Insight into and Computational Studies of the Selective Synthesis of 6H-Dibenzo[b,h]xanthenes

Article abstract of DOI:10.1021/acs.joc.6b00864

Starting from 2-hydroxy-1,4-naphthoquinone (lawsone), we synthesized eight new 6H-dibenzo[b,h]xanthene derivatives selectively under solvent-free conditions. Spectroscopic investigations confirmed that only the isomer 6H-dibenzo[b,h]xanthene was obtained

Full text of DOI:10.1021/acs.joc.6b00864

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Article
Insight and Computational Studies on the
Selective Synthesis of 6H-dibenzo[b,h]xanthenes
Paula F. Carneiro, Maria do Carmo F. R. Pinto, Roberta K. F. Marra, Vinicius R.
Campos, JACKSON A. L. C. RESENDE, Maicon Delarmelina, José Walkimar M.
Carneiro, Emerson Silva Lima, Fernando de Carvalho da Silva, and Vitor F. Ferreira
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00864 • Publication Date (Web): 09 Jun 2016
Downloaded from http://pubs.acs.org on June 14, 2016
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Insight and Computational Studies on the Selective Synthesis of 6H-dibenzo[b,h]xanthenes
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Paula F. Carneiro,† Maria do Carmo F. R. Pinto,† Roberta K. F. Marra,‡ Vinícius R. Campos,‡
Jackson Antônio L. C. Resende,‡ Maicon Delarmelina,‡ José Walkimar M. Carneiro,‡ Emerson S.
Lima,§ Fernando de C. da Silva,‡ Vitor F. Ferreira*,‡
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†Universidade Federal do Rio de Janeiro, Instituto de Pesquisas de Produtos Naturais, 21944ꢀ970,
Rio de JaneiroꢀRJ, Brazil.
‡Universidade Federal Fluminense, Instituto de Química, 24020ꢀ150, NiteróiꢀRJ, Brazil.
§Universidade Federal do Amazonas, Faculdade de Ciências da Saúde, 69010ꢀ300, Manaus, AM,
Brazil.
GRAPHICAL ABSTRACT
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Abstract: Starting from 2ꢀhydroxyꢀ1,4ꢀnaphthoquinone (lawsone), eight new 6Hꢀ
dibenzo[b,h]xanthene derivatives were synthesized selectively under solventꢀfree conditions.
Spectroscopic investigations confirmed that only the isomer 6Hꢀdibenzo[b,h]xanthenes was obtained
in all eight cases. Computational studies provide a rationalization for the selective appearance of
these isomers having as intermediate an addition product.
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Keywords: Naphthoquinone, xanthene, benzoxanthene, dibenzo[b,h]xanthene.
INTRODUCTION
9HꢀXanthene (1, Figure 1) is a general class of natural and synthetic heterocyclic
compounds1ꢀ3 with many biological applications in addition to functionality as fluorescent dyes.4 In
the biological field, these heterocyclic compounds exhibit a broad spectrum of activities, including
trypanothione reductase inhibiting,5 antiviral,6 antibacterial,7,8 antiplasmodial,9,10 antiꢀmalarial,11
antiꢀfungal,12 antiꢀinflammatory,13 anticancer,14ꢀ17 and antihypertensive18 activity as well as use in
photodynamic therapy.19 Due to their biological properties, 9Hꢀxanthene derivatives have been
prepared by several procedures.20ꢀ23
The biological activity of quinones24 against several biological targets has shown that the
activities of these molecules are due to their ability to accept one or two electrons in the soꢀcalled
redox cycle to form an anion or dianion in situ that is known as a reactive oxygen species (ROS).25,26
Thus, the semiꢀquinone radicals can improve the conditions for intracellular hypoxia by producing
superoxide anions.27ꢀ30 Through this mechanism, quinones are cytotoxic to both normal and tumor
cells in mammals as well as to various microorganisms, ultimately leading to programmed cell death
(apoptosis).31,32
Several procedures have been described for the preparation of type 1 xanthenes (Figure 1),
most of them based on a twoꢀ or threeꢀcomponent reaction of βꢀnaphthol with aldehydes.33ꢀ44 When
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naphthoquinones are fused to the xanthenes, two subꢀclasses of products may be produced, which
have also been prepared by several synthetic methods (Figure 1): benzoxanthenes with one
naphthoquinone moiety, represented by compound 2 and its isomer 3 and compound 4 and its isomer
5,45ꢀ52 and dibenzoxanthenes with two naphthoquinone moieties attached to the central pyran ring,
which can have 3 possible isomers 6, 7 and 8. Tisseh et al.53 were the first to report a simple and
efficient method for the preparation of dibenzoxanthene derivatives under solventꢀfree conditions (pꢀ
toluenesulfonic acid 10 mol%), which they assumed to be the [b,i]ꢀisomers, but the products suffered
from very poor spectroscopic characterization.53 The 1H NMR (DMSOꢀd6) for 6 (Ar = Ph) reported
all the aromatic signals as one broad signal, δ 7.16ꢀ8.08 (13H) ppm. After this publication, further
studies referred to these results and reported the same symmetrical structure 6.44,54ꢀ62 Despite the
several methods described in the literature for preparing dibenzoxanthene 6 (dibenzo[b,i]xanthene),
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the corresponding synthesis of dibenzoxanthenes of types 7 (dibenzo[b,h]xanthene) and
(dibenzo[c,h]xanthene) has not yet been reported.
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According to the literature, the formation of dibenzoxanthenes starts by the addition of
lawsone to the appropriate aldehydes, yielding an intermediate oꢀquinone methide that reacts further
with another molecule of lawsone to afford the corresponding open adduct 9,63 which upon
cyclization can form the isomeric compounds 6, 7 or 8. Mathieson and Thomson described the
formation of three possible isomers when they attempted to cyclize an open ring adduct of lawsone
and acetaldehyde.64 Based on the observation of 3 carbonyl bands in the infrared spectrum, they
believed that they obtained the dibenzoxanthene type 7. Since then, most of the reports in the
literature describe that the reactions of lawsone and aldehydes65 under acidic catalysis with and
without solvents forms exclusively or in high yields dibenzo[b,i]xanthene isomers of type 6.
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Figure 1. General structures of xanthenes, benzoxanthenes and dibenzoxanthenes
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In this work, we study a series of reaction conditions in the hope of optimizing the formation
of each of these dibenzoxanthene isomers.
RESULTS AND DISCUSSION
Reactions for preparing benzoxanthenes of type 6 (paraꢀpara isomer) have been reported in
solvents using acid catalysis with solvents or solventꢀfree condition. Our synthetic study toward
compounds 6 was initiated by reacting lawsone with benzaldehyde in ethanol/water (1:1) under
reflux (Scheme 1). It was observed that the reaction led to the formation of a yellow precipitate in the
reaction flask that was filtered and stored in a desiccator with phosphorus pentoxide to remove the
residual water. The solid was obtained in 83 % yield, and its structure was elucidated by
spectroscopic techniques. Hydroxyl bands were observed in the infrared spectra, indicating that the
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structure is the open bis(2ꢀhydroxynaphthaleneꢀ1,4ꢀdione) (9a, R = Ph). To confirm the structures of
the compound, a reaction described by Tisseh and Bazgir66 was performed by running the same
reaction in the presence of a catalytic amount of LiCl in aqueous media. The same compound 9a was
obtained in 87 % yield. Our product was compared with the one obtained in reference 66: mp 201
(lit. 202ꢀ204 °C); hydroxyl and carbonyl bands in the IR spectrum at 3335 (lit. 3332 cmꢀ1) and 1641
(lit. 1669 cmꢀ1); and a methine proton at δ 6.25 ppm (lit. δ 6.00 ppm). Despite little difference
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between the carbonyl (Cꢀ1 and Cꢀ4) absorption bands in the infrared spectrum 9a, the H NMR
spectrum show the structure is symmetrical. All these data indicate that compound 9a was obtained
in the reactions in both ethanol/water (1:1) and water/LiCl. Additionally, compound 9a was fully
methylated by treatment with Me2SO4/K2CO3, producing compound 10a (Scheme 1).
Scheme 1. General synthetic routes used in this study
Because there are several reports showing that this reaction can be performed without
solvent, producing compounds of type 6 in good yields, we decided to perform the reaction of
lawsone with benzaldehyde in the presence of a catalytic amount of pꢀtoluenesulfonic acid at 80 °C.
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These are the same conditions used by Bazgir et al.62 The solid ground mixture was heated in a preꢀ
heated oven for 6ꢀ7 hours, and a deep red product was isolated in 79 % yield.
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The IR spectra of the red product did not indicate the presence of a hydroxyl group as in
compound 9a, and its m.p. (277ꢀ280 ºC) was much lower than those of the isomers of type 6 (R1, R2,
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R3 = H, 305ꢀ307 ºC53,62) reported in the literature. The 1H NMR and Hꢀ1H COSY in CDCl3 of the
product were quite different from the data reported for compounds of type 6, showing three sets of
signals: pꢀquinone, oꢀquinone and phenyl ring. These unsymmetrical signals of the aromatic region
also eliminate the possibility of the red compound being an isomer of type 8 (orthoꢀortho). The
methine proton (Hꢀ7) in 1H NMR was at δ 5.37 ppm, lower than that of 9a (δ 6.25 ppm) and higher
than that of 6 (δ 5.09 ppm53,62). Similarly, the 13C NMR showed many more signals than expected for
a symmetrical structure like 6 and two different signals at 156.1 and 148.5 ppm for the sp2 carbons
bonded to the oxygen of the pyran ring. The complete and unambiguous assignment of hydrogens for
structure 7a was based on the analysis of the multiplicity patterns of proton resonances and also on
the use of a homonuclear 1Hꢀ1H COSY spectrum (Figure 2) that showed all the hydrogens correlated
to the orthoꢀpara quinone. We described the hydrogens of the orthoꢀquinone side as δ 8.14 (dd, J 7.8
and 1.0 Hz, 1H, Hꢀ1); 7.63 (dt, J 7.8 and 1.0 Hz, 1H, Hꢀ2); 7.83 (dt, J 7.8 and 1.0 Hz, 1H, Hꢀ3) and
8.27 (dd, J 7.8 and 1.0 Hz, 1H, Hꢀ4). For the paraꢀquinone side, we observed δ 7.74ꢀ7.79 (m, 2H, Hꢀ
10 and Hꢀ11); 8.04ꢀ8.06 (m, 1H, Hꢀ12); and 8.19ꢀ8.21 (m, 1H, Hꢀ9).
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Figure 2. 1H-1H Correlation Spectroscopy of 7a in CDCl3
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To confirm the structure of 7a, we decided to prepare an oꢀphenylenediamine derivative
(Scheme 2). This reagent reacts only via its orthoꢀquinone moiety. The adduct 11a was obtained in
good yield and recrystallized in a mix of hexane and dichloromethane, providing suitable crystals for
the Xꢀray crystallography study. The structure of substance 11a was confirmed by Xꢀray diffraction
(Figure 3), which confirms the pattern of orthoꢀ and paraꢀnaphthoquinone for 7a. The phenyl ring is
oriented nearly perpendicular to the ring plane in benzoxanthenes.
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Scheme 2. Phenazine 11a derivative from ortho- and para-naphthoquinone for 7a
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O
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AcONa/AcOH
NH2
O
N
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O
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N
O
NH2
7a
11a
, 75%
Figure 3. ORTEP diagram of compound 11a showing 50% probability ellipsoids. Hydrogen,
carbon, nitrogen and oxygen atoms are represented in white, gray, blue and red, respectively
The reaction between lawsone and other aldehydes was tested for eight examples, and the
produced 6Hꢀdibenzo[b,h]xanthenes 7a-h were obtained in high yields (Scheme 3). Depending on
the reactivity of the aldehyde, the reaction takes 6ꢀ7 h to complete. Liquid aldehydes at 80 °C reacted
quickly. For the best performance of this methodology, the temperature must be approximately 80
°C, because by increasing the temperature to 100 °C, the yield decreases dramatically, and when the
temperature exceeds 120 °C, there is complete degradation of the starting material and the product.
An example of this is that substance 7h at 80 °C has a yield of 72 %, while at 100 °C it is 19 %, and
above 120 °C, it is not possible to isolate the product. All compounds had the same spectroscopic
characteristics as derivative 7a (see supporting information).
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Scheme 3. Optimized conditions to prepare 6H-dibenzo[b,h]xanthenes (7a-h)
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To test if compound 9a is the intermediate for 7a, we attempted to cyclize it under several
conditions such as with H2SO4 (concentrated) and
pꢀtoluenesulfonic acid without solvent (80 °C). In
all cases, the 6 ꢀdibenzo[b,h]xanthene (7a) was formed.
H
These data contradict what is reported in the literature.53,62,66 Therefore, we decided to conduct
a computational study to understand the mechanism involved in this reaction and further corroborate
the results.
The xanthene derivatives can be obtained after the in situ formation of the quinone methide
and the subsequent cycloaddition reaction with a second lawsone molecule.67 A proposed mechanism
for the quinone methide formation in a protic media is shown in Scheme 4. After the nucleophilic
attack of lawsone to the protonated aldehyde 12, followed by water elimination, the quinone
methides 16 and 17 may be formed by protonation/deprotonation in an acidꢀbase equilibrium.
The reaction mixture can be described as a protic media even when an aprotic solvent is used,
as lawsone itself has some acidic character and may dissociate into lawsonate and hydronium ions in
the presence of a weak base.
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Scheme 4. Quinone methide formation in protic medium
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H
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OH
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H
O
12
Lawsone
Protic media
O
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+H+/-H+
+H+/-H+
-H2O
OH
OH
OH
H
H
-H2O
OH
H
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O
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O
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O
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O
H
-H+
OH
H
OH
or
or
H
H
+H+
O
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Water elimination from 13 affords the quinone methides as
Eꢀ (14) or Zꢀisomers (15). The
dehydration process is not reversible, and an isomer interconversion equilibrium will not be observed
during the subsequent cycloaddition reaction with lawsone. The computation of the relative
stabilities of the two isomers shows that the
Zꢀisomer (15 and 17) is the most stable, but by less than
1.0 kcal molꢀ1 (See Supplementary Information, Table S1). Due to this small energy difference
between the
E and Z isomers, both were investigated in the following computations.
The next point we investigated was the reaction between the quinone methides and the second
lawsone molecule, which may happen by either an addition reaction or an asynchronous
cycloaddition. Due to the asymmetric nature of these molecules, at least sixteen distinct transition
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structures for the reaction between lawsone and quinone methides 16 and 17 may be predicted,
depending on the different arrangements for approximation between the two reactants (18ꢀ25, Figure
4). A clear picture emerges from preliminary gas phase calculations. When the lawsone approaches
the quinone methides in an orientation where the carbon atom bearing the hydroxyl group of lawsone
(C2) forms a carbonꢀcarbon bond with the substituted carbon atom (C11) of the quinone methides
(arrangements 18, 20, 23 and 25, Figure 4), the relative activation energies of the corresponding
transition structures are much higher than those computed when the approach occurs in the opposite
way (structures 19, 21, 22 and 24, Figure 4). These results lead us to exclude these alternatives from
the following discussion. Additionally, for all examples we computed, transition structures in an
endo orientation have lower relative energies than the corresponding ones in an exo orientation,
although in these cases, the energy differences between two isomers differing only in the endo or exo
orientation are much lower.
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Figure 4. Gas phase relative Gibbs free energy for possible transition structures for the
reaction between lawsone and the quinone methide E- (a) or Z-isomer (b). The values are the
relative Gibbs free energies in kcal mol-1, taking the 22,endo-TS structure as the reference.
Method: wb97xd/6-31+G(d,p)
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Among the structures with an endo orientation, structures 19 and 22, derived from the Eꢀ and
Z
ꢀquinone methide isomers, respectively, have the lowest relative energies. Therefore, we considered
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these two isomers (19 and 22) to compute the activation Gibbs free energy and the reaction Gibbs
free energy. In Figure 5, we provide results obtained from gas phase calculations (bold) as well as
those obtained with the Polarized Continuum Solvation Model (IEFPCM) (in parentheses) using
water as an implicit solvent.
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Figure 5. Activation and reaction Gibbs free energy for the reaction between quinone methides
(16 and 17) and lawsone. Gas phase (bold) and IEFPCM (in parentheses, solvent: water)
results are given. IC stands for initial complex, a stationary point formed by a loose complex
between the two reactants. Values are given in kcal mol-1 relative to the energy of the 22,endo-
IC initial complex. Method: wb97xd/6-31+G(d,p)
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All four arrangements lead to activation free energies (ꢁGⱡ) between 22 and 26 (20 and 23 in
the solvent) kcal molꢀ1, with the lowest value obtained for the 22,endo case. Intrinsic reaction
coordinate (IRC) calculations confirmed the connection between the reactants and the corresponding
intermediates 19 and 22. As indicated, the cyclic intermediates result from a DielsꢀAlder type
cycloaddition reaction, with the intermediate obtained from the 22,endo approach being the most
stable. Potential energy representations obtained from the IRC calculations are consistent with a oneꢀ
step oneꢀstage process for these reactions. The polar solvent water reduces the activation energy by
2ꢀ3 kcal molꢀ1 and leads to more polar transition structures typical of a twoꢀstage process.
The transition structures have a high degree of asynchronicity. The formation of the CꢀC bond
occurs in a much earlier stage than the formation of the CꢀO bond, resulting in much different CꢀC
and CꢀO bond distances in the transition structures. Figure 6 shows the relevant distances for each
isomer (19 and 22) obtained from geometry optimization in the gas phase. The CꢀC bond distances in
the transition state range from 1.94 to 2.05 Å, while the CꢀO bond distances range from 2.43 to 2.45
Å.
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Figure 6. Transition state structures for the formation of the intermediates 19 and 22 starting
from the deprotonated quinone methides 16 and 17. Distances are in Angstroms. Method:
wb97xd/6-31+G(d,p)
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An acidꢀbase equilibrium is involved in the in situ formation of the quinone methides (see
Scheme 3). As low activation energies are common in these prototropic equilibria, the protonated
forms of the quinone methides (14 and 15) could compete with the deprotonated forms (16 and 17)
and may also undergo addition/cycloaddition reaction in the presence of lawsone. To verify this
hypothesis, we reꢀperformed all the calculations using the protonated forms of the quinone methides
(14 and 15) in the 26-29 approach modes (Figure 7). As could be anticipated, the most basic site of
the quinone methides is the 1,2ꢀquinone moiety, with the proton sitting between the two carboxyl
groups. This is the form we adopted in all the calculations reported below. The ꢁGⱡ values for the
two possible mechanisms were compared.
Figure 7. Relative activation and reaction Gibbs free energy for the reaction of protonated
quinone methides (a - 14 and b - 15) with lawsone. Gas phase (bold) and IEFPCM (in
parentheses, solvent: water) results are given. All values are in kcal mol-1 and are given relative
to the 28,endo-IC initial complex. Method: wb97xd/6-31+G(d,p)
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The first point to call attention to is the considerable reduction in the activation energy. The
calculated ꢁGⱡ values for the reaction using the protonated quinone methides (Figure 7) are 10ꢀ16
kcal molꢀ1 lower than the corresponding activation energies for the reaction using the deprotonated
systems (Figure 5). Therefore, as the medium has at least the residual proton from the formation of
the quinone methide (see Scheme 3), the most probable reaction pathway in the second step of the
reaction surely involves one of the protonated forms of the quinone methides. Additionally, as the
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protonation of the 1,2ꢀquinone moiety of the quinone methide increases the electrophilicity of the
carbon atom Cꢀ11 (see insert in Figure 4), the reaction becomes still more asynchronous than the
corresponding reaction with the deprotonated form of the quinone methide, which, as commented
above, is already considerably asynchronous. This introduces a new alternative to the reaction
mechanism. For these highly asynchronous reactions, addition, instead of cycloaddition, may be
observed, in line with the experimental findings. The relative activation energies provided in Figure
7 show that the cycloaddition reaction is not always the less energetic process for the reaction of a
protonated quinone methide with lawsone. Therefore, the acidꢀbase equilibrium involving the
protonated forms of the quinone methides (14 and 15) provides a second pathway for the reaction.
As indicated in Figure 7, the nucleophilic approach of lawsone to the protonated quinone
methide (arrangements 27 and 28) may lead to the addition adduct 31, with an activation energy that
is at least competitive with that of the cycloaddition process. Indeed, the lowest activation energy
overall was found for the formation of the addition adduct 31. Depending on the orientation of some
CꢀH bonds, the optimization of 30 (Figure 8) results in intramolecular hydrogen transfer to directly
give the open species 31 and 9a, which are the same species that were experimentally characterized.
Of course, a similar hydrogen transfer may also be facilitated by any base present in the reaction
mixture. Transition structures to form a direct DielsꢀAlder intermediate could be located only when
approaching the lawsone on the deprotonated moiety of the quinone methide, although with
activation energies that are of the same magnitude or higher than those of the corresponding reaction
for the formation of the addition adduct.
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Figure 8. Formation of the open adduct 9a
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The orientation of the phenyl group of the quinone methide seems to have an important role in
the product formation when the lawsone nucleophile approaches the quinone methide. The
approximation of the lawsone over the phenyl ring of the
Zꢀisomer (15) resulted in the less energetic
pathway (28) and produced the open adduct 31. The ortho
ꢀparaꢀcycloaddition (26,endo) product
was obtained when the lawsone nucleophile approached over the phenyl group of the Eꢀisomer (14).
The quinone methides are electronꢀpoor dienes. In the presence of an electronꢀrich dienophile,
they may undergo an inverse electron demand DielsꢀAlder reaction.68 The electrophilicity of the
diene is increased by the electronꢀwithdrawing effect when the 1,2ꢀquinone moiety of the quinone
methide is protonated, increasing the polar interaction due to charge transfer from the dienophile to
the diene, with a corresponding decrease in the activation energy barrier.69,70 A low distortion energy
also contributes to the reduced activation free energy, as a highly polar DielsꢀAlder mechanism
demands a lower reactant distortion to form the transition state.71
For the systems studied in the present work, highly asynchronous transition states were
observed, changing from a concerted oneꢀstage mechanism to a twoꢀstage (26 and 29, Figure 7) or a
stepwise pathway (27 and 28, Figure 7). The latter is an extreme case where addition, with the
formation of an open adduct, instead of cyclization, is the main pathway. The high ability of the
protonated diene to stabilize the increasing electronic density due to the addition process resulted in a
stable intermediate that did not proceed further to cyclization72 Therefore, the whole spectrum of
possible alternatives may be included in a continuum of reaction paths, where one extreme is
represented by the fully synchronous symmetrical transition structures and the other is represented
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by the addition, a oneꢀstep reaction. Experimental design may modulate the necessary conditions
leading from one mechanism to the other, with a polar, ionic medium favoring the addition reaction.
Figure 9 shows the CꢀC and CꢀO bond distances in the transition structures leading to the open
adduct obtained from the protonated quinone methides in the 27 and 28 approach modes. As can be
seen, the two distances are sufficiently different, with the CꢀC bond distance always much shorter
than the CꢀO bond distance, justifying the stepwise pathway.
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Figure 9. Transition structures for the 27 and 28 approach modes from the protonated quinone
methide to lawsone. Bond distances are in Angstroms. Method: wb97xd/6-31+G(d,p)
To confirm the formation of the addition adduct in the protonated case, the final geometry
obtained in the IRC calculation was optimized. The open adduct (31) was obtained, rather than the
cycloaddition product, for the 27 and 28 approximation modes. Optimization using water as an
implicit solvent starting from the intermediate obtained in the IRC calculation of 29,exo-TS also
afforded the addition adduct 31, although the optimization in the gas phase of the same intermediate
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resulted in the cycloaddition product. The solvation effect can also contribute to the stabilization of
the partial transient negative charge in the transition state for the formation of the open adduct.
To completely reconcile the computational results with the experimental findings, we have to
9
consider the relative stabilities of the starting quinone methides. As discussed before, the Zꢀisomer
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(15) is the most stable one (See Supplementary Information, Table S1). Although isomer
interconversion equilibrium is not possible, this should be the preferable isomeric configuration for
the quinone methide obtained in situ during the reaction of lawsone with the aldehyde. Formation of
15 allows kinetic competition between processes 28 and 29 (Figure 7). The transition structure
28,endo-TS is preferable against 29,endo-TS by an energetic difference of 2.64 kcal molꢀ1 (1.73 kcal
molꢀ1 in water), affording the open adduct (31 and 9a, see Figure 8). This would result in the
exclusive formation of the open adduct 9a, in agreement with the experimental evidence.
The last step is the cyclization of the open adduct 9a to form the final cyclic xanthenes, which
is most easily performed in highly acidic conditions. The protonation of 9a results in 31 (Figure
10a), and the cyclization of 31 followed by dehydration forms the xanthene derivatives.
A proposed mechanism for the formation of the orthoꢀparaꢀxanthene (7a) from 31 is given in
Figure 10b. Protonated 31 undergoes intermolecular cyclization by the nucleophilic attack of the
deprotonated carboxyl group on the carbon atom containing the hydroxyl group in the protonated
naphthoquinone core. Dehydration follows after the protonation of the hydroxyl group and the
release of a water molecule, affording the xanthene derivative. A similar mechanism could, of
course, also be proposed for the formation of the orthoꢀorthoꢀxanthene (8) derivative. However, the
relative Gibbs free energy shows that species 7a is more stable than 8 by 5.81 kcal molꢀ1. Therefore,
the preferential formation of the ortho-para derivative is evident.
Figure 10. Enthalpy (plain in parentheses) and Gibbs free energy (bold in parentheses) changes
for the protonation of the open adduct 9 (a). Proposed cyclization mechanism for 31 in acidic
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media and relative enthalpy (plain) and Gibbs free energy (bold) of para-ortho 7a and ortho-
ortho-xanthene 8 derivatives (b). All values are in kcal mol-1. Method: wb97xd/6-31+G(d,p)
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The activation energy barriers for the intermolecular cyclization reaction of 31 (Figure 11) and
the reverse process range from 1.4 to 5.4 kcal molꢀ1. With these low activation barriers, the kinetic
control is not relevant, and the cyclization proceeds to the most stable products, consistent with the
experimental formation of the orthoꢀparaꢀxanthene derivative (7a).
Figure 11. Gibbs free energy change for the cyclization reaction of 31 in the gas phase. All
values are in kcal mol-1. The total Gibbs free energy of structure 31 was taken as zero. Method:
wb97xd/6-31+G(d,p)
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CONCLUSION
A new method for the synthesis of 6
was developed and used to synthesize a series of eight new 6
yields. This reaction explored in situ the generation of ꢀquinone methides via the Knoevenagel
H
ꢀdibenzo[b,h]xanthenes under solventꢀfree conditions
Hꢀdibenzo[b,h]xanthenes (7a-h) in good
o
condensation between lawsone and appropriate aldehydes followed by nucleophilic addition. The
reactions were evaluated under both conventional heating and microwave irradiation, but they
worked better under conventional heating conditions. The structure of 6
Hꢀdibenzo[b,h]xanthenes 7a
was confirmed by spectroscopic techniques and Xꢀray crystallography of the
o
ꢀphenylenediamine
derivative 11a, which indicated that under these experimental conditions, ortho
ꢀpara isomers were
formed.
The reaction mechanism may occur via an open intermediate obtained after the addition
reaction between the protonated ꢀquinone methide and a second lawsone molecule. This protonated
Z
species can be present in the reaction mixture due to the protonation/deprotonation equilibrium of the
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1,2ꢀquinone moiety during the in situ formation of the quinone methide. The calculated energy
barrier for the addition process is 10ꢀ16 kcal molꢀ1, lower than for the competitive process that would
directly afford the dibenzo[b,h]xanthene derivative. This stepwise pathway proceeds through a
highly asynchronous transition state characterized by highly polar interactions and low distortion
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energy. The 6Hꢀdibenzo[b,h]xanthene derivative is formed in a second step by the
cyclization/dehydration of the open intermediate, where the higher stability of the ortho-para isomer
controls the regioselectivity of the reaction.
EXPERIMENTAL SECTION
General Methods. Melting points were measured and are uncorrected. IR spectra were
recorded on a spectrophotometer in anhydrous KBr. 1H and 13C NMR spectra were obtained on a 500
MHz spectrophotometer in the solvents indicated using tetramethylsilane (TMS) or the solvent as an
internal reference. The chemical shift values (δ) are given in ppm. Mass spectra were collected on a
Highꢀresolution TOF apparatus, using the technique of "electrospray ionization". The fragments are
described as the relation between atomic mass units and the load (m/z).
General procedure for the preparation of 6H-dibenzo[b,h]xanthene derivatives (7a-h).
A roundꢀbottom flask was charged with lawsone (2 mmol, 348 mg), an appropriate aldehyde (1
mmol) and dry pꢀtoluenesulfonic acid (0.6 mmol, 100 mg). The compounds were thoroughly mixed
and heated in an oven preꢀheated to 80ꢀ100 °C for 6ꢀ7 hours. At the end of the heating, the solid
mixture was poured into aqueous 5 % sodium bisulfite and then washed with water. The solid was
washed with hot ethanol and hexane to remove impurities.
7ꢀPhenylꢀ6Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7a): brickꢀred solid; yield 79 %
(330 mg); m.p. 277ꢀ280 ºC (with decomposition); IR νmax (cmꢀ1, KBr): 1659, 1590, 1489, 1456,
1
1361, 1334, 1290, 1230, 1191, 1093, 1014, 977, 944, 911, 844, 802, 774, 720, 699, 670; H NMR
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(500 MHz, CDCl3) δ ppm: 8.26 (dd,
J
7.8 and 1.0 Hz, 1H), 8.19ꢀ8.21 (m, 1H), 8.14 (dd,
J
7.8 and
7.8
1.0 Hz, 1H), 8.06ꢀ8.04 (m, 1H), 7.83 (dt,
J
7.8 and 1.0 Hz, 1H), 7.79ꢀ7.74 (m, 2H), 7.64 (dt,
J
7
8
9
and 1.0 Hz, 1H), 7.45ꢀ746 (m, 2H), 7.25ꢀ7.28 (m, 2H), 7.17ꢀ7.20 (m, 1H), 5.37 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ ppm: 182.4, 177.9, 177.4, 177.3, 156.1, 148.5, 140.9, 135.6, 134.7, 134.0,
131.8, 131.6, 130.6, 129.9, 129.8, 129.7, 128.8, 128.7, 127.8, 126.8, 126.6, 125.2, 124.9, 116.1, 33.2;
HRESIMS m/z: [M+Na]+ 441.0729 (Calculated for C27H14O5Na+: 441.0733).
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7ꢀ(4ꢀbromophenyl)ꢀ6Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7b): yellow solid; yield
73 % (362 mg); m.p. 295ꢀ296 ºC; IR νmax (cmꢀ1, KBr): 1663, 1610, 1588, 1487, 1355, 1273, 1229,
1197, 1095, 1069, 1010, 975, 946, 834, 771, 715, 672, 639; 1H NMR (500 MHz, CDCl3 + CF3CO2D)
δ ppm: 8.30 (d, J 7.6 Hz, 1H), 8.24ꢀ8.26 (m, 1H), 8.08 (d, J 7.6 Hz, 1H), 8.07ꢀ8.09 (m, 1H), 7.91 (dt,
J
7.7 and 1.1 Hz, 1H), 7.83ꢀ7.85 (m, 2H), 7.72 (dt,
J
7.7 and 1.1 Hz, 1H), 7.43 (d,
J 8.8 Hz, 2H), 7.32
(d,
J
8.8 Hz, 2H), 5.31 (s, 1H); 13C NMR (125 MHz, CDCl3 + CF3CO2D) δ ppm: 183.3, 179.1,
178.5, 178.1, 158.4, 148.5, 138.8, 136.7, 135.9, 135.7, 134.8, 134.3, 132.8, 132.7, 132.1, 131.9,
131.2, 130.7, 130.2, 129.3, 127.2, 125.8. 122.3, 32.8; HRESIMS m/z: 518.9849 [M+Na]+
(Calculated for C27H13BrO5Na+: 518.9838).
7ꢀ(3ꢀchlorophenyl)ꢀ6Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7c): red solid; yield 79
% (357 mg); m.p. 269ꢀ273 ºC (with small decomposition); IR νmax (cmꢀ1, KBr): 1661, 1609, 1576,
1477, 1430, 1352, 1294, 1270, 1231, 1195, 1166, 1078, 1009, 949, 896, 854, 794, 757, 726, 683; 1H
NMR (500 MHz, CDCl3 + CF3CO2D) δ ppm: 8.30 (d,
7.0 Hz, 1H), 8.06ꢀ8.09 (m, 1H), 7.99 (d, 8.2 Hz, 1H), 7.90 (dt,
1H), 7.71 (d, 7.6 Hz, 1H), 7.62ꢀ7.68 (m, 1H), 7.46 (d, 8.2 Hz, 1H), 7.38ꢀ7.42 (m, 1H), 7.18ꢀ7.24
J
7.6 Hz, 1H), 8.22ꢀ8.25 (m, 1H), 8.18 (d,
J
J
J
7.6 and 1.1 Hz, 1H), 7.81ꢀ7.84 (m,
J
J
(m, 1H), 5.31 (s, 1H); 13C NMR (125 MHz, CDCl3 + CF3CO2D) δ ppm: 182.8, 178.8, 177.8, 171.5,
158.0, 148.6, 142.1, 136.5, 135.4, 134.9, 134.7, 132.7, 130.6, 130.4, 130.2, 130.1, 129.5, 129.4,
128.6, 128.5, 128.4, 127.4, 127.2, 127.1, 125.9, 115.2, 33.1; HRESIMS m/z: 475.0354 [M+Na]+
(Calculated for C27H13ClO5Na+: 475.0343).
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7ꢀ(4ꢀchlorophenyl)ꢀ6Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7d): yellow solid; yield
82 % (370 mg); m.p. 259ꢀ260 ºC (with small decomposition); IR νmax (cmꢀ1, KBr): 1662, 1609, 1587,
7
8
1489, 1408, 1354, 1272, 1228, 1194, 1165, 1090, 1034, 1009, 946, 897, 837, 796, 771, 715, 643; 1H
9
NMR (500 MHz, CDCl3 + CF3CO2D) δ ppm: 8.29 (d,
7.4 Hz, 1H), 8.07ꢀ8.08 (m, 1H), 7.90 (dt, 7.4 and 1.3 Hz, 1H), 7.81ꢀ7.55 (m, 2H), 7.71 (dt,
and 1.3 Hz, 1H), 7.38 (d, 8.7 Hz, 2H), 7.27 (d,
J
7.4 Hz, 1H), 8.23ꢀ8.25 (m, 1H), 8.18 (d,
J
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J
J
7.4
J
J
8.7 Hz, 2H), 5.32 (s, 1H); 13C NMR (125 MHz,
CDCl3 + CF3CO2D) δ ppm: 185.5, 183.1, 179.1, 178.1, 148.8, 138.9, 136.8, 135.7, 134.9, 134.4,
132.9, 131.6, 130.8, 130.6, 130.3, 129.7, 129.6, 129.4, 127.4, 127.4, 127.4, 126.0, 125.2, 33.0;
HRESIMS m/z: [M+Na]+ 475.0354 (Calculated for C27H13ClO5Na+: 475.0343).
7ꢀ(perfluorophenyl)ꢀ6
80 % (406 mg); m.p. 115ꢀ116 ºC; IR νmax (cmꢀ1, KBr): 1662, 1612, 1591, 1504, 1359, 1275, 1231,
1195, 1013, 994, 960, 885, 774, 718, 670; 1H NMR (500 MHz, CDCl3 + CF3CO2D) δ ppm: 8.31 (d,
Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7e): yellow solid; yield
J
7.8 Hz, 1H), 8.23ꢀ8.25 (m, 1H), 8.14 (dd,
J
7.8 and 1.5 Hz, 1H), 8.08ꢀ8.10 (m, 1H), 7.88 (dt,
J 7.8
and 1.5 Hz, 1H), 7.82ꢀ7.84 (m, 2H), 7.72 (dt,
J
7.8 and 1.5 Hz, 1H), 5.66 (s, 1H); 13C NMR (125
MHz, CDCl3 + CF3CO2D) δ ppm: 182.8, 178.6, 177.6, 177.2, 159.3, 149.5, 136.6, 135.5, 134.8,
133.0, 131.0, 130.5, 130.2, 130.1, 129.3, 129.0, 128.3, 128.2, 127.2, 127.0, 124.8, 124.1, 120.9,
126.8, 126.0, 111.5, 23.4; HRESIMS m/z: 531.0287 (Calculated for C27H9F5O5Na+: 531.0262).
7ꢀ(2,4ꢀdichlorophenyl)ꢀ6Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7f): yellow solid;
yield 68 % (330 mg); m.p. 243ꢀ244 ºC; IR νmax (cmꢀ1, KBr): 1662, 1586, 1471, 1354, 1331, 1289,
1231, 1193, 1162, 1093, 1048, 1012, 975, 946, 848, 814, 762, 716, 665; 1H NMR (500 MHz, CDCl3
+ CF3CO2D) δ ppm: 8.33 (d, J 7.6 Hz, 1H), 8.24ꢀ8.27 (m, 1H), 8.19 (d, J 7.6 Hz, 1H), 8.06ꢀ8.10 (m,
1H), 7.92 (t,
J
7.6 Hz, 1H), 7.84ꢀ7.87 (m, 2H), 7.73 (dt,
J 7.6 and 1.2 Hz, 1H), 7.53 (d, J 8.8 Hz, 1H),
7.34 (d,
J
2.3 Hz, 1H), 7.26 (dd, J
8.8 and 2.3 Hz, 1H), 5.60 (s, 1H); 13C NMR (125 MHz, CDCl3 +
CF3CO2D) δ ppm: 183.2, 182.8, 179.1, 177.9, 158.8, 149.2, 136.7, 136.0, 135.6, 135.0, 134.8, 133.9,
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132.9, 131.4, 130.9, 130.9, 130.7, 130.5, 130.4, 129.5, 129.4, 128.7, 128.3, 127.7, 127.3, 126.0, 32.7;
HRESIMS m/z: 508.9968 (Calculated for C27H12Cl2O5Na+: 508.9954).
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7ꢀ(3ꢀnitrophenyl)ꢀ6Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7g): orange solid; yield
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72 % (333 mg); m.p. 300ꢀ305 °C (with decomposition); IR νmax (cmꢀ1, KBr): 1661, 1589, 1523,
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1485, 1348, 1299, 1273, 1229, 1191, 1162, 1094, 1015, 953, 908, 878, 802, 754, 723, 666; 1H NMR
(500 MHz, CDCl3 + CF3CO2D) δ ppm: 8.35 (d,
J 8.0 Hz, 1H), 8.27ꢀ8.29 (m, 1H), 8.23 (s, 1H), 8.20
(d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 2H), 8.06ꢀ8.08 (m, 1H), 7.98 (d,
J 8.0 Hz, 1H), 7.95 (t, J 8.0
Hz, 1H), 7.84ꢀ7.88 (m, 2H), 7.75 (t,
J
8.0 Hz, 1H), 5.47 (s, 1H); 13C NMR (125 MHz, CDCl3 +
CF3CO2D) δ ppm: 183.5, 179.4, 178.5, 178.3, 159.1, 149.3, 148.6, 142.7, 137.2, 136.5, 136.1, 135.4,
133.4, 131.5, 131.1, 130.6, 130.3, 129.6, 129.5, 127.7, 127.6, 126.5, 124.5, 123.7, 123.7, 114.7, 33.8;
HRESIMS m/z: [M+Na]+ 486.0579 (Calculated for C27H13NO7Na+: 486.0584).
7ꢀoꢀtolylꢀ6Hꢀdibenzo[b,h]xantheneꢀ5,6,8,13(7H)ꢀtetraone (7h): orange solid; yield 72 % (311
mg); m.p. 304ꢀ306 °C (with small decomposition); IR νmax (cmꢀ1, KBr): 1671, 1606, 1519, 1480,
1
1343, 1259, 1212, 1094, 1041, 989, 859, 792, 719; H NMR (500 MHz, CDCl3 + CF3CO2D) δ ppm:
8.26 (d
J
7.8 Hz, 1H), 8.16ꢀ8.18 (m, 1H), 8.06 (d,
J
7.8 Hz, 1H), 7.97ꢀ8.00 (m, 1H), 7.84 (dt,
J 7.8
and 1.0 Hz, 1H), 7.71ꢀ7.84 (m, 3H), 7.63ꢀ7.66 (m, 2H), 7.48 (dd,
J
7.8 and 2.0 Hz, 1H), 7.29 (d,
J
7.8 Hz 1H,), 5.45 (s, 1H), 2.96 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3 + CF3CO2D) δ ppm: 183.4,
181.2, 179.5, 178.1, 158.7, 149.0, 141.1, 136.8, 136.0, 135.6, 134.8, 134.1, 132.9, 131.7, 131.5,
130.6, 130.4, 129.6, 129.3, 127.5, 127.3, 127.2, 127.0, 126.2, 125.5, 125.1, 30.6, 20.1; HRESIMS
m/z: [M+Na]+ 455.0880 (Calculated for C28H16O5Na+: 455.0890).
General Procedure for the Preparation of 3,3’-(Phenylmethylene)bis(2-
hydroxynaphthalene-1,4-dione (9a). A 50 mL solution of lawsone (2 mmol) and benzaldehyde (1
mmol) in EtOH/H2O (1:1 v/v) was refluxed for 12 h. The solid that was formed was filtered, and the
precipitate was washed with water and then with EtOH. The solid was stored in a desiccator with
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phosphorus pentoxide to remove residual water to afford the pure product 9a: yellow solid; yield 83
% (361 mg); m.p. 201ꢀ202 ºC (lit. 202ꢀ204 ºC). IR νmax (cmꢀ1, KBr): 3335, 1641, 1591, 1496, 1459,
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8
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1326, 1299, 1275, 1158, 1080, 1039, 1020, 972, 896, 866, 791, 767, 722, 650; H NMR (500 MHz,
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CDCl3) δ ppm: 8.18 (bs, 1H); 8.10 (d,
J 7.3 Hz, 2H), 8.09 (d, J 7.3 Hz, 2H), 7.75 (t, J 7.3 Hz, 2H),
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7.69 (t,
J
7.3 Hz, 2H), 7.33ꢀ7.19 (m, 5H, Ph), 6.25 (s, 1H, Hꢀ3); 13C NMR (125 MHz, CDCl3) δ ppm:
37.5, 122.5, 126.3, 126.7, 127.2, 128.0, 128.3, 129.5, 132.6, 133.2, 135.0, 137.8, 154.8, 181.2, 184.7;
HRESIMS m/z: [M+Na]+ 459.0835 (Calculated for C27H16O6Na+: 459.0839).
General Procedure for the Preparation of 3,3’-(Phenylmethylene)bis(2-
methoxynaphthalene-1,4-dione (10a). A 30 mL solution of 9a (0.48 mmol), dimethyl sulfate (0.49
mmol) and potassium carbonate (0.49 mmol) in acetone was refluxed for 6 h. The potassium
carbonate was removed by filtration and by the evaporation of acetone to afford the product 10a:
brown solid; yield 60 % (133 mg); m.p. 110 ºC (with decomposition); IR νmax (cmꢀ1, KBr): 1670,
1
1591, 1516, 1343, 1294, 195, 1109, 1048, 978, 855, 787, 717; H NMR (500 MHz, CDCl3 +
CF3CO2D) δ ppm: 8.02 (d,
J 5.4 Hz, 2H), 8.01 (t, J 5.4 Hz, 2H), 7.68ꢀ7.66 (m, 4H), 7.26ꢀ7.25 (m,
5H), 6.04 (s, 1H), 3.70 (s, 6H); 13C NMR (125 MHz, CDCl3) δ ppm: 40.0, 58.5, 126.0, 126.3, 126.6,
128.1, 128.2, 128.4, 131.4, 132.0, 133.3, 133.9, 135.2, 158.2, 181.9, 184.7. HRESIMS m/z:
[M+Na]+ 487.1152 (Calculated for C29H20O6Na+: 487.1134).
General
benzo[a]benzo[6,7]chromeno[2,3-c]phenazine-11,16(17H)-dione (11a). A mixture of 7a (1
mmol), ꢀphenylenediamine (2.3 mmol) and sodium acetate (7.9 mmol) was solubilized in glacial
Procedure
for
the
Preparation
of
17-phenyl-11H-
o
acetic acid (5 mL). The mixture was stirred overnight at room temperature and then poured into cold
water (25 mL). The precipitate was filtered and washed in water until neutrality to afford the product
11a:73 orange solid; yield 76 % (372 mg); m.p. 328ꢀ331 ºC (with decomposition); IR νmax (cmꢀ1,
KBr): 1681, 1590, 1529, 1495, 1449, 1409, 1352, 1260, 1232, 1085, 1061, 1032, 986, 952, 799, 758,
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729, 698; 1H NMR (500 MHz, CDCl3) δ ppm: 8.32 (d,
J
7.3 Hz, 1H), 8.26ꢀ8.25 (m, 1H), 8.16 (d,
J
5
6
7
8
7.3 Hz, 1H), 8.13ꢀ8.03 (m, 2H), 7.91 (t,
(dd,
J
7.3 Hz, 2H), 7.84ꢀ7.77 (m, 3H), 7.71 (t,
J
7.3 Hz, 2H), 7.55
J
7.3 and 1.3 Hz, 1H), 7.32ꢀ7.16 (m, 4H) 5.62 (s, 1H); 13C NMR (125 MHz, CDCl3 + CF3CO2D)
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δ ppm: 183.8, 179.4, 178.4, 178.3, 159.1, 149.3, 137.0, 136.7, 136.1, 135.8, 135.0, 134.3, 134.2,
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133.1, 133.0, 131.6, 130.9, 130.8, 130.5, 129.8, 129.7, 129.6, 127.8, 127.5, 127.4, 127.1, 126.2,
123.9, 121.7, 114.3, 33.1. HRESIMS m/z: [M+H]+ 491.1380 (Calculated for C33H19N2O3 :
+
491.1390). Xꢀray crystal structure of 11a. A single crystal of derivative 11a was selected for
crystallographic analysis. Xꢀray diffraction data were collected at 150 K using monochromatic
MoKα radiation on a Bruker D8 Venture diffractometer System with a CMOS Photon 100 detector.
Intensities were collected with ω and φ scans and were corrected for Lorentz and polarization effects
with APEX2 suite. An empirical absorption correction (multiꢀscan) was also applied to all measured
intensities using the SADABS program. The structures were solved by direct methods and refined by
fullꢀmatrix leastꢀsquares on F2 using a combination of the SHELXꢀ2013 package74 and Olex2
software.75 All nonꢀhydrogen atoms were refined with anisotropic displacement parameters.
Hydrogen atoms bonded to C atoms were placed at their idealized positions using standard geometric
criteria. Crystallographic data for 11a: C33H18N2O3, FW 490.49, colorless block (crystal dimensions:
0.122 x 0.251x 0.431 mm3), monoclinic, space group Pꢀ1, a= 10.6689(4) Å, b= 10.9978(5) Å, c =
11.8961(6) Å, α = 81.299(2)°, β = 66.4970(10)°, γ = 62.7020(10)°, volume = 1136.62(9) Å3, Z = 2,
Dc =1.43 g/cm3, µ = 0.093 mm−1, F(000) = 508. A total of 31178 reflections were measured, of
which 4323 were independent. Rint= 0.0397, Dataset ꢀ12 ≤ h ≤ 13, ꢀ13 ≤ k ≤ 13, ꢀ14 ≤ l ≤ 14. The
final anisotropic fullꢀmatrix leastꢀsquares refinement on F2 with 343 variables converged at R1
= 3.86 %, for the observed data and R2 = 10.88 % for all data. CCDC number: 1415612.
Computational Methods. To shed some light on the possible mechanism for this reaction,
we performed a set of computational studies for the most relevant steps. Full geometry optimizations
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were carried out in the gas phase using the wb97xd76 functional together with the 6ꢀ31+G(d,p) basis
set.77,78 The default Gaussian convergence criterion was employed. For each optimized stationary
point, the secondꢀorder Hessian matrix was computed at the same level to confirm the stationary
point as a minimum, a geometry with all eigenvalues positive, or a transition structure, with just one
negative eigenvalue of the Hessian matrix. For each transition structure, the negative normal mode
was animated to confirm that it connects the desired minima. Additionally, an intrinsic reaction
coordinate (IRC) calculation,79ꢀ81 starting from the transition structure, was conducted to confirm that
the forward and backward reactions passing through that transition structure connect the reactants to
the products and vice versa. The final points obtained from the IRC calculations were employed as
initial geometries for the optimization and energy calculation of the local minima. The normal mode
calculations were also useful to compute the thermodynamic parameters at 298 K using standard
statistical thermodynamic equations. All relative energy values are given as the Gibbs free energy
(ꢁG298), computed using unscaled frequencies.
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Solvation effects were accounted for during the optimization by using water as an implicit
solvent in the Polarized Continuum Solvation Model (IEFPCM).82,83 All computations were carried
out with the G09 software package.84
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: cegvito@vm.uff.br
ACKNOWLEDGMENT
The authors are grateful to the CAPES, CNPq and FAPERJ for funding this research project. The
authors also thank LaReMN/UFF and LAREꢀDRX/UFF (FAPERJ) for the NMR and xꢀray data.
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