMP2 − ∆EMP2 )Aug−cc−pVTZ (12)

The values of ∆G0 and ∆H were reported for direct comparison with experimental values.
No special treatment of vibronic modes for the correction of entropy or enthalpy was applied.
For the B3LYP and MP2 calculations of 1 H chemical shielding, the gauge-independent atomic
orbital (GIAO) method [45] with the Aug-pcS-2 basis set [46] was used. These computations were
performed on the structures optimized with the Aug-cc-pVQZ basis set using the same method as the
subsequent NMR calculations.
PIMD simulations were performed by the CASTEP program [47], version 17.2, using an NVT
ensemble, the temperature of 300 K, a Langevin thermostat, a 0.5-fs integration time step, ultrasoft
pseudopotentials [48], and a planewave cutoff energy of 300 eV. The integrals were taken over the
Brillouin zone using a Monkhorst–Pack [49] grid of the minimum k-point sampling of 0.1 Å−1 .
Electron-correlation effects were modeled using the generalized-gradient approximation of Perdew,
Burke, and Ernzerhof [50]. The acetic acid monomer and dimer were placed in a cubic periodic box of
15 × 15 × 15 Å−1 , and the atomic positions were optimized by energy minimization prior to the PIMD
runs at the same computational level. No symmetry constraints were applied during the simulation
of the dimer. The production runs of the monomer and dimer simulation of the lengths of 4 and
6 ps, respectively, were preceded by 2-ps equilibration. The path-integral propagation used a Trotter
decomposition of all nuclei into 16 beads.
Time-averaged NMR parameters were computed from 1000 snapshots from the MD and PIMD
simulations. The B3LYP functional with the Aug-pcS-2 basis set was employed for the calculation of
NMR shieldings.

3. Results and Discussion

3.1. NMR Experiments

In order to obtain accurate thermodynamic parameters of acetic acid complexation, we performed
variable-temperature and variable-pressure NMR measurements. Initially, we carried out the
experiments in glass inserts. These inserts were torch-sealed in order to ensure a constant amount of
acetic acid throughout the measurements. Figure 1 shows an example of the 1 H–NMR spectrum of
acetic acid in a glass insert at the temperature of 60 ◦ C. Two sets of signals were present, corresponding
to the gas and liquid states of acetic acid. The temperature series of the 1 H–NMR spectra of acetic acid
in the glass insert are in Figure 2 and in the Supplementary Materials (Figures S4–S6). The signal of the
methyl group in gaseous acetic acid was shifted from the signal of the liquid by about 1.7 ppm towards
higher frequencies. This was the result of the different magnetic susceptibility of both environments.
The diamagnetic nature of liquid acetic acid caused the shielding of all nuclei within, but there was no
such effect in gases. In addition to that, a different intermolecular bonding environment led to further
chemical-shift changes.
Molecules 2020, 25, 2150 7 of 16

Figure 1. The 1 H–NMR spectrum of acetic acid in a glass insert at the temperature of 60 ◦ C. The spectrum
was not referenced.

An unexpected temperature-dependent line broadening of the COOH signal was observed in the
spectra of gaseous acetic acid in the glass insert. Strangely, the broadening became more prominent
as the temperature increased. This dependence is depicted in Figure 3 and is also noticeable in the
spectra (Figure 2 and Figures S4–S6). Though some broadening can be expected in solution, where it
can indicate a chemical exchange between various supramolecular structures, it is surprising in the
gas phase. In our model, we assumed only one process, which was the dimerization of acetic acid
monomers. We expected this process to have a relatively high exchange rate at the temperatures
attained in our experiments, leading to narrow averaged signals. This broadening pointed to another
unexpected exchange process. One of the possible explanations may be related to water presence in the
sample. However, we did not expect a considerable interaction, such as hydrogen bonding between
acetic acid and water molecules in the gas phase because of the high purity of the sample. Water content
was determined to be far below 1% (molar) using liquid NMR (see the Methods and Supplementary
Materials for more details). Moreover, we expected the interaction with water to be energetically
less favorable than the binding to another acetic acid molecule. The only other explanation of the
unexpected line broadening was the interaction of acetic acid molecules with the walls of the glass
insert, specifically with the oxygen-containing functional groups on its surface. The existence of these
interactions has already been indicated in a previous study [51].
The temperature dependence of the chemical-shift difference ∆δ = δOH − δMe was further analyzed.
The basic dimerization Model (2) was fitted to the experimental data. The optimized parameters
(∆δM , ∆δD , ∆H and ∆S) showed a strong dependence on the pressure ptot , despite the fact that they
were expected to be pressure-independent. This supported the hypothesis of the presence of another
chemical exchange with molecules adsorbed on the glass walls.
To eliminate the influence of the glass surface on the observed data, we decided to utilize a different
material for the NMR tube insert. There are commercially available tube liners made of FEP, which is
a highly inert material. Unfortunately, these inserts are not airtight, which causes complications when
they are used to measure gas samples. However, we exploited the slow gas leakage for the measurement
of the pressure dependence of NMR spectra, where pressure is a function of time. The inserts were
filled with a few drops of liquid sample and subsequently heated up to the desired temperature.
Figure 4 shows an example of the time and thus indirect pressure dependence of the 1 H–NMR spectra
of acetic acid. The signal broadening was no longer present in the spectra, which suggested that this
was, indeed, a glass-specific effect. This fact also provided a possible explanation for the inaccuracy of
the resultant values of ∆H and ∆S in the previous NMR study discussed in the introduction, in which
glass NMR tubes were used [8].
Molecules 2020, 25, 2150 8 of 16

Figure 2. Temperature series of 1 H–NMR spectra of acetic acid (c = 7:9 mM) in the glass insert.
The spectra were not referenced.

Figure 3. Temperature dependence of the half width of the 1 H–NMR signal of the acetic acid COOH
group in the glass insert.
Molecules 2020, 25, 2150 9 of 16

Figure 4. An example of the time dependence of the acetic acid 1 H–NMR spectra in the fluorinated
ethylene propylene copolymer (FEP) insert at the temperature of 80 ◦ C. The gas-phase signals are
highlighted by red color. The spectra were not referenced.

The signal intensities varied during the initial phase of the experiment in the FEP insert due to
the line shape broadening caused by the exchange between the liquid and gas states. It is evident
from Figure 5 that the line broadening was exhibited by both acetic acid signals. Whereas the COOH
linewidth showed a strong dependence on time, the signal of the methyl group tended to have
a constant width, with the only disruption during the l + g → g transition.
During the measurements in the FEP inserts, another set of acetic acid signals was also present in
the spectra. These, however, did not come from the inside of the FEP insert; rather, they came from
the small space between the insert and the enclosing NMR tube. The vapors escaping from the insert
tended to condensate there; therefore, the signals corresponded to liquid acetic acid. The signals of the
gas-state molecules inside the insert were thus not affected by those “outer” molecules.

Figure 5. The 1 H–NMR line broadening in the presence of acetic acid vapors and condensate.
A transition is observed after the liquid evaporation.

The thermodynamic parameters ∆H and ∆S were globally fitted to four datasets at temperatures
25, 60, 80, and 100 ◦ C (Figure 6), yielding the values ∆H = (−15.4 ± 0.5) kcal/ mol, ∆S = (−36.6 ± 1.5)
cal/ mol·K, and ∆G0 = (−4.48 ± 0.12) kcal/ mol. The chemical-shift difference ∆δ of the dimer was
separately determined for each dataset, with the average value being ∆δD = 10.55 ppm. The chemical
shift of the monomer ∆δM = 3.76 ppm was obtained through the extrapolation of the chemical-shift
dependence at 150 ◦ C to zero pressure.
A visual analysis of the fitted data (Figure 6) showed a worse fit at lower temperatures, especially
at 25 ◦ C. This could have partly been caused by a higher noise in the data at lower temperatures,
which is also apparent in the picture. However, the possibility of another chemical exchange between
other supramolecular structures cannot be excluded. Since these supramolecular forms (e.g., trimers
and tetramers) would be entropically less stable than dimers, they would only exist in the acetic acid
Molecules 2020, 25, 2150 10 of 16

vapors at low temperature and/or high pressure. This hypothesis would explain why our model,
which considers only monomers and dimers, fit better to the high-temperature data.

3.2. Computations
Three different computational methods were employed for the calculation of the binding energy
of the acetic acid dimer. B3LYP is a widely used DFT functional due to its speed and good results for
organic molecules. The second-order Møller–Plesset perturbation theory was chosen as a popular
representative of post-Hartree–Fock methods. MP2 scaled sensibly with the system size and allowed for
the geometry optimization of the acetic acid dimer with a quadruple-ζ basis set. The quite demanding
coupled-cluster method with single, double excitations, and triple excitations as a perturbation CCSD(T)
is one of the most precise methods for electronic-energy calculations today.

Figure 6. The pressure dependence of the chemical shift of acetic acid vapors in the FEP insert fitted
using Expression (2). The chemical shift ∆δM was obtained independently through extrapolation from
a 150 ◦ C dataset. Note that the ptot values used in the fit were based on the experimentally obtained
concentration. The experimental temperatures were (a) 25 ◦ C, (b) 60 ◦ C, (c) 80 ◦ C and (d) 100 ◦ C.

3.2.1. The Structure of the Acetic Acid Dimer

Geometry optimization was carried out using DFT and MP2 with the Aug-cc-pVQZ basis set.
In the DFT case, the B3LYP functional was used both with and without Grimme’s empirical dispersion
corrections (GD3). Table 1 summarizes selected inter-atomic distances in the optimized structures of the
acetic acid dimer. The dispersion correction added slightly more cohesion to the system. This affected
the interatomic distance between the oxygens involved in hydrogen bonding (O···H–O), where the
shortening of 0.007 Å was observed when compared to the dispersion-uncorrected B3LYP. The distance
shortening of 0.01 Å was also observed between the carboxylic carbons, which was related to the
valence-angle change of the carboxylic group. There was no significant change of the C–O and
C–C bond lengths. Generally, dispersion correction seemed to change the B3LYP geometry more
towards the MP2-optimized structure. The atomic coordinates of these structures can be found in the
Supplementary Materials.
Molecules 2020, 25, 2150 11 of 16

Table 1. Interatomic distances (Å) and the O–C–O valence angle (^, ◦ ) in the cyclic dimer of acetic acid
obtained at the second order Møller–Plesset perturbation theory (MP2) level and their differences from
the values obtained at the B3LYP level. GD3: Grimme’s dispersion correction.

Distance/Angle MP2 B3LYP B3LYP and GD3

O–H 0.998 0.002 0.003
O–H···O 2.650 0.012 0.005
C1,C1’ 3.832 0.015 0.005
C1–C2 1.495 0.006 0.006
C=O 1.226 −0.003 −0.003
C–O 1.319 0.000 −0.001
^ O–C–O 123.90 −0.16 0.00

3.2.2. Dimerization Energy

Thermodynamic contributions to the ∆H and ∆S of dimerization were obtained from
thermochemical calculations using the Aug-cc-pVTZ basis set. These values were added to the
single-point energies in order to obtain the standard Gibbs energy ∆G0 (at T = 298 K and p = 1 atm),
the enthalpy ∆H, and entropy ∆S of the dimer formation, which are directly measurable and were thus
better suited for the comparison with the experiments than the change of electronic energy ∆E.
Table 2 shows that the B3LYP functional without dispersion corrections systematically
underestimated the binding energy in comparison with MP2 and CCSD(T) approaches. On the
other hand, the use of dispersion-corrected B3LYP led to the value of dimerization energy being more
than 1 kcal/mol higher than the experimentally observed value. Post-HF methods, MP2 and CCSD(T),
gave much more accurate energies, with deviations from the experimental values of enthalpy and Gibbs
energy lower than 0.2 kcal/ mol at the CBS limit. One should keep in mind the experimental errors of
0.1 kcal/ mol for Gibbs energy and 0.5 kcal/ mol and 1.5 cal/ mol·K for enthalpy and entropy, respectively.
The basis set superposition error: The binding energies in Table 2 were not corrected for the
BSSE. Table S4 shows BSSE estimates based on the counterpoise method. B3LYP computations with
the Aug-cc-pVQZ basis set exhibited a relatively small BSSE (0.13 kcal/mol), regardless of whether
the dispersion correction was applied or not. Even after the BSSE correction, the B3LYP functional
provided an inaccurate prediction of acetic acid binding energies.
Like in the case of B3LYP, the BSSE was estimated by the counterpoise method on the
MP2/Aug-cc-pVQZ structure. As arises from Table S4, the BSSE was nearly six times higher
(0.87 kcal/mol) in the case of MP2 than in the case of B3LYP with the identical basis set. The application
of these corrections led to lower binding energy than the CBS extrapolation. In the case of MP2,
even the BSSE-uncorrected binding energy was closer to the CBS value than the counterpoise-corrected
one. This is not uncommon; it is known that the counterpoise method systematically overestimates
the BSSE [52]. Extensive studies of this subject suggest that there is an error cancellation between
the BSSE and the basis set completeness error (BCE), as a result of which the compensation of the
BSSE may cause the worsening of the binding-energy value due to the effective decompensation of
the BCE [25,53]. It has previously been observed that the average of BSSE-corrected and uncorrected
values yields better agreement with the calculations at the CBS limit [54]. Our calculations confirmed
this observation; taking only one half of the BSSE improved the result significantly (Table S4).
NMR shielding calculation and PIMD simulations: The calculated 1 H–NMR chemical-shift
differences δOH –δMe of the acetic acid monomer and dimer are summarized in Table 3. In the case
of the monomer, both the MP2 and B3LYP methods performed similarly. The deviation from the
experimental value was between 0.1 and 0.25 ppm, where B3LYP seemed to provide slightly better
results. These small deviations can be explained by vibrational effects, which are discussed below.
A quite different situation occurred in the case of the dimer. Though the B3LYP- and MP2-calculated
chemical shifts were nearly the same (with the differences being smaller than 0.15 ppm), the calculated
value was more than 1 ppm higher than the experimental value. This suggests that the deviation from
the experimental value probably did not originate in the inaccuracy of the methods used.
Molecules 2020, 25, 2150 12 of 16

We hypothesize that the large difference between the experimental and calculated values of ∆δD
could have originated from the lack of vibrational averaging in the calculations. In the case of the monomer,
the vibrational corrections to both the COOH and methyl protons have been found to be similar in several
cases [55] and thus might largely have cancelled out in the reported ∆δM value. However, the vibrational
correction of the carboxylic hydrogen might have been significantly higher in the dimeric case because of
the more prominent potential anharmonicity than in the case of the monomer.

Table 2. The calculated values of the dimerization enthalpy (kcal/mol), entropy (cal/mol·K), and Gibbs
energy (kcal/mol) of acetic acid at different computational levels. The results for the MP2 and
CCSD(T) (coupled cluster with single, double and perturbative triple excitation) methods rely on
MP2/Aug-cc-pVTZ thermochemical calculation. Aug-cc-pVDZ: augmented correlation-consistent
double-ζ; V5Z: quintuple-ζ; CBS: complete basis set.

Method Basis Set ∆H ∆S ∆G0

B3LYP Aug-cc-pVQZ −14.27 −37.43 −3.11
B3LYP and GD3 Aug-cc-pVQZ −16.77 −37.25 −5.67
MP2 Aug-cc-pVTZ −15.93 −37.12 −4.86
MP2 Aug-cc-pVQZ −15.57 * −4.51 *
MP2 Aug-cc-pV5Z −15.34 * −4.28 *
MP2 CBS [a] −15.31 * −4.24 *
CCSD(T) Aug-cc-pVDZ −15.83 * −4.76 *
CCSD(T) Aug-cc-pVTZ −16.08 * −5.02 *
CCSD(T) CBS [b] −15.46 * −4.40 *
exptl. −15.38 −36.6 −4.48
[a] The complete basis set limit according to Equation (3); [b] The MP2-based complete basis set limit according to
Equation (4). The asterisks indicate enthalpy and Gibbs energy values, for which different computational levels for
electronic energy and thermochemistry were used.

In order to estimate the importance of the vibrational-averaging contribution to the chemical shifts,
we performed PIMD simulations of the monomer and dimer of acetic acid. This method was chosen for
its ability to comprehend nuclear quantum effects such as quantum nuclear delocalization and tunneling,
exhibited especially by low-mass atoms like hydrogen. It has previously been demonstrated that PIMD
simulations combined with DFT shielding calculations provide excellent agreement with experimental
solid-state NMR chemical-shift changes induced by temperature change or by deuterium isotope
substitution, which are the consequences of vibrational averaging [56,57]. However, these calculations
also revealed that the PBE functional used in these simulations underestimated the energetic barriers
of proton transfer [58]. Furthermore, the PIMD simulations and subsequent shielding calculations
are computationally very demanding because a large number (hundreds to thousands) of geometry
snapshots must be used to obtain sufficiently converged results.
As can be seen in Table 3, the PIMD-based vibrational correction to the monomer ∆δM value was small
and negative, and when added to the B3LYP or MP2 values, the agreement with experiment was improved.
However, in the case of the dimer, the shielding calculations did not converge, even after averaging
1000 geometry snapshots from the PIMD simulation. This poor convergence led to differences between
the shieldings of the equivalent OH protons in the dimer. Furthermore, the probability distributions of the
calculated ∆δD values were very broad (Figure S9), and insufficient convergence could thus have led to
large errors in the calculated ∆δD values. We also noticed that the use of the PBE functional in the PIMD
simulations led to the oversampling of the dimer geometries, which were characterized by high values of
the chemical-shift difference ∆δD (Figure S10). Therefore, the values of the vibrational correction for the
dimer were probably biased towards positive values and unreliable.
Molecules 2020, 25, 2150 13 of 16

Table 3. The calculated 1 H–NMR chemical-shift differences δOH –δMe (ppm) of the acetic acid monomer
and dimer. The computations were performed on the structures optimized with the Aug-cc-pVQZ
basis set using the same method as the subsequent NMR calculation.

Method Monomer Dimer

MP2 4.01 11.77
B3LYP 3.90 11.81
B3LYP and GD3 3.86 11.91
Vibrational correction [a] −0.08 −0.05
Experiment 3.76 10.55
[a] Calculations based on path-integral molecular dynamics (PIMD) simulations and the averaging of NMR
parameters calculated for 1000 geometry snapshots.

4. Conclusions
We performed gas-phase NMR measurements of acetic acid at variable pressures and temperatures.
These experiments allowed us to extract the thermodynamic parameters of acetic acid dimerization.
These values were in good agreement with previous values based on IR experiments and vapor-density
or thermal-conductivity measurements. We noticed, however, that the gas-phase measurements of
acetic acid had to be performed in inert polymer tubes because interactions of acetic acid with the
surface of glass tubes led to significantly biased results. These experiments also provided chemical
shifts of isolated monomeric and dimeric forms of acetic acid.
The temperature and pressure dependence of the observed chemical shifts of acetic acid was
in very good agreement with the dependences derived for the basic dimerization model. We only
observed minor deviations for the lowest experimental temperature (25 ◦ C). These deviations may
indicate the presence of other supramolecular form(s), such as those of the trimer or tetramer, of acetic
acid at low temperatures in the gas phase.
The experimental thermodynamic parameters and chemical shifts were compared with those
obtained by DFT, MP2, and CCSD(T) calculations. The calculated thermodynamic parameters of the
dimerization and the chemical-shift difference δOH –δMe of the acetic acid monomer were in very good
agreement with the experimental values. However, the calculated chemical-shift difference δOH –δMe
of the acetic acid dimer was ca 1 ppm higher than the experimental value. We hypothesize that this
overestimation was caused by neglecting the vibrational averaging in the calculations. We intended
to estimate the vibrational contribution to the chemical shifts by PIMD simulations and subsequent
shielding calculations for geometry snapshots. Unfortunately, we found out that the computational
method used in the PIMD simulations (the PBE functional) was not suitable for this task because it
oversampled the geometries with very short OH···O hydrogen-bond distances. However, these results
demonstrate the importance of an accurate treatment of vibrational corrections to NMR parameters.

Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/25/9/2150/s1.

Detailed derivation of expressions used in the data fitting, Antoine equations for vapor pressure of acetic acid,
and estimation of the water content in the acetic acid samples, Figure S1: 1 H–NMR spectra at –6 ◦ C of a mixture of
acetic acid and water, which remains after freezing of pure acetic acid out of the solution. Figure S2: Temperature
dependence of chemical shift of acetic acid at various concentrations. Table S1: Optimized thermodynamic parameters
of dimerization and chemical shifts of monomer and dimer from measurements of acetic acid in the glass insert.
Figure S3: Temperature dependence of the half width of the 1 H–NMR signal of acetic acid COOH group in the glass
insert. Figure S4: Temperature series of 1 H–NMR spectra of acetic acid (c = 1.1 mM) in the glass insert. Figure S5:
Temperature series of 1 H–NMR spectra of acetic acid (c = 4.4 mM) in the glass insert. Figure S6: Temperature series of
1 H–NMR spectra of acetic acid (c = 7.9 mM) in the glass insert. Figure S7: Pressure dependence of the chemical shift
difference of acetic acid in the FEP insert. Table S2: Optimized thermodynamic parameters of dimerization and the
chemical shift difference of the dimer obtained from the measurements of acetic acid in the FEP insert. Figure S8:
Complete basis set limit of correlation energy of acetic acid monomer and dimer. Table S3: Computed energy values
used for the CBS extrapolation. Table S4: Calculated values of dimerization energies of acetic acid at different
computational levels. Table S5: Cartesian coordinates of the acetic acid monomer optimized at the MP2/Aug-cc-pVQZ
level. Table S6: Cartesian coordinates of the acetic acid dimer optimized at the MP2/Aug-cc-pVQZ level. Figure S9:
Distribution of chemical shifts of acetic acid monomer and dimer (bottom) during the PIMD simulation. Figure S10:
Correlation between B3LYP calculated chemical shift and O-H distance in the dimer of acetic acid. Table S7: B3LYP
calculated 1 H chemical shieldings (ppm) and vibrational corrections based on the PIMD geometries.
Molecules 2020, 25, 2150 14 of 16

Author Contributions: Conceptualization, O.S. and M.D.; methodology, O.S.; investigation, O.S.; writing—original
draft preparation, O.S.; writing—review and editing, M.D.; supervision, M.D. All authors have read and agreed to
the published version of the manuscript.
Funding: This research was funded by the Czech Science Foundation, grant no. 20-01472S, and by the Charles
University Grant Agency, project no. 1494119.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.

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