Theoretical Calculations: Can Gibbs Free Energy

for Intermolecular Complexes Be Predicted Efficiently

and Accurately?

OLEXANDR ISAYEV, LEONID GORB, JERZY LESZCZYNSKI

Computational Center for Molecular Structure and Interactions, Jackson State University,
Jackson, Mississippi 39217

Received 27 October 2005; Revised 12 December 2005; Accepted 28 December 2005

DOI 10.1002/jcc.20696
Published online 5 March 2007 in Wiley InterScience (www.interscience.wiley.com).

Abstract: The theoretical study has been performed to refine the procedure for calculations of Gibbs free energy
with a relative accuracy of less than 1 kcal/mol. Three benchmark intermolecular complexes are examined via sev-
eral quantum-chemical methods, including the second-order Moller-Plesset perturbation (MP2), coupled cluster
(CCSD(T)), and density functional (BLYP, B3LYP) theories augmented by Dunnings correlation-consistent basis
sets. The effects of electron correlation, basis set size, and anharmonicity are systematically analyzed, and the results
are compared with available experimental data. The results of the calculations suggest that experimental accuracy
can be reached only by extrapolation of MP2 and CCSD(T) total energies to the complete basis set. The contribution
of anharmonicity to the zero point energy and TDSint values is fairly small. The new, economic way to reach chemi-
cal accuracy in the calculations of the thermodynamic parameters of intermolecular interactions is proposed. In addi-
tion, interaction energy (De) and free energy change (DA) for considered species have been evaluated by Carr-Parri-
nello molecular dynamics (CPMD) simulations and static BLYP-plane wave calculations. The free energy change
along the reaction paths were determined by the thermodynamic integration/’’Blue Moon Ensemble’’ technique.
Comparison between obtained values, and available experimental and conventional ab initio results has been made.
We found that the accuracy of CPMD simulations is affected by several factors, including statistical uncertainty and
convergence of constrained forces (TD integration), and the nature of DFT (density functional theory) functional.
The results show that CPMD technique is capable of reproducing interaction and free energy with an accuracy of
1 kcal/mol and 2–3 kcal/mol respectively.
q 2007 Wiley Periodicals, Inc. J Comput Chem 28: 1598–1609, 2007

Key words: free energy; interaction energy; intermolecular complex; ab initio; density function theory; Carr-Parri-
nello molecular dynamics; thermodynamic integration

Introduction Another well-established technique to predict the electronic

Canonical quantum chemistry that is quite often called ‘‘wave
function-based quantum chemistry methods’’ is capable of deter-
mining molecular properties at a very high level of accuracy.
The most common area of its application is the study of small-
or medium-sized systems, especially gas phase phenomena.
There is also plenty of evidence that the wave function-based
quantum chemistry methods are able to predict gas-phase prop-
erties of molecular systems up to virtually any desired accuracy
as a result of systematically improving the correlation treatment
together with the wave function representation. For example, the
modern techniques are capable of reaching about 10 cm
1 accu-
racy for fundamental vibrational frequencies1 and 0.002–0.003 Å
accuracy in equilibrium bond distances.2–4
structure of molecules and molecular systems is the density
functional theory (DFT).5 Since the DFT treatment is usually
much faster than the application of methods employing tradi-
tional quantum chemistry, the DFT methods are known to lead
to amazingly good predictions for a wide variety of systems of
small, moderate, and large sizes.6–14 However, dramatic failures
Correspondence to: J. Leszczynski; e-mail: jerzy@ccmsi.us
Contract/grant sponsor: National Science Foundation; contract/grant
numbers: NSF CREST HRD-0125484
Contract/grant sponsor: Office of Naval Research; contract/grant num-
bers: ONR N00034-03-1-0116

q 2007 Wiley Periodicals, Inc.

 Efficient and Accurate Prediction of Gibbs Free Energy
of this technique are also well documented in the literature.15–19
Among them the most significant, probably, is the incapacity of
most of the DFT methods to correctly describe van der Waals
interactions.15,16 This is a serious limitation in the prediction of
the properties of intermolecular complexes.
There is one area where extremely high accuracy is crucially
important and has significant impact. This is in the determina-
tion of thermodynamic parameters of molecular species and
chemical reactions when those species are involved. The avail-
able techniques represent various compromises between accu-
racy and computational cost. The most efficient technique in-
cludes calculations at the CCSD(T) level using extended basis
sets or extrapolated to complete basis sets (CBSs), which
according to definition should provide extremely accurate
results.20 It is estimated that this level of theory, including rela-
tivistic effects and non-Born-Oppenheimer terms, leads to an
uncertainty of 60.05 kcal/mol in binding energy of water
dimer.21 There are also several less time consuming thermo-
chemicals protocols such as the ‘‘Gaussian-n’’ (Gn) family of
methods.22–24 These methods first provided accuracy of the ther-
mochemistry of small molecules in the kilocalories per mole
range; currently such methods possess an average absolute devi-
ation of 1.07 kcal/mol. The Gn theory relies on relatively small
basis sets, additivity approximations, and empirical corrections.
Similar remarks apply to the CBS family of methods by Peters-
son and coworkers,25,26 which involve intricate combinations of
pair correlation extrapolations and empirical corrections. Among
recent developments, it should also be mentioned that there are
more accurate but computationally more expensive approxima-
tions of the Wn (Weizmann) family27,28 and the HEAT theory29
which provides accuracy within 1 kJ/mol. These methods in-
clude explicit corrections, for anharmonicity, relativistic correc-
tions and treatment of electron correlation at the coupled-cluster
level of theory.
A common feature of these methods is the use of the QCI,
CCSD(T), or even CCSDTQ levels of theory at the final step,
which is definitely necessary to reach very high levels of accu-
racy. However, such an approach has a very serious disadvant-
age since it currently limits the size of the considered systems to
approximately 6–10 atoms of the second row of the Periodic Ta-
ble. In addition, the majority of available computational proto-
cols are devoted to the prediction of the enthalpy of formation
and Gibbs free energy of isolated molecules, ions, and radicals.
In contrast, the related area of an ab initio prediction of the
thermodynamic parameters of intermolecular interactions is not
well represented. To fill this gap, the present study exclusively
focused on the discussion and development of efficient and
accurate protocols for the determination of thermodynamic pa-
rameters of intermolecular complexes.
We also would like to mention that the amount of trustwor-
thy experimental data that include not only the interaction en-
thalpy (DHint) but also the interaction entropy (DSint) as well as
interaction Gibbs free energy (DGint) values is extremely limited.
On the other hand, the accurate prediction of DGint is most im-
portant for intermolecular complexes, since in contrast to most
molecules and ions, this value can be significantly different
when compared to DHint. For example, in the case of the forma-
tion of a Watson–Crick DNA base pair between guanine and cy-
Journal of Computational Chemistry
1599
tosine, the difference between interaction energy and interaction
Gibbs free energy is about 12 kcal/mol.30
The goal of this study is the evaluation of procedures for pre-
dictions of thermodynamic parameters (DHint, DSint, DGint) of
intermolecular interactions by relatively computationally inex-
pensive quantum chemical techniques such as DFT5 in conjunc-
tion mostly with the B3LYP functional31,32 (For the develop-
ment of new DFT functionals that are also able to describe ther-
modynamics and kinetics of chemical reactions, see ref. 33 We
are planning to undertake a special study for the comparison of
our approach with the ones suggested in ref. 33), the second
order of Möller-Plesset perturbation theory,34 or the combination
of these procedures. To elucidate our problem, we have chosen
three diverse intermolecular systems. They are well character-
ized by experimental data. Among them are the well-known val-
ues for water dimer interactions at 373 K,35 along with the same
parameters for the formic acid dimer,36 and the HCN. . .Liþ
complex37 at 298 K. These three systems represent intermolecu-
lar complexes that are formed by single and double hydrogen
bonds, and the ion–molecular species. Their thermodynamic pa-
rameters can be considered as a benchmark for our ab initio
simulations.
The evaluation of the thermodynamic parameters of molecu-
lar species and chemical reactions in the way described earlier
uses the static methods of quantum mechanics. The dynamic
methods are incorporated in numerous molecular dynamics (MD)
techniques. Computing free energies and entropies at this level
is one of the main goals and major efforts of MD simulations.
Unfortunately, these two statistical properties are not easily ac-
cessible for simulations as their evaluation in principle requires
an infinitely long simulation to scan the entire space. Neverthe-
less, significant progress in studying free-energy differences has
been achieved, showing that it is, in spite of all the sampling
problems, possible to obtain reasonable free-energy estimates.38–
45
The reason is that, in order to obtain a free-energy difference
between two states, the evaluation of the complete partition
function is not really necessary; the extensive sampling of the
relevant parts where the two states differ suffices.45,46 In addi-
tion, the advantage of MD techniques is that the thermal effects,
such as entropy contribution, are included explicitly. Moreover,
most MD approaches, applied at the ab initio level, are BSSE
free. Therefore, for the sake of comparison we have also
included in this study the results of an evaluation of the relative
free energies obtained in the framework of a dynamic quantum-
chemical approximation.
Computational Methods
The ab initio linear combination of the atomic-orbitals–molecu-
lar-orbitals method was used in this study. The calculations were
carried out using the GAUSSIAN 03 (ref. 47) code. The total
and interaction energies have been evaluated at the second order
of the Möller-Plesset perturbation theory34 and the DFT level
using the B3LYP and BLYP functionals31,32 and the counter-
poise-corrected optimization procedure as employed in Gaussian
03. The optimization procedure has been described in ref. 48.
This procedure results in direct optimization of the counterpoise-
DOI 10.1002/jcc
1600 Isayev, Gorb, and Leszczynski • Vol. 28, No. 9 • Journal of Computational Chemistry

corrected interaction energy, which is calculated according to 0.0241888 fs) was used for the numerical integration of the
the equation equations of motions, according to the velocity Verlet algorithm.
In order to determine the properties averaged within the canoni-
X
n X
n cal ensemble, a Nose-Hoover chain thermostat58 with a length
e ¼ Esp

DCP Emiopt þ ðEmij
Emij Þ (1) of 4 and a characteristic frequency of 500 cm
1 was used on the
i¼1 i¼1 nuclear degrees of freedom. Plane wave geometry optimization
was performed with the ODIIS algorithm.59
where DCPe is the counterpoise-corrected interaction energy; Esp Deuterium has been utilized instead of hydrogen to allow a
is the energy of the complex; Em represents the energies of the larger time step. Therefore, in the discussion below (Molecular
individual monomers, with the subscripts ‘‘opt’’ and ‘‘f’’ denot- Dynamics Simulations), it should be kept in mind that all spe-
ing the individually optimized monomers frozen in their super- cies that include hydrogen atoms are in fact deuterium contain-
molecular geometries; the asterisks (*) denote monomers calcu- ing species.
lated with ‘‘ghost’’ orbitals. Two energetic parameters have been evaluated from the MD
The cc-pvdz, cc-pvtz, and aug-cc-pvdz basis sets have been simulation: the interaction energy, which is determined as
used. The vibrational frequencies were always evaluated at the
X
same level as the geometry optimization. Single point calcula- De ¼ hEcomplex i
hEi i (4)
tions have been performed at the CCSD(T) level of theory. i
The MP2 and CCSD(T) total energies were extrapolated to
the CBS values 2-3 (cc-pvdz and cc-pvtz basis sets, respectively) where hEi is the averaged energy values of the intermolecular
according to the expression of Truhlar49 complex and its components and the change of the free energy
DA. To evaluate DA, the phase space along the reaction path has
3
3
been explored by the Blue Moon method,60 keeping the
Etot;1 ¼ EHF;3

EHF;2
3

2
3
2
r(O

O), r(C

C), or r(Li

N) length constrained. After short

3 3 equilibration (2–3 ps) at 300 K by velocity scaling, the equa-
þ  
Ecorr;3
 Ecorr;2 ð2Þ
3
2 3
2 tions of motion have been integrated with a time step of 4 a.u.
for a time about 2–3 ps in the NVT ensemble, and the change
in the free energy value between states 1 and 2 has been calcu-
where
is equal to 3.4, and  is equal to 2.2 and 2.4 for MP2 lated using the thermodynamic integration method:
and CCSD(T), respectively, and to the expression of Helgaker
Z
and coworkers50 2 hZ
1=2 ½li0

A ¼
f0 d0 ; f 0 ¼ (5)
1 hZ
1=2 i0
EHF;X ¼ EHF;1 þ a expð
bXÞ
X3 ðX
1Þ3 where  is the value of the constrained reaction coordinate,
Ecorr;1 ¼ E
3 corr;X

Ecorr;X
1 ð3Þ
X3
ðX
1Þ X3
ðX
1Þ3 and l is the Lagrange multiplier on the constraint which is pro-
portional to the force due to constraint.
Note that all DA values are free energies calculated at constant
where EHF,X, Ecorr,X, and Ecorr,X
1 are Hartree-Fock and correla- volume; therefore they are Helmholtz’s free energies. However,
tion energies as a function of the cardinal number X of the cc- for most reactions the volume change of the reaction is fairly
pvXz basis set, X ¼ 3. small (including the interactions, considered in this paper); there-
The thermodynamic parameters of the intermolecular interac- fore, DA is approximately equal to DG under ambient pressure.
tions (interaction enthalpy (DHint), interaction entropy (DSint),
and interaction Gibbs free energy (DGint)) were calculated from
standard expressions using rigid rotor-harmonic oscillator-ideal
Results and Discussion
gas approximations.51
The Car-Parrinello molecular dynamics simulations52 were Dissociation Energies and Interaction Enthalpies
performed with the CPMD program53 using a plane-wave basis
and BLYP functional.31,32 The wave function was expanded at Benchmark calculations of the dissociation energies and interac-
the point in a plane-wave basis set with the kinetic energy cutoff tion enthalpies of intermolecular complexes are presented and
of 70 and 120 Ry respectively. A large 18-Å cubic box was analyzed elsewhere (see, for example, refs. 61–63). The avail-
used under the periodic boundary conditions; this unit cell is able published data include a wide range of the interaction ener-
sufficiently large to ensure negligible overlap of the wave func- gies, starting from dispersion interactions through hydrogen-
tions with the periodic images.54 bonded systems to ion–molecular complexes. We will not pres-
The form of the nonlocal pseudopotential according to Klein- ent here a comprehensive survey of these interactions. However,
man and Bylander was employed,55 and the core electrons were for the purposes of our discussion it is important to highlight the
described by the Troullier and Martins pseudopotentials.56 The following point. As follows from the literature, accurate MP2
Goedecker–Teter–Hutter pseudopotentials57 were used for the and accurate CCSD(T) calculations are able to reproduce the
lithium compounds. The time step 4 a.u. (where 1 a.u. ¼ dissociation energies and interaction enthalpies with experimen-

Journal of Computational Chemistry DOI 10.1002/jcc

 Efficient and Accurate Prediction of Gibbs Free Energy 1601

Table 1. DH and D0 (in kcal/mol) for Selected Intermolecular Complexes (Comparison Theoretical
Estimations and Experiment).

Ref. Ref.
System Method Theor. D0(theor) DHint(theor) D0(expt) DHint(expt) expt.

(H2O)2 MP2/aug-cc-pVTZ, CP 64 4.83
5.4460.7 35

MP2/aug-cc-pVQZ, CP 64 4.92
CCSD(T)/cc-pVTZ, CP 64 4.48
(CONH2)2 MP2/D95V**, CP 65
3.24
3.34 66
(HF)2 B3LYP/6-311þG(2df,p), CP 9 2.68 3.0360.02 67,68
MP2/6-311þG(2df,p), CP 2.30
QCISD/6-311þG(2df,p), CP 2.18
MP2/cc-pVTZ//MP2/6-311G(d,p) 69
3.9 4.660.3 (De) 70
W1 71 4.57
(CH3OH)2 MP2/cc-pVTZ//MP2/6-311G(d,p) 69
4.82
4.6 to
5.9 (De) 72,73
MP2/CBS//MP2/6-311G(d,p)
5.58
CCSD(T)/CBS//MP2/6-311G(d,p)
5.45
HCN. . .HF B3LYP/cc-pVTZ 69
6.35
6.9 (De) 74
MP2/cc-pVTZ//MP2/6-311G(d,p)
6.43
CCSD(T)/CBS//MP2/6-311G(d,p)
7.11
CH3COCH3. . .Naþ MP2(full)/6-311þG(2d,2p)//MP2/6-31G* 75
30.0
30.860.5 76
Imidazole. . .Naþ MP2(full)/6-311þG(2d,2p)//MP2/6-31G* 75
34.9
33.7 76
H2O. . .Liþ MP2/6-311þþG(d,p) 77
35.3
32.7 78
MP2/6-311þG(d,p) 79
36.1
34.0 37
CH3CN. . .Kþ B3LYP/6-311þG*(2df,2p) 80 101.9 102.1 81
Ne2 MP2/aug-cc-pV5Z 69
0.05
0.08 82
CCSD(T)/aug-cc-pV5Z
0.07
Ar2 MP2/aug-cc-pV5Z 69
0.30
0.28 82
CCSD(T)/aug-cc-pV5Z
0.26

tal accuracy. This indicates that the difference between the MP2
and CCSD(T) or even higher level computational data are insig-
nificant values, and the difference between accurately calculated
and experimental values also does not exceed 0.5 kcal/mol (or
even less). To confirm this conclusion, we have presented in
Table1 the selected available data.
Let us now briefly describe the situation with the intermolec-
ular complexes of interest. In the case of a water dimer, a dis-
cussion of the accuracy of the calculated values of interaction
enthalpies has a long history. Overall, the water dimer is prob-
ably the most demanded intermolecular complex ever. The most
accurate calculations performed at the MP2 and CCSD(T) levels
which use counterpoise-corrected optimizations,61–63,83,84 total
energy-extrapolated to a CBS,71 and anharmonic values of vibra-
tional frequencies85,86 allow to reproduce the experimental value
of the interaction energy35 and the enthalpy of formation with
an uncertainty of about 60.2–0.3 kcal/mol.
Two other complexes have received less attention. The for-
mic acid dimer was investigated at the HF, MP2, DFT, and
CCSD(T) levels of theory.69,87,88 The best DFT (B3LYP and
PW91 with cc-pV5Z) and CCSD(T)/CBS calculated interaction
enthalpy results are within 0.5 kcal/mol from experimental data.
To our knowledge, there is only one systematic study of the
HCN. . ..Liþ complex. It was investigated at the B3LYP/6-311 þ
G(d,p) level of theory,89 and the calculated DHint value was 0.8
kcal/mol larger than the available experimental data.
Calculated and available experimental data for the water
dimer, formic acid dimmer, and HCN. . ..Liþ are presented in
Tables 2–4. The results obtained at the MP2 level along with
cc-pvdz, cc-pvtz, and aug-cc-pvtz basis sets exhibit unsatisfac-
tory correspondence to the experimental measurements since the
calculated DHint values deviate from the experimental results by
1.5–3.5 kcal/mol. The DFT results are much better; thus, the
calculated DHint values lie within a 1–1.5 kcal/mol range of the
experimental data. Not surprisingly, our data that include extrap-
olation to a CBS insignificantly deviate from the experimentally
observed values. For all cases, the most accurate results are
obtained by either the CBS extrapolated MP2 energies from full
MP2 optimization or the CBS extrapolation of single point MP2
energies from the B3LYP/cc-pvtz geometry.
An analysis of the data presented in Tables 2–4 allows a few
important results to be summarized.
i. Experimental accuracy is reached only at the MP2 and
CCSD(T) levels, if one will use the extrapolation to the
CBS.
ii. We did not use anharmonic corrections in our calculations;
however, as follows from the data presented in Tables 2–4,
experimental accuracy in the calculation of DHint is reached
even for vibrational frequencies calculated at the harmonic
approximation. A similar conclusion for thermodynamical
evaluations that target an accuracy of 0.25 kcal/mol is sug-
gested by a few other studies.27,86,90–92 It was also pointed
out that the anharmonic contributions to the zero point
energy (ZPE) can be safely neglected, at least for molecules
of medium size. To our knowledge, there are only a few

Journal of Computational Chemistry DOI 10.1002/jcc

1602 Isayev, Gorb, and Leszczynski • Vol. 28, No. 9 • Journal of Computational Chemistry

Table 2. Calculated Total Energies E (in a.u.) and Thermodynamical Parameters (in kcal/mol) for Water
Dimer Interaction at 373 K.

E (H2O) E ((H2O)2) DHint TDSint DGint

B3LYP /cc-pvdz
76.42063
152.84867
3.02
7.05 4.04

/cc-pvtz
76.45984
152.92693
2.91
7.49 4.58
/aug-cc-pvdz
76.44464
152.89643
2.86
7.52 4.66

BLYP /cc-pvdz
76.39887
152.80450
2.66
7.27 4.61

/cc-pvtz
76.44146
152.88958
2.59
7.31 4.72

MP2 /cc-pvdz
76.22867
152.46405
2.58
7.02 4.44

/cc-pvtz
76.31866
152.64443
2.86
6.92 4.06
/aug-cc-pvdz
76.26091
152.52894
2.86
7.39 4.52

Truhlar CBS (cc-pvdz–cc-pvtz)
76.37015
152.74844
3.46 MP2/cc-pvdz 3.56

3.50 MP2/cc-pvtz 3.43

Helgaker CBS (cc-pvdz–cc-pvtz)
76.35327
152.71406
3.07 MP2/cc-pvdz 3.95

3.30 MP2/cc-pvtz 3.72

Truhlar CBS //B3LYP/cc-pvtz
76.35335
152.71428
3.58 B3LYP/cc-pvtz 3.92

//B3LYP/aug-cc-pvdz
76.35325
152.71409
3.61 B3LYP/aug-cc-pvdz 3.91

Helgaker CBS //B3LYP/cc-pvtz
76.35335
152.71428
3.12 B3LYP/cc-pvtz 4.37

//B3LYP/aug-cc-pvdz
76.35325
152.71409
3.14 B3LYP/aug-cc-pvdz 4.38

CCSD(T) /cc-pvtz//MP2/cc-pvtz
76.33213
152.67122
2.73 MP2/cc-pvtz 4.77

CCSD(T), Truhlar CBS //B3LYP/aug-cc-pvdz
76.37922
152.76651
3.44 B3LYP/aug-cc-pvdz 4.08

//B3LYP/cc-pvtz
76.37932
152.76668
3.42 B3LYP/cc-pvtz 4.07
//MP2/cc-pvtz
76.37921
152.76642
3.40 MP2/cc-pvdz 4.12

Expt., from ref. 35
3.59
6.93 3.34

references86,90,91 that discuss the specific contribution to
ZPE or thermal correction to the enthalpy which came from
anharmonicity. For example, a recent study of anharmonic-
ity effects on zero point energies in weakly bonded molecu-
lar clusters such as (Ne)n (HF)2, (H2O)2, Ar-H2O, etc.,
finally concluded that ‘‘the potential surfaces of weakly
bound complexes often display considerable anharmonicity,
but there can be offsetting effects that make for only small
differences between harmonic and fully anharmonic ZPE.’’86
In particular, the difference between calculated harmonic
and diffusion quantum Monte-Carlo anharmonic ZPE
amounts to 120 cm
1 (0.34 kcal/mol) for a water dimer.
iii. There is an economic way to reach experimental accuracy
in the calculation of a DHint. One may optimize the geome-
try of the intermolecular complex at the B3LYP/cc-pVTZ
level with a counterpoise correction and then perform single
point MP2/cc-pvdz and MP2/cc-pvtz calculations and
extrapolate the obtained values to the CBS. As follows
from the data presented in Tables 2–4, the obtained results
are virtually the same as the ones obtained for the optimiza-
tion at the MP2 level using the same extrapolation to the
CBS.
The explanation of the results marked as (iii) is quite
obvious. One may see that the geometrical parameters predicted
at the MP2/cc-pvtz, and B3LYP/cc-pvtz levels are virtually the
same (see Fig. 1).
Interaction Entropies and Interaction Gibbs Free Energies
Since the value of DGint can be significantly different when
compared to DHint because of significant contribution of TDSint,
an accurate prediction of DSint is of the same importance as the
prediction of DHint. However, as already mentioned, the avail-
able experimental data on DSint are rather unreliable. This fact
limits theoretical estimations also, since theoretical and experi-
mental values could not be compared accurately.
The literature survey suggests the presence of two types of
data. Some of them are those where the correspondence between
theoretical and experimental results is good or very good. In
other words, these calculations reach experimental accuracy.
Several examples are listed in Table 5. Another group of data
(see Table 5 again) relates to the poor correspondence between
the experimental and calculated results. Comparing the data pre-
sented in Table 5, one would note that there is both good and

Journal of Computational Chemistry DOI 10.1002/jcc

 Efficient and Accurate Prediction of Gibbs Free Energy 1603

Table 3. Calculated Total Energies E (in a.u.) and Thermodynamical Parameters (in kcal/mol) for Formic
Acid Dimer Interaction at 298 K.

E (HCOOH) E ((HCOOH)2) DHint TDSint DGint

B3LYP /cc-pvdz
189.77327
379.57018
13.39
11.07
2.32

/cc-pvtz
189.84066
379.70523
13.56
11.08
2.48
/aug-cc-pvdz
189.79537
379.61473
13.61
11.50
2.11

BLYP /cc-pvdz
189.73750
379.49700
12.24
11.24
1.34

/cc-pvtz
189.80885
379.63978
12.51
11.08
1.43

MP2 /cc-pvdz
189.28132
378.58172
10.17
10.58 0.41

/cc-pvtz
189.47113
378.96511
12.53
10.58
1.94

Truhlar CBS (cc-pvdz–cc-pvtz)
189.58122
379.18959
15.23 MP2/cc-pvdz
4.65

15.23 MP2/cc-pvtz
4.64

Helgaker CBS (cc-pvdz–cc-pvtz)
189.54459
379.11410
13.84 MP2/cc-pvdz
3.25

MP2/cc-pvtz
3.25

Truhlar CBS //B3LYP/cc-pvtz
189.58189
379.19094
15.60 B3LYP/cc-pvtz
4.52

//B3LYP/aug-cc-pvdz
189.58164
379.19034
15.53 B3LYP/aug-cc-pvdz
4.03

Helgaker CBS //B3LYP/cc-pvtz
189.54479
379.11462
14.26 B3LYP/cc-pvtz
3.18

//B3LYP/aug-cc-pvdz
189.54459
379.11411
14.19 B3LYP/aug-cc-pvdz
2.69

CCSD(T) /cc-pvtz//MP2/cc-pvtz
189.49950
379.02281
13.14 MP2/cc-pvtz
2.55

CCSD(T), Truhlar CBS //B3LYP/aug-cc-pvdz
189.60319
379.22749
11.79 B3LYP/aug-cc-pvdz
0.29

//B3LYP/cc-pvtz
189.60347
379.22932
12.59 B3LYP/cc-pvtz
1.51
//MP2/cc-pvtz
189.60439
379.23248
13.43 MP2/cc-pvdz
2.85

Expt, from ref. 36 Via peak height
14.860.5
10.860.6
4.0 61.1
Via band area
13.760.7
2.9

14.161.5
10.7
3.4

poor correspondences among complexes having very similar
structures. It might suggest that some experimental data are just
not accurate enough.
There are six degrees of freedom that are mostly affected by
the formation of intermolecular complexes. Three of those are
the relative translational motions of the two monomers. The
other three are rotational degrees of freedom corresponding to
their relative orientation; three other rotational degrees of free-
dom, corresponding to the overall rotations of the complex, do
not affect the association. Upon complex formation these six
degrees of freedom convert into ‘‘oscillations’’ (vibrations and/or
hindered rotations) within the potential well of the complex. In
general, these oscillations are ‘‘soft,’’ i.e., their frequencies are
low, with average energies per mode of the order of kT, where k
is the Boltzmann’s constant and T the absolute temperature.
Therefore, we need to return to an analysis of the accuracy of
the vibrational component, since in contrast to ZPE, mostly low
frequencies will contribute to the TDSint value.
Generally, the situation is quite similar as discussed earlier:
there are only a few papers discussing the difference in the con-
tribution of harmonically and anharmonically calculated frequen-
cies in DSint.85,90 The estimations that we performed using the
data presented in ref. 103 for a water dimer at 373 K suggest
that the difference between the TDSint component that includes
anharmonic frequencies and the one that includes frequencies
calculated in a harmonic approximation is between 0.56 and
0.41 kcal/mol. Indeed, an analysis of our data (Tables 2–4) sug-
gests a quite optimistic conclusion: in all considered cases the
MP2 counterpoise-corrected optimization is able to provide the
quality of the TDSint term which is of virtually the same accu-
racy as the experimental data. This indicates that for the studied
complexes the rigid rotor-harmonic oscillator-ideal gas approxi-
mation, which is used for the estimation of entropy values at the
harmonic approximation level, is accurate enough for achieving
the goals of the present study.
Concluding the discussion on DSint, we would like to empha-
size that in our study the values of the TDSint term evaluated at
the DFT/B3LYP level are practically of the same quality as the
ones obtained at the MP2 level; that is, they differ at most by
about 0.50 kcal/mol when compared with the experimental data
for a water dimer (in this case the MP2 data are virtually the
same as the experimental data), about 0.3–0.7 kcal/mol for the
formic acid dimer (the MP2 data provide the largest difference
in about 0.1–0.2 kcal/mol), and about 0.8 kcal/mol (the same

Journal of Computational Chemistry DOI 10.1002/jcc

1604 Isayev, Gorb, and Leszczynski • Vol. 28, No. 9 • Journal of Computational Chemistry

þ
Table 4. Calculated Total Energies E (in a.u.) and Thermodynamical Parameters (in kcal/mol) for HCN. . .Li
Interaction at 298 K.

E (HCN) E (Liþ) E(HCN. . .Liþ) DH TDS DG

B3LYP /cc-pvdz
93.43018
7.28511
100.77261
35.25
6.89
28.36

/cc-pvtz
93.46137
7.28538
100.80634
36.58
7.00
29.58
/aug-cc-pvdz
93.43705
7.28514
100.78036
35.70
6.99
28.71

BLYP /cc-pvdz
93.40687
7.27787
100.74100
34.59
6.86
27.73

/cc-pvtz
93.44037
7.27814
100.77681
35.78
6.97
28.80

MP2 (full) /cc-pvdz
92.87848
7.23612
100.17497
33.00
6.88
26.12

/cc-pvtz
93.28116
7.24726
100.58442
34.31
6.96
27.35

Truhlar CBS (cc-pvdz–cc-pvtz)
93.34581
7.25481
100.65798
35.22 MP2/cc-pvdz
28.33

35.15 MP2/cc-pvtz
28.20

Helgaker CBS (cc-pvdz–cc-pvtz)
93.32345
7.25187
100.63219
34.92 MP2/cc-pvdz
28.03

34.86 MP2/cc-pvtz
27.90

Truhlar CBS //B3LYP/cc-pvtz
93.34761
7.25482
100.66008
35.37 B3LYP/cc-pvtz
28.37

//B3LYP/aug-cc-pvdz
93.34746
7.25482
100.65984
35.29 B3LYP/aug-cc-pvdz
28.33

Helgaker CBS //B3LYP/cc-pvtz
93.32398
7.25186
100.63297
35.04 B3LYP/cc-pvtz
28.04

//B3LYP/aug-cc-pvdz
93.32396
7.25186
100.63288
34.96 B3LYP/aug-cc-pvdz
28.01

CCSD(T) (full) /cc-pvtz//MP2 cc-pvtz
93.30332
7.249353
100.60880
34.39 MP2/cc-pvtz
27.43

CCSD(T) (full), Truhlar CBS //B3LYP/cc-pvtz
93.36434
7.25726
100.67938
35.45 B3LYP/cc-pvtz
28.45
//B3LYP/aug-cc-pvdz
93.36397
7.25726
100.67893
35.38 B3LYP/aug-cc-pvdz
28.39
//MP2/cc-pvtz
93.36416
7.25726
100.67912
35.38 MP2/cc-pvtz
28.42

Expt., from ref. 37
36.4
7.7
28.7

difference has been obtained at the MP2 level) for the
HCN. . .Liþ system.
Next we consider the accuracy of the parameter that is gener-
ally responsible for the stability of intermolecular complexes,
the Gibbs free energy. Since the best results in the estimation of
DHint have been obtained using extrapolation of total energy to
the CBS, we have obtained also quite a satisfactory accuracy of
DGint using the same approximation. One may see that our best
estimated value for a water dimer differs by only 0.09 kcal/mol
from experimental data. As follows from the data presented in
Table 2, this result has been obtained for the procedure that
included the MP2 geometry optimization followed by the CBS
interpolation using the Truhlar formula [see eq. (2)] and the
MP2/cc-pvtz data for the calculations of vibrational frequencies.
The deviation of 0.58 kcal/mol has been obtained for the pro-
cedure that included geometry optimizations at the B3LYP/cc-
pvtz level followed by CBS interpolation using the Truhlar for-
mula and calculations of frequencies at the B3LYP/cc-pvtz level.
The deviation of 0.65 kcal/mol has been reached for the for-
mic acid dimer using the MP2 geometry optimization followed
by CBS interpolation using the Truhlar formula and the MP2/cc-
pvtz data for calculations of vibrational frequencies. The results
of the geometry optimization at the B3LYP/cc-pvtz level fol-
lowed by CBS interpolation using the Truhlar formula and cal-
culation of frequencies at the B3LYP/cc-pvtz level are virtually
the same as the ones using the MP2 optimization. However,
optimizations at the B3LYP/aug-ccpvdz level followed by the
Truhlar extrapolation and calculations of frequencies at the
B3LYP/aug-ccpvdz level result in virtually the same result as
the experimental value of DGint. The results based on Helgaker
extrapolation [see eq. (3)] are also quite accurate.
The tendencies that we obtained for analyzed data for water
and formic acid dimers are confirmed by the results obtained for
the HCN. . .Liþ system. The most accurate (the difference
between the experimental and calculated values is 0.67 kcal/
mol) are the data that we obtained within the MP2 geometry
optimization followed by CBS interpolation using the Truhlar
formula and the MP2/cc-pvtz data for calculations of vibrational
frequencies. Virtually the same results were reached using a ge-
ometry optimization at the B3LYP/cc-pvtz level followed by
CBS interpolation using the Truhlar formula and calculations of
frequencies at the B3LYP/cc-pvtz level. The results obtained
with the aid of the Helgaker technique are almost as accurate as
described earlier.
Again, the results in the prediction of DGint obtained at the
MP2 counterpoise-corrected optimization level followed by
extrapolation to the CBS values are practically the same as those
that include the counterpoise-corrected optimization at the B3LYP

Journal of Computational Chemistry DOI 10.1002/jcc

 Efficient and Accurate Prediction of Gibbs Free Energy 1605

Figure 1. Optimized geometries (bond length in angstroms and angles in degrees) of considered com-
plexes at (a) MP2/cc-pVTZ CP, (b) B3LYP/cc-pVTZ CP, (c) BLYP/cc-pVTZ CP, and (d) CPMD-
BLYP/PW.

level with further extrapolation of the total energy to the CBS at
the single point MP2 level. Therefore, we expect that such an
approach when applied for the intermolecular complexes of
moderate or large size will be able to provide a deviation in ac-
curacy of DGint within less than 1 kcal/mol.
Molecular Dynamics Simulations
Let us start the presentation of the Carr-Parrinello molecular dy-
namics (CPMD) data from the analysis of interaction energies
which are presented in Table 6. We ran a series of simulations
for 2, 5, and 10 ps. As was expected, the results are very con-

Table 5. DS (in cal/mol K) of Selected Intermolecular Complexes (Comparison Theoretical Estimations and
Experiment).

System Method Ref., theor. DSint(theor) DSint(expt) Ref., expt

Good correspondence
(H2O)2 MP2/aug-cc-pVTZ 93 7.82 6.93 35
MP2/aug-cc-pVTZ, anharm. 93 7.41
(HF)2 B3LYP/cc-pVDZ 94
20.86
20.71 94
B3LYP/cc-pVTZ 94
21.41
CH3OH. . .Naþ MP2(full)/6-311þG(2d,2p)//MP2/6-31G* 75 21.8 20.5 62 75
CH3NH2. . .Naþ MP2(full)/6-311þG(2d,2p)//MP2/6-31G* 75 23.4 22.6 62 75
CO(CO2)2Hþ. . .CO2 MP2/6-31G(d,p) 95
22.8
22.7 96
(CO)2Hþ. . .CO MP2/6-31G(d,p) 95
22.1
24 97
G2(MP2) 98 15.9 16.0 99
G2(MP2) 98 17.9 17.3 99
MP2/6-311þþG(2df,2pd) 100
24.15
20.163 101

Poor correspondence
OCHþ. . .CO2 MP2/6-31G(d,p) 95
15.8
21.4 96
(CO)2Hþ. . .CO MP2/6-31G(d,p) 95
22.1
15.0 102
G2(MP2) 98 16.2 13.4 99
MP2/6-311þþG(2df,2pd) 100
13.95
22.363 101

Journal of Computational Chemistry DOI 10.1002/jcc

1606 Isayev, Gorb, and Leszczynski • Vol. 28, No. 9 • Journal of Computational Chemistry

Table 6. Interaction (De)and Free (DA) Energies of Formations (in kcal/mol) Evaluated from CPMD and
Comparison with Available Experimental Data.

De DA DG

System Timescale (ps) MDa TIb PW opt. Expt. TI DAþZPE Expt.

(H2O)2 2
4.0
3.95
4.3
5.0 6 0.1c 4.1 5.7 3.34c

5
4.1
10
4.2

(HCOOH)2 2
11.5
13.1
14.1
13.2d
2.3
0.8
3.4 to
4.0e

5
11.8
10
11.6

HCN. . .Liþ 2
35.5
34.8
36.8
36.4 (DH0)f
26.9
26.1
28.7f
5
35.0
35.9 (De)g
10

a
MD ¼ results from unconstrained MD.
b
TI ¼ Thermodynamic Integration via internal energy change.
c
From ref. 35.
d
From ref. 104.
e
From ref. 36.
f
From ref. 37.
g
Our estimate (Truhlar 2-3 CBS MP2), this work.

sistent and have deviations between them of 0.5 kcal/mol or
less. Since the experimental data on De are not available for the
HCN. . .Liþ complex the value included in Table 6 represents
our best estimate calculated at the MP2 level with extrapolation
to CBS. It was found that the average error in the De values is
about 0.8 kcal/mol for the water dimer and about 0.9 kcal/mol
for the HCN. . .Liþ complex. The error in the De estimation for
the formic acid dimer of 1.1 kcal/mol is found to be the largest
among all selected molecules. Similar results were obtained for
evaluation of De using thermodynamic integration (making the
assumption that the internal energy change DhEi during com-
plexation is equal to the interaction energy) except for the for-
mic acid dimer where the difference between experimental and
calculated values is only 0.1 kcal/mol.
In addition, we have calculated the geometrical parameters
and interaction energies from conventional BLYP/PW geometry
optimizations. The resulting values are listed in Figure 1 and Ta-
ble 6. As can be seen, the obtained results exhibit practically the
same accuracy as the results of the CPMD simulations. Devia-
tions among BLYP/plane waves and BLYP/cc-pVTZ are smaller
that 0.005 Å for the covalent bonds and within 0.025 Å for the
weak intermolecular bonds. Differences between BLYP/PW and
MP2 are within acceptable limits, thus BLYP inter- and intramo-
lecular bond lengths are deviated up to 0.04 and 0.02 Å when
compared to MP2 results respectively. Differences between bond
angles are within 18 for the all approaches. On the other hand,
the accuracy of the interaction energies is very close to the static
results that use the BLYP functional and the Gaussian type tri-
ple- basis sets (for comparison see the results presented in
Tables 2–4).
Before discussing the CPMD results on the free energy esti-
mation we would such as to highlight two points.
First, the quality of the thermodynamic integration has been
monitored by the constrained force convergence. To analyze the
convergence of the constrained force, i.e., the minimum time to
obtain trustworthy values of the average force at particular points
of the reaction coordinate, the running average of the Lagrangian
multiplier hli (see Fig. 2a) is plotted. As can be seen, the force
convergence of the average value is less than 800 fs. In addition
the constraint force autocorrelation function h(0)l(t)i (Fig. 2b)
relaxes extremely fast. Since dynamical properties like the auto-
correlation function are very sensitive to changes taking place in
the system, they can serve as a convenient criterion to monitor
the dissociation process. Figure 2 represents just one snapshot for
the water dimer at r(O

O) ¼ 3.5 A; however, all other systems
exhibit the same behavior. Analysis indicates that, while the error
decreases with increases in the time steps, any trajectory over
10,000 time steps will usually give convergence to 1 kcal/mol (or
less). More steps might be needed for considerably large systems
or complex reaction coordinates.
Second, since in the CPMD approach the nuclei are treated
as classical particles, a CPMD free energy is not corrected by
the ZPE value. Therefore, to compare them with the experimen-
tal values and the values obtained in previous sections, they
would have to be adjusted by ZPEs and thermal corrections.
Currently, there is no capable implementation to calculate accu-
rate enough harmonic vibrational frequencies and thermal cor-
rections in CPMD. Therefore, we have adjusted the values of
DA by the corresponding calculated (BLYP/cc-pVTZ) values of
thermal correction (Table 6; column marked as DAþZPE).
Analyses of adjusted DA values demonstrate rather poorly the
accuracy, with deviations between the calculated and experimen-
tal free energies for all three systems (about 2.5 kcal/mol). This
difference is higher than the one for unadjusted DA since the

Journal of Computational Chemistry DOI 10.1002/jcc

 Efficient and Accurate Prediction of Gibbs Free Energy
Figure 2. (a) Fluctuations of the constraint force and running aver-
age of hli for water dimer  ¼ 3.5 E; (b) The constraint force auto-
correlation function (ACF) h(0)l(t)i for the same point. [Color
figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
contribution of the thermal correction is positive. Therefore we
conclude that all calculated free energy values are higher than the
experimental values, i.e., this approach systematically underesti-
mates the stability of selected species. This tendency is also typi-
cal for the conventional BLYP approach since both techniques uti-
lize the same functional. The performance of CPMD for the free
energy estimation is also worse than for De, since more statistical
uncertainties contribute to its value. On the other hand, the accu-
racy of the obtained thermodynamic parameters is in agreement
with previous estimates105,106 for bulk water and other species.
Conclusions
Analysis of the calculated values of the thermodynamical param-
eters (DHint, DSint, and DGint) of the intermolecular interaction
Journal of Computational Chemistry
1607
for the species that represent the complexes having single and
double hydrogen bonds and ion–molecular interactions ((H2O)2,
(HCOOH)2, and HCN. . .Liþ) suggests that the MP2 level of ab
initio theory is able to reproduce accurately not only an enthalpy
of the intermolecular interaction but also the Gibbs free energy.
To reach such accuracy, the values of total energies should be
extrapolated to the CBS. Accuracy that is better than 1 kcal/mol
has been obtained using the vibrational frequencies calculated
within the harmonic approximation. It is also important to
emphasize that optimizations at the B3LYP/cc-pvtz level result
in virtually the same geometrical parameters as the one per-
formed at the MP2/cc-pvtz level. Therefore, we recommend the
geometry optimization at the B3LYP/cc-pvtz level followed by
single point MP2 calculations and extrapolation obtained total
energy to CBS value to obtain accurate thermodynamic parame-
ters for the systems of medium and large size.
We found that anharmonic contribution to the entropic and
thermal terms is small for three considered systems. Thus, it can
be safely neglected even for high accuracy calculation of ther-
modynamical parameters. This assumption, in principle, can be
extended to the all similar intermolecular system. However, to
generalize this conclusion one should study extensive set of
intermolecular complexes.
The interaction energy (De) and free energy change (DA) for
considered systems have been obtained from Car-Parrinello ab
initio MD simulations. We found that the accuracy of CPMD
simulations is lower than that of the data obtained at the MP2
level. The reason is, in our opinion, in utilizing the BLYP func-
tional, which is not capable of treating the intermolecular inter-
actions as accurately as does the MP2 theory.
Acknowledgments
We thank the Mississippi Center for Supercomputer Research
(MCSR) and Army High Performance Computer Research Cen-
ter (AHPCRC) for a generous allotment of computer time. We
thank Dr. Axel Kohlmeyer for useful suggestions and stimulat-
ing discussions concerning molecular dynamics. We also thank
Dr. David Close for reading the manuscript.
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