The stability and reactivity of activated acryloylcarbamates as reagents for the synthesis of N-1 substituted thymine and uracil - An NMR and DFT study

Article abstract of DOI:10.1002/poc.1775

The mechanism of the decomposition of acryloylcarbamates 7a-b yielding highly reactive isocyanates 3a-b was proposed based on NMR measurements and quantum chemical calculations. A good agreement between the experimental kinetic data and DFT calculations allowed us to demonstrate that the stability of 7a-d depends on the presence of methyl in the acryloyl moiety and the position of the nitro group in the nitrophenolic part of the molecule. Furthermore, the reactivity of 7a-d with weakly nucleophilic and sterically hindered 2,4,6-tri-tert-butylaniline was explored by ¹H NMR demonstrating the usefulness of reagents 7a-d offering access to a variety of 1-N-substituted uracils and thymines with potentially interesting biological properties. Copyright

Full text of DOI:10.1002/poc.1775

Research Article
Received: 22 January 2010,
Revised: 14 April 2010,
Accepted: 22 June 2010,
Published online in Wiley Online Library: 24 August 2010
(wileyonlinelibrary.com) DOI 10.1002/poc.1775
The stability and reactivity of activated
acryloylcarbamates as reagents for the
synthesis of N-1 substituted thymine and
uracil – an NMR and DFT study
a
a
a
*
ˇ
Radek Pohl , Lubomı´r Rulı´sek and Dominik Rejman
The mechanism of the decomposition of acryloylcarbamates 7a–b yielding highly reactive isocyanates 3a–b was
proposed based on NMR measurements and quantum chemical calculations. A good agreement between the
experimental kinetic data and DFT calculations allowed us to demonstrate that the stability of 7a–d depends on
the presence of methyl in the acryloyl moiety and the position of the nitro group in the nitrophenolic part of the molecule.
Furthermore, the reactivity of 7a–d with weakly nucleophilic and sterically hindered 2,4,6-tri-tert-butylaniline was
1
explored by H NMR demonstrating the usefulness of reagents 7a–d offering access to a variety of 1-N-substituted
uracils and thymines with potentially interesting biological properties. Copyright ß 2010 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.
Keywords: DFT; mechanism; NMR; nucleosidation; thymine; uracil
alternative approach to the pyrimidine nucleoside analogues (e.g.
INTRODUCTION
carbocyclic nucleosides), a synthesis of 1-N-substituted nucleo-
bases starting from a primary amine and isocyanates 3a–b or
carbamates 6a–b were described fifty years ago by Shaw and
Warrener.[16,17] The key isocyanates 3a–b, accessible through two
independent routes[18,19] (Scheme 1), were used as intermediates
Many biologically active compounds belong to the class of
nucleosides and nucleotides analogues, which play an important
role in anticancer therapy[1,2] or act as antiviral compounds.[3]
Specific examples also involve carbocyclic nucleosides[4,5]
(Carbovir1) and acyclic phosphonate nucleotides[6] (Viread,
Cidofovir, Tenofovir, Hepsera), which represent biologically
important compounds in which the nucleobase is not connected
via a glycosidic bond.
ˇ
for the synthesis of carbamates 6a–b described by Hrebabecky
´
et al.[20]
Isocyanates 3a–b are an unusually moisture-sensitive species
and also very reactive compounds, capable of forming carba-
mates with free hydroxy groups.[21] Therefore, the reaction is
usually carried out either with the appropriately protected
substrate or without protection at low temperature (<ꢀ20 8C).
This property seems to be the main factor responsible for the
varying yield of the reported uracil and thymine derivatives
(usually ꢁ20–80%, in most cases <60%) found in the lite-
rature.[22–33] The formation of uracil and thymine rings is a
two-stage reaction consisting of the aminolysis of carbamates
6a–b or the addition of amine to isocyanates 3a–b followed by a
cyclisation of the acryloylureas 9 formed (Scheme 2).[34]
Till date, there has not been any general, high-yield method
available for the attachment of uracil and thymine moieties to
From a synthetic point of view, a crucial step in their preparation
is the attachment of the nucleobase – the nucleosidation reaction.
The most common synthetic routes to purine nucleoside
analogues are represented by direct alkylation of the appropriate
nucleobases (adenine, 6-chloropurine or 2-amino-6-chloropurine)
with the halo, tosyloxy or mesyloxy derivatives in dipolar aprotic
solvents (DMF, DMSO) using cesium carbonate as a base.[7–9]
Alternatively, Mitsunobu reaction of 6-chloropurine or
2-amino-6-chloropurine with appropriate hydroxyderivative can
be used.[8,10,11] Recently, N-bis-Boc-protected[6] adenine was
successfully used as a substrate for the Mitsunobu reaction
during the synthesis of neplanocin A.[12] However, all of these
methods for the introduction of pyrimidine nucleobases (uracil,
thymine and cytosine) suffer from both low regioselectivity and
low yield of the 1-N-substituted product. The direct alkylation of
nucleobases is usually accompanied by a competing elimination
reaction, which further decreases the yield of the desired pro-
duct.[8,9] Some improvement (both in regioselectivity and overall
yield) can be obtained through the use of 2,4-dimethoxy-
pyrimidine or 2,4-dimethoxy-6-methylpyrimidine for the alky-
lation instead of uracil or thymine, respectively.[13–15] As an
*
Correspondence to: D. Rejman, Institute of Organic Chemistry and Biochem-
´
istry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czech Republic.
E-mail: rejman@uochb.cas.cz
ˇ
R. Pohl, L. Rul´ısek, D. Rejman
Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo
a
´
nam. 2, 166 10 Prague 6, Czech Republic
J. Phys. Org. Chem. 2011, 24 423–430
Copyright ß 2010 John Wiley & Sons, Ltd.

´ˇ
R. POHL, L. RULISEK AND D. REJMAN
Scheme 2. The reaction of reagents 3, 6 and 7 with amines and
subsequent cyclisation providing 1-N-substituted pyrimidines
Scheme 1. The reagents for the preparation of 1-N-substituted pyrimi-
dine nucleobases
sterically hindered secondary, tertiary or even aromatic carbon
atoms.
sterically hindered 2,4,6-tri-tert-butylaniline to ensure that decom-
position of 7a–b does not limit their synthetic usage in pre-
paration of N-1 substituted thymines and uracils. These findings
represent a useful and successful conjunction of theoretical and
experimental efforts extending our understanding of the organic
reactions pertinent to this class of compounds.
It was the extreme reactivity and moisture sensitivity of
isocyanates 3 on the one hand and the low yields of 9 obtained
using carbamates 6 on the other that prompted us to develop
more advantageous reagents 7, which proved to be reactive
enough with a variety of amines. Moreover, they can be stored for
longer time (several months in refrigerator), which enabled us to
use them in modular syntheses of uracils and thymines 10.[35] The
synthesis of the reagents 7a–d followed the procedure described
for 6,[20] in whose last step of the ‘one-pot’ synthesis, a 2- or
4-nitrophenol solution in dioxane was added instead of ethanol.
The reagents 7a–d were tested in reactions with a wide variety
of amines (including those bonded to secondary, tertiary and
aromatic systems), giving consistently high yields of correspond-
ing 1,3-disubstituted urea derivatives. The desired uracil and
thymine derivatives were obtained by the cyclisation of the urea
intermediates using Dowex 50 in Hþ form, providing again very
high yields.[35]
RESULTS AND DISCUSSION
Kinetics of decomposition studied by NMR
Reagents 7a–d were prepared according Scheme 1 and fully
characterised by 1H and 13C NMR, elemental analysis, IR and MS.
In the course of the NMR characterisation of 7b, we found
that the reagent decomposes, yielding a complex mixture. The
1H NMR spectrum of 7b recorded in commercial grade CDCl3
(refer Supporting Information) showed a mixture of at least four
compounds identified as 3-ethoxy-2-methylacryloylcarbamic
acid (as the product of reagent hydrolysis), 3-ethoxy-2-methyl-
acryloylamide (i.e. the product of the decarboxylation of the
former compound), 2-nitrophenol and reagent 7b (Scheme 3).
To rule out the effect of water, which might be present in
regular CDCl3, the 1H NMR spectra were recorded in dried CDCl3
and a sealed NMR tube (refer Experimental section). The
experiment has again shown the decomposition of compound
7b, and the final products of decomposition were identified
as acryloylisocyanate 3b and 2-nitrophenol. Reagent 7b was
In this work, we wish to address an unprecedented decom-
1
position of the reagent 7b in CDCl3 solution observed in the H
NMR measurements, to analyse and quantitatively characterise
the reaction mechanism of the decomposition reaction. To this
end, we conducted a series of NMR experiments to yield reliable
kinetic data and a series of DFT calculations to provide a plausible
mechanistic view of the studied reaction. In order to understand
the reaction mechanism in detail, we have compared the experi-
mental data with other reagents 7a, 7c and 7d. We have also
investigated the reaction of 7a–d with low nucleophilic and
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J. Phys. Org. Chem. 2011, 24 423–430

STABILITY AND REACTIVITY OF ACTIVATED ACRYLOYLCARBAMATES
performed for the other reagents, 7a, 7c and 7d, and the results
have been summarised in Table 1. The decomposition of 7a was
reversible reaction with first order kinetics (Table 1 and Sup-
porting Information), while compounds 7c and 7d were stable
and did not decompose at all.
As arises from Table 1, the kinetic measurements demonstrate
a surprisingly strong dependence on the reagents and their
structure. Reagents 7c and 7d (possessing a nitro group in the
para position) do not undergo any degradation. On the other
hand, the derivatives with the ortho-nitro group in nitrophenol
moiety decompose readily, with the decomposition of the
7b-bearing methyl group in the acryloyl part of the molecule
being approximately fifty times faster than the decomposition of
the 7a-lacking methyl substituent. The different stability of the
reaction products reflected in the molecular structure was further
explored by DFT calculations.
Scheme 3. The decomposition of 7b via hydrolysis and decarboxylation
Reaction mechanism of decomposition. Theoretical
calculations
Scheme 4. The chemical proof of 3b structure
We first optimised all 16 planar geometries for each of 7a–d, viz.
all the possible arrangements of four double or partial double
bonds in the system (64 molecular geometries in total) at the
DFT(PBE)/def2-SVP level with the single-point energy calculated
at the DFT(B3LYP)/def2-TZVP level. The solvation effect, zero-
point energy, and contribution to the enthalpy and entropy
(using the ideal gas approximation) were included as well (for
details, refer Experimental section). The results of this extensive
conformational search are summarised in Tables S1–S5 (refer
Supporting Information). As can be seen in Tables S1–S4, the
characterised by NMR only when a high concentration of sample
and a short measurement time were applied.
To ascertain that acryloylisocyanate 3b is the decomposition
product, we allowed the decomposed mixture to react with dry
methanol, yielding methyl ester 12, i.e. the same product as that
formed through the reaction of 7b with methanol in the presence
of Et3N (Scheme 4). In addition, isocyanate 3b was identified by
IR measured in dry CHCl3 (the characteristic band being at
2244 cmꢀ1 for asymmetric stretching vibrations of the —NCO
group) and by 13C NMR (with the characteristic chemical shift of
—NCO carbon at 130.47 ppm).
The rate of decomposition was estimated based on the 1H NMR
kinetic measurement in dry CDCl3 and sealed NMR tube at 25 8C.
The concentrations of starting compounds and decomposition
product(s) were obtained by integration of several corresponding
signals with similar relaxation times. The rate constant for the
irreversible first order kinetic model was obtained from plots of
the logarithm of the starting compound concentrations versus
time, while rate constant for the reversible first order kinetic
model was obtained from plots of the logarithm of the starting
compound concentrations minus equilibrium concentration
versus time and from equilibrium constant. Experimental data
for decomposition of 7b fitted irreversible reaction with first
order kinetics (Table 1 and Supporting Information) with half-
life (t1/2) of about 18 min. The kinetics measurements were also
calculations predict (in all cases) the most stable isomers to
—
possess trans-configuration on the —C C— double bond. This
—
fact has been corroborated experimentally by a missing NOE
interaction between the Me group and the proton on the double
bond for 7a–b or by a missing NOE between the protons of the
double bond for 7c–d. At the same time we observed NOE
between protons of CH2 group from EtO and H or CH3 on double
bond in alpha position to CO.
With regard to the proposed reaction mechanism, we have also
investigated the possible isomers with the proton on either of the
oxygens adjacent to the central —NH— group (these calcu-
lations were carried out only for the most stable isomers). The
results are also listed in Tables S1–S4 (including various terms in
overall Gibbs energies), and all 24 structures of 7b (assuming an
—
E configuration on the —C C— double bond) have been
—
schematically depicted in Fig. 1.
The calculations have shown that the 2NH-ZZZ conformer is
the most stable structure for the keto-tautomer of 7b whereas
1
Table 1. The kinetics of 7a–d degradation monitored by H NMR
Degradation
Reaction
Kinetics
k (hꢀ1
)
t1/2 (h)
7a
7b
7c
7d
Reversible
Irreversible
No degradation observed
No degradation observed
First-order
First-order
3.00 ꢂ 10ꢀ2(a)
23.1
0.30
2.32
(a) k ¼ 1.83 k .
þ
ꢀ
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´ˇ
R. POHL, L. RULISEK AND D. REJMAN
Figure 1. The planar geometries of E-7b investigated by density functional theory calculations
3OH-ZZE is the lowest energy enol-form of the same compound. It
can be noted that 3OH-ZZE geometry is nicely preorganised to
form a six-membered transition state with bifurcated hydrogen
bonding.
of degradation shown in Scheme 5. It can be mentioned that all
saddle points are characterised by a single imaginary frequency
corresponding to the reactive coordinate and are therefore true
transition states for the studied reactions. By small changes of the
geometry in the direction of reactant and product we ascertained
that it connects the desired reactant and products structures
(IRC-like calculation). A more complete listing of the calculated
values of activation barriers can be found in Tables S1–S4.
Furthermore, the reaction coordinate with the structures of all
the key points on the potential energy surface is depicted in
Fig. 2.
As mentioned above, the transition state is characterised by
the six-membered ring arrangement and is structurally close to
the enol-form with activation barriers of 72–88 kJ molꢀ1 (Table 2).
We have also investigated an alternative pathway starting from
the more stable keto-form and involving the direct hydrogen
However, a rather surprising finding is the relatively small
difference in energies between all the studied isomers. Consi-
dering the planar models depicted in Fig. 1, some of the struc-
tures would have been expected to have substantial intramo-
lecular crowding. Even for such structures (e.g. 2NH-ZEE, 2NH-EEE)
the energy or free energy differences amount to only ꢁ15–
25 kJ molꢀ1. This demonstrates a relatively high level of flexibility
in the studied molecules (the systems avoid crowding by adop-
ting a helical form). Thus, we had to consider several reaction
pathways for the elimination reaction. The lowest saddle points
and their energies are summarised in Table 2 for all studied
compounds (7a–7d) and for the proposed reaction mechanism
Table 2. The theoretical calculations of reaction free energies and activation barriers carried out using the B3LYP/def2-TZVP//
RI-PBE/def2-SVP method
Degradation
DGcalc (kJ molꢀ1
)
DGz
(kJ molꢀ1
)
kexp(sꢀ1
)
DGz (kJ molꢀ1
)
calc
exp
7a
7b
7c
7d
ꢀ24.6
ꢀ30.2
ꢀ3.9
84.1
72.0
88.4
79.1
8.33 ꢂ 10ꢀ6
6.44 ꢂ 10ꢀ4
102.0
91.2
—
—
—
ꢀ15.1
—
The solvation effects were included through COSMO calculations and the energies corrected for zero-point energies, thermal
corrections to enthalpy and entropic terms (using ideal gas approximation) to obtain free energy estimates. The experimental data
are shown in the right part of the table (DGz were calculated using Eyring equation (in SI units): DGz ¼ RT[23.76 ꢀ ln(k/T)]).
exp
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STABILITY AND REACTIVITY OF ACTIVATED ACRYLOYLCARBAMATES
Scheme 5. The degradation of 7b – a proposed mechanism
transfer from the nitrogen atom to the oxygen atom of the
nitrophenol ring. The activation barrier involving a four-mem-
scope of this work (for a thorough discussion on the subject,
we refer the reader to Reference [36]), we mostly want to highlight
the excellent agreement in the relative difference between the
two reactions (7a, 7b) for which the comparison is available.
bered transition state was considerably higher (ꢁ160–180 kJ molꢀ1
,
refer Tables S1, S3, S4) for the 2NH-EEZ isomer (which has the most
favourable arrangement of the atoms and highest thermodyn-
amic stability of the reactants). This clearly favours the pathways
involving the six-membered transition states described above.
As arises from Table 2, the presence of the ortho-nitro group
plays an important role in the bifurcated hydrogen bond and
lowers the free enthalpy of degradation DGcalc. On the other
DDGz ¼ 10.8 kJ molꢀ1, whereas DDGz ¼ 12.1 kJ molꢀ1
.
exp
calc
NMR characterisation of the reactivity of 7a–d towards
amines
In our previous work,[35] we showed that reagents 7a,b react with
a variety of amines, including acyclic, cyclic, and aromatic, and
also amino acids. All of the reactions were completed within one
hour at room temperature. Nevertheless, the reaction kinetics
were not addressed in detail. Herein, the reactivity of 7a–d with
low nucleophilic and sterically hindered 2,4,6-tri-tert-butylaniline
is presented (Scheme 6).
—
hand, the methyl group on the —C C— double bond lowers
—
the free energy of activation, DGzcalc, likely due to the effect
of hyperconjugation. The computational results are in good
agreement with the experimentally calculated DGzexp computed
from the rate constants using Eyring equation. Since the accurate
ab initio determination of the absolute rate constant is beyond the
The kinetic measurements were performed in dry CDCl3 at
25 8C and monitored by 1H NMR. The concentrations of starting
compounds and products were obtained by integration of
several corresponding signals with similar relaxation times (for
example CH3 on double bond in 7b and 11b). The rate constants
were obtained from plots of the logarithm of the starting
compound concentrations versus time. Obtained data fitted
first order kinetics and the results of the measurements are
summarised in Table 3. The kinetic data show relatively high
difference in reaction rates that might be explained by observed
decomposition described above. Similar reaction rates for 7c–d
confirm the finding that these compounds do not decompose
and reaction with amine can be viewed as aminolysis of 4-
nitrophenyl ester. On the other hand, very fast reaction rate for 7b
corresponds with decomposition of the compound and can be
therefore assumed that 2,4,6-tri-tert-butylaniline reacts with
isocyanate 3b formed in course of the decomposition 7b. The
Figure 2. The reaction coordinate for the degradation of E-7b
J. Phys. Org. Chem. 2011, 24 423–430
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´ˇ
R. POHL, L. RULISEK AND D. REJMAN
Table 3. The kinetics of the reaction of the reagents 7a–d
with 2,4,6-tri-tert-butylaniline in dry CDCL3 at 25 8C.
Reagent
k (hꢀ1
)
t1/2 (h)
7a
7b
7c
7d
2.7 ꢂ 10ꢀ2
1.2
25.7
0.6
9.4
2.6
7.4 ꢂ 10ꢀ2
2.7 ꢂ 10ꢀ1
aromatic amines, which offers access to a variety of 1-N-
substituted uracils and thymines with potentially interesting
biological properties.
CONCLUSIONS
It has been shown that the studied reagents 7a–d are highly
reactive even with low-nucleophilic and sterically hindered
amines and can be successfully applied for a modular synthesis of
various 1-N-substituted uracils and thymines, which is difficult to
achieve with other synthetic methods. The stability of reagents
7a–d in dry CDCl3 was investigated by experimental and
theoretical methods. It has been proved that the decomposition
of the studied molecules is strongly affected by the presence of
—
the Me-group on the —C C— double bond and the position of
—
the nitro group on the phenol ring. While the former is assumed
to lower the activation barrier of the reaction probably due to
hyperconjugation, the latter plays a role in hydrogen bonding
and influences the thermodynamics of the reaction. The exp-
erimental NMR observations are in good agreement with the
results predicted by the DFT calculations, which allowed us to
postulate a plausible reaction mechanism, presumably extending
our understanding of the reactivity and stability of this class of
compounds. It should be noted here that all the reagents are
stable enough in the solid state to be stored for a long time.
Moreover, the decomposition of the 2-nitrophenyl derivatives 7a
and 7b yields an isocyanate product that could react in the same
manner as the parent reagents. These compounds could be seen
as an ‘instant form’ of the previously described isocyanates 3a–b.
EXPERIMENTAL SECTION
NMR experiments
NMR spectra were acquired on a Bruker Avance 500 spectrometer
(500.0 MHz for 1H and 125.7 MHz for 13C) in dry CDCl3. CDCl3
was dried prior to use by anhydrous K2CO3 and distilled. The
measurements were performed in an oven-dried NMR tube,
which was sealed after sample preparation. The concentration of
the samples was 38 and 40 mM for the degradation kinetics and
kinetics of reaction with amines, respectively. All of the kinetic
measurements were performed at 25 8C. Temperature calibration
Scheme 6. The reaction of 7a–d with 2,4,6-tri-tert-butylaniline
only anomaly is reactivity of 2,4,6-tri-tert-butylaniline with 7a. In
this case the amine probably reacts either with acryloylcarba-
mate 7a or with its decomposition product 3b and overall
reaction rate is indeed anomalous. The reaction was complete for
all the studied reagents, providing substituted acryloylureas as
products. The results of the kinetics show that novel reagents
7a–d are capable of reaction even with sterically hindered
1
was done using the standard method with a MeOH sample. H
and 13C resonances were assigned based on PFG H,C-HSQC and
H,C-HMBC experiments (for numbering refer Supporting Infor-
mation). 1H and 13C NMR of compounds 7a–d have been already
reported.[35]
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STABILITY AND REACTIVITY OF ACTIVATED ACRYLOYLCARBAMATES
Computational details
123.04 (C-30,50); 129.30 (C-10); 147.97 (C-20,60); 149.53 (C-40); 154.33
(C-2); 158.71 (C-6); 169.64 (C-4).HR-MS for C25H41N2O3 (M þ H)þ
calcd 417.3112, found 417.3111.
All the density functional theory (DFT) calculations reported in
the study were carried out using the Turbomole 6.0 program.[37]
The Perdew–Burke–Ernzerhof (PBE)[38] and hybrid three-para-
[39–42]
´
meter Beckes
(B3LYP) functionals were used throughout.
Methyl (E)-3-ethoxy-2-methylacryloylcarbamate (12)
The calculations were expedited by expanding the Coulomb
integrals in an auxiliary basis set, the resolution-of-identity (RI-J)
approximation.[43,44] All the geometry optimisations were con-
ducted using the def2-SVP basis set,[45,46] whereas the single-
point energies were recomputed in the def2-TZVP (triple-zeta
valence with two polarisation functions on each atom).[47]
To account for the solvation effects, the conductor-like
screening model (COSMO) method[45–48] was used with the
dielectric constant corresponding to chloroform (er ¼ 4.9). In order
to account for dispersion, we used the DFT þ D method (i.e. the
DFT method with the empirical dispersion terms) available in
Turbomole 6.0.[49] The Gibbs free energy was then calculated as
the sum of these contributions:
1H NMR (CDCl3, 500.0 MHz): 1.33 t, 3H, J(CH3,CH2) ¼ 7.1
(CH3CH2O); 1.83 d, 3H, J(CH3,6) ¼ 1.2 (5-CH3); 3.79 s, 3H (CH3O);
4.08 q, 2H, J(CH2,CH3) ¼ 7.1 (OCH2CH3); 7.42 q, 1H, J(6,CH3) ¼ 1.2
(H-6); 7.79 bs, 1H (H-3). 13C NMR (CDCl3, 125.7 MHz): 9.07 (5-CH3);
15.26 (CH3CH2O); 52.72 (CH3O); 70.12 (OCH2CH3); 107.09 (C-5);
151.93 (C-2); 157.59 (C-6); 165.97 (C-4).HR-MS for C8H13NO4Na
(M þ H þ Na)þ calcd 210.0742, found 210.0741.
Acknowledgements
The authors gratefully acknowledge the financial support by the
Ministry of Education, Youth, and Sports of the Czech Republic
(Research projects Z40550506, 2B06065, and LC512) and the
Ministry of Health (Grant NR/9138 – 3).
G ¼ Eel þ Gsolv þ EZPE ꢀ RT lnðqtrans qrot qvibÞ;
where Eel is the in vacuo energy of the system (at the B3LYP/
def2-TZVP level and the geometry optimised at the RI-PBE/
def2-SVP level), Gsolv is the solvation free energy (at the RI-PBE/
def2-SVP level), EZPE is the zero-point energy and ꢀRT ln(qtrans qrot
qvib) accounts for the entropic terms and the thermal correction
to the enthalpy obtained from a frequency calculation using the
same method and software as for the geometry optimisation at
the RI-PBE/def2-SV(P) level, 298 K, and 1 atm using the ideal-gas
approximation.[50]
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