Hetero-Diels-Alder Reactions of Quinone Methides: The Origin of the α-Regioselectivity of 3-Methylene-1,2,4-naphthotriones

Article abstract of DOI:10.1021/acs.joc.0c00215

The regioselective formation of α-and β-lapachone via hetero-Diels-Alder reactions was investigated by experimental and computational approaches. The experimentally observed α-selectivity was explored in detail, revealing that the lower energy barrier for the formation of α-lapachone is a result of lower Pauli repulsion throughout the reaction path, when compared to the β-isomer. By comparing equivalent points on both α-and β-lapachone potential energy surfaces (PES), according to the activation strain model (ASM) and energy decomposition analysis (EDA), we were able to demonstrate that the Pauli repulsion term increases more significantly when going from reactants to TSβ than to TSα, resulting in lower interaction energy in the early stages of the reaction path and in a later transition state for β-lapachone. Moreover, we confirmed that regio-and diastereoselectivity trends previously reported for other quinone methide intermediates are also observed for 3-methylene-1,2,4-naphthotriones, such as small endo/exo diastereoselectivity, as well as pronounced ortho/meta regioselectivity for reactions performed with dienophile containing electron-releasing groups. The results presented here provide a deeper understanding of the reactivity of quinone methide derivatives, aiding the future rational design of the reaction condition, structural modification of possible quinone methide intermediates, and the development of more selective synthetic routes for quinone derivatives.

Full text of DOI:10.1021/acs.joc.0c00215

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Article
Hetero-Diels-Alder Reactions of Quinone Methides: the origin
of the #-regioselectivity of 3-methylene-1,2,4-naphthotriones
Maicon Delarmelina, Sabrina B Ferreira, Fernando de C. da
Silva, Vitor F. Ferreira, and José Walkimar de M. Carneiro
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00215 • Publication Date (Web): 05 May 2020
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Hetero-Diels-Alder Reactions of Quinone Methides: the origin
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of the α-regioselectivity of 3-methylene-1,2,4-naphthotriones
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Maicon Delarmelinaa,b, Sabrina B. Ferreirac, Fernando de C da Silvaa, Vitor F.
Ferreiraa,d, José Walkimar de M. Carneiroa,*
aInstituto de Química, Universidade Federal Fluminense, Niterói, Rio de Janeiro, 24020-141,
Brazil. E-mail: jose_walkimar@id.uff.br.
bSchool of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK.
cInstituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-909,
Brazil.
dFaculdade de Farmácia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, 24241-002,
Brazil.
ABSTRACT
The regioselective formation of α- and β-lapachone via Hetero-Diels-Alder
reactions was investigated by experimental and computational approaches. The
experimentally observed α-selectivity was explored in detail, revealing that
lower energy barrier for formation of α-lapachone is a result of lower Pauli
repulsion throughout the reaction path, when compared to the β-isomer. By
comparing equivalent points on both α- and β-lapachone Potential Energy
Surfaces (PES) according to the Activation Strain Model (ASM) and Energy
Decomposition Analysis (EDA), we were able to demonstrate that the Pauli
repulsion term increases more significantly when going from reactants to TSβ
than to TSα, resulting in lower interaction energy in the early stages of the
reaction path and in a later transition state for β-lapachone. Moreover, we
confirmed that regio- and diastereoselectivity trends previously reported for
other quinone methide intermediates are also observed for 3-methylene-1,2,4-
naphthotriones, such as small endo/exo diastereoselectivity, as well as
pronounced ortho/meta regioselectivity for reactions performed with dienophile
containing electron-releasing groups. The results presented here provide
deeper understanding of the reactivity of quinone methide derivatives, aiding
future rational design of reaction condition, structural modification of possible
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quinone methide intermediates, and the development of more selective
synthetic routes for quinone derivatives.
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INTRODUCTION
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The quinone methide intermediate 1a (X = O, Figure 1) has been widely
explored in the last decades as a versatile synthon in organic synthesis, and
more recently inspirational applications were shown in asymmetric1-4 and
natural product synthesis5,6, in the preparation of bioactive derivatives7-12
,
synthesis of heterocycles13, free-metal catalysis14, photochemical reactions15,
and biomedicine16-18. This class of intermediate is usually obtained in situ and it
can also be found as dimethane- (1b, X = C, Figure 1), aza- (1c, X = N, Figure
1) and thio- (1d, X = S, Figure 1) congeners, as well as ortho- (1, Figure 1) and
para-isomers (2, Figure 1).
(a) Quinone methide scaffold
X
O
O
X
X
O
-moiety
R
1
2
3
4R
-moiety
X
= C, N, O, S
4
(b) Preparation of R by Knoevenagel condensation
O
O
OH
O
R
O
H
+
H
R
- H2O
O
O
Lawsone
4R
Figure 1. Quinone methide derivatives and formation of 4R by Knoevenagel condensation.
Amongst the available methodologies for the in situ preparation of quinone
methide intermediates, one of the simplest and most efficient one is the
Knoevenagel condensation (Figure 1b). This methodology has been
extensively explored by our group, yielding the intermediate 3-methylene-1,2,4-
naphthotriones 4R and allowing the preparation of large set of bioactive pyran
naphthoquinone derivatives by hetero-Diels-alder reactions19-23
.
The
intermediate 4R presents increased complexity when compared to the parent
quinone methide 1, as now two almost-symmetrical reaction sites are present:
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the α- and β-moieties (Figure 1a). Such feature is very convenient for the
synthesis of natural products and bioactive compounds since two regioisomers
(α- and β-lapachones) can be formed, depending on the reaction conditions
employed.
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In an important contribution to the rationalization of the regio- and
diastereoselectivity of the reaction of 1 as diene in hetero-Diels-Alder reactions,
Wang and coworkers24 (Figure 2a) investigated the alternative reaction
channels by DFT methods (B3LYP/6-31G(d,p)) and observed that: (i) meta
isomers are kinetically disfavored against the ortho isomers, for which ortho
transition states are more asynchronous than meta transition states; (ii)
reactivity, ortho selectivity, and asynchronicity of such processes are enhanced
by electron-releasing groups bonded to the dienophile fragment; (iii) solvent
effect increases the asynchronicity of the transition state structure, reducing the
energy barrier for the hetero-Diels-Alder reaction; and, finally, (iv) charge
separation in the transition state can lead to distinct mechanisms, ranging from
an asynchronous concerted to a zwitterionic transition state24.
To the best of our knowledge, one of the few mechanistic investigations
involving the 3-methylene-1,2,4-naphthotriones 4R were performed by Peng and
coworkers (Figure 2b)25. Peng investigated the formation of siloxy-containing α-
lapachones in a regioselective reaction between 4R and a set of silyl enol
ethers. Analysis of the transition state structures obtained by DFT methods
(B3LYP/6-31G(d)) confirmed their zwitterionic character.
Later, our own group investigated the reactivity of 4R in the preparation of
xanthene derivatives from lawsone (Figure 2c)12. We have shown that,
depending on the chosen reaction conditions, the concerted hetero-Diels-Alder
reaction is replaced by a two-step process, in which the first step is a Michael
addition with formation of an open intermediate (experimentally isolated),
followed by the cyclization/dehydration process in acidic conditions. Under
these reaction conditions, ortho,para-xanthene derivatives were exclusively
obtained12.
Herein we report our theoretical and experimental investigation on the α/β-
regioselectivity of hetero-Diels-Alder reaction between the quinone methide 4H
and a set of representative dienophiles (ethene, propene, styrene,
methoxyethene, cyanoethene, cyclopentadiene and ethynyl benzene). Using a
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new approach for describing the reaction coordinate, we were able to determine
quantitatively earlier or later transition state structures involved in the formation
of the α/β-isomers and to rationalize the observed regioselectivity for these
reactions. Energy Decomposition Analysis (EDA) and Activation Strain Model
(ASM) were instrumental for exploring the reaction progress along the reaction
coordinate up to the formation of the transition state structures. For the first
time, the distinct energy barriers for the formation of α and β-lapachone from 3-
methylene-1,2,4-naphthotriones were rationalized.
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2005
(a) Wang, H.; et al. J. Org. Chem.
, 70, 4910
Ortho
Meta
Endo
Exo
Endo
H
Exo
H
H
H
R
R
H
H
X
R
H
R
H
R
H
H
H
6
5
H
1
2
3
+
O
O
O
O
4
discreet endo/exo
diastereoselectivity
Kinetically disfavoured
2008
(b) Peng, D.-Q.; et al. Synthesis
, 8, 1182
O
O
O
OSi(CH3)3
OSi(CH3)3
O
O
O
Alternative Michael
addition pathway via
Zwitterionic-like TS
structure
Formation of the -isomer
2016
(c) Carneiro, P. F.; et al. J. Org. Chem.
, 81, 5525
HO
O
O
O
O
OH
HO
R
Protic
media
O
O
O
O
R
H+
O
O
O
O
O
R
O
Lawsone
Xanthene derivatives:
formation of ortho,para-isomer
Michael addition pathway
Open intermediate
(d) This work:
O
O
O
O
O
O
+
R
R
+
O
O
O
R
Mixture of regioisomers:
Rationalization of regioselectivity
Figure 2. Mechanistic investigation on the regio- and stereoselectivity of the quinone methide
intermediate upon hetero-Diels-Alder reactions12,24,25
.
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RESULTS AND DISCUSSION
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Experimental investigation
The α- and -lapachone isomers were prepared by an improved
methodology recently reported by the current authors22: Ortho quinone methide
was generated in situ by the Knoevenagel condensation of lawsone with
paraformaldehyde, followed by the hetero-Diels-Alder reaction with different
dienophiles in dioxane (Table 1).
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Table 1. Dienophiles employed in the preparation of α- and -lapachone derivatives
and α:β isomer ratio obtained in each case.
O
O
O
R
O
R
O
O
+
+
O
O
O
-isomer
α:β (%) Entry
o-Quinone methide
-isomer
R
Entry
1
Dienophile
Product
Dienophile
Product
α:β (%)
5
80:20
70:30
67:23
88:12
75:25
80:20
7
8
11
75:25
O
F
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3
4
5
6
6
7
12
13
14
15
80:20
70:30
80:20
60:40
O
Cl
O
9
8
10
11
H3CO
9
10
The reaction produced a mixture of α and β isomers in good chemical
yields, which was separated on silica gel column chromatography. However, it
was only for cyclopentadiene, cyclohexadiene and for the styrene derivatives
that was possible to analyze the β isomers by characterization techniques. After
separation of the α derivatives from the final product mixture, the β derivatives
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of compounds 5, 6 and 7 were obtained in very small amount and, despite
being quantified, their NMR analysis was not possible due to the difficulty of
solubility of the material in different deuterated solvents.
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The compounds were fully characterized by proton and carbon nuclear
magnetic resonance spectroscopy (1H NMR and 13C{1H} NMR, respectively),
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1
infrared spectroscopy (IR) and elemental analysis. The H NMR spectra show
signals between 5.07 – 5.35 ppm for the hydrogen present in the ortho- carbon
of the chromogenic ring of the  derivatives, which appeared as a double
1
doublet. The aromatic region in the H NMR spectrum was used to identify the
α- and β-naphthoquinones. The aromatic hydrogens of the β-naphthoquinones
split into four signals, while those in the α-naphthoquinones split into only two
13
signals due to the symmetry of the structures. The C{1H} NMR spectra also
show the formation of the desired products by the signals between 75.0-79.9
ppm due to the differences at carbon 1 of the chromogenic ring. For the reaction
with ethynyl benzene as the dienophile, the double bond can be confirmed by
the presence of a triplet at 5.68 ppm (3JH,H = 3.6 Hz) in the H NMR spectrum
1
(300 MHz, CDCl3), by the highest field shift of the signal of the hydrogens
present in the pyran ring (3.35 ppm - 3JH,H = 3.6 Hz), as well as by the absence
of the signal in the region between 5.00 - 6.00 ppm, corresponding to the
hydrogen of the ortho- carbon of the chromogenic ring. The quaternary carbon
was observed at 100.6 ppm in the 13C-APT NMR spectrum. The cis-
configuration of the product obtained using cyclopentadiene as dienophile was
determined based on the coupling constants between the pyran hydrogens,
found in the range of 3.9 Hz.
In order to demonstrate the practical utility of the method as a synthetic
tool, the synthesis of products 10a and 10b was performed at larger synthetic
scale. In this experiment, 28.71 mmols (5 grams) of lawsone and 86.13 mmols
(8.97 grams) of styrene were used. 100% conversion was observed and the
products 10a and 10b were obtained in 75% (3.7 grams) and 25% (1.3 grams)
yields, respectively.
For all investigated dienophiles (Table 1) it was observed higher selectivity
towards the production of the α-isomer with only small variations caused by
distinct neighboring groups to the alkenyl moiety. Such interesting feature in the
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reactivities of α- and β-moieties within the quinone methide intermediate,
although very evident experimentally, represents an unexpected behavior for
such species, as both moieties are almost-symmetrical and chemically very
similar. In order to rationalize this distinct behavior of α- and β-moieties within
the quinone methide intermediate, we further explored these reactions by DFT
methods, as will be discussed next.
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Regioselectivity in the reactions of dienophiles with the quinone methide
intermediate (QM) and related energy barriers
The energy barriers for the hetero-Diels-Alder reaction of 4H with seven
dienophiles (ethene, propene, styrene, methoxyethene, cyclopentadiene and
ethynyl benzene), representing those dienophiles that were employed
experimentally, were computed. Cyanoethene was also included at this stage of
the investigation to complete the set of electron withdrawing groups (EWG) and
electron releasing groups (ERG) present in the investigated dienophiles. For
each of them, eight approaching modes (reaction channels) of the dienophile
over 4H were considered, with formation of eight distinct transition state
structures. Such approaching alternatives are shown in Figure 3 and the
calculated free-energy barriers for their formation are shown in Figure 4.
Meta
Ortho
Exo
Endo
Exo
Endo
H
H
H
H
R
H
R
H
H
H
R
R
H
H
H
O
H
O
O
O
O
-moiety
O
O
O

O
O
O
O
H
O
O
O
H
H
H
H
R
H
R
H

-moiety
H
R
R
H
O
H
H
H
4H
O
O
O
O
O
O
O
O
O
O
O
Figure 3. Approaching modes (ortho/meta and endo/exo) of the dienophiles over the quinone
methide intermediate 4H.
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Figure 4. Calculated free-energy barriers for the hetero-Diels-Alder reaction of 4H and a set of
dienophiles (ethene, propene, styrene, methoxyethene, cyanoethene, cyclopentadiene, ethynyl
benzene).
In all cases, the lowest energy barriers were obtained for the ortho-endo
approaching mode, as could be expected from earlier works24. We also
observed a small endo/exo diastereoselectivity (energy difference less than 4
kcal mol-1) and ortho/meta regioselectivity, which is more pronounced for the
dienophiles containing an electron releasing group, such as styrene,
methoxyethene, cyclopentadiene and ethynyl benzene.
In general, it was observed that regioselectivity is dictated by the
ortho/meta approach modes of the dienophile to the quinone methide. Electron
delocalization in the acrolein-type diene of the quinone methide results in a
partial negative charge on the oxygen atom of the acrolein moiety and partial
positive charge on the methylene carbon atom. As will be shown below, due to
asynchronicity in the formation of the two new bonds, the carbon-carbon bond is
formed earlier than the carbon-oxygen bond. This has a direct consequence on
the regioselectivity: lower activation energies are expected for orientation of the
dienophile´s dipole (when it exists) such that its negative pole is closer to the
carbon than to the oxygen atom of the quinone methide (Figure 5). This in turn
depends on the nature of the substituent group in the dienophile. Electron
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releasing groups (ERG) in the dienophile induce a negative pole in the terminal
carbon atom (C1, Figure 5a) while electron withdrawing groups (EWG) induce a
positive charge in the terminal carbon atom (C1, Figure 5b). These partial
charges developed at the carbon atoms C1 and C2 of the dienophile result in
either larger or smaller energy increase in the transition structure, depending on
the chemical identity of the substituent group bonded to C2. For ERG, e.g. -
OCH3, a partial negative charge is developed on C1, favoring the ortho
approaching mode (Figure 5a), while for EWG, e.g. -CN, a partial positive
charge is developed on the methylene group C1 (Figure 5b). The relevance of
the stabilization of the partial charges developed in the dienophile is illustrated
by the cyclopentadiene case. In the orientation shown in Figure 5c, the partial
positive charge is stabilized by electron delocalization through the vicinal double
bond, while in the orientation shown in Figure 5d the partial positive charge is
isolated from the double bond and undergoes much lower stabilization. The
consequence is that only one of the isomers (ortho) is observed experimentally.
A similar reasoning may be applied to rationalize preferential formation of only
one isomer (ortho) from the reaction with styrene. The discussion above is
centered on the α derivative, but the same may also be applied to the β one.
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Figure 5. Induced dipole over the dienophiles and the effect of a) electron releasing (ERG) and
b) electron withdrawing (EWG) groups in the approach to the diene. c) and d) illustrate the case
of cyclopentadiene, favoring the ortho approaching mode.
For dienophiles containing an electron withdrawing group, the meta
approaching mode could be expected as the most stable configuration,
however, this is not the case. The carbocationic character developed in the
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terminal carbon C1 (primary carbocation) (Figure 5b) results in significant
destabilization of the dienophile. Consequently, the energy barriers for the
hetero-Diels-Alder reactions in which the dienophile contains an electron
withdrawing group are much higher than those computed when R is an electron
releasing group. Interestingly, the overall effect is that the ortho approaching
mode is the preferential one, even for the dienophiles with an electron
withdrawing group. In summary, the ortho products are the preferential ones for
all derivatives, with dienophiles containing an ERG leading to low activation
energies, while reactions with dienophiles containing EWG have much higher
activation energies.
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The reaction with ethynyl benzene apparently undergoes a stepwise
mechanism, as we were unable to find a suitable transition state structure with
this dienophile corresponding to a concerted cycloaddition process. Our results
indicate that the substrate undergoes Michael addition with formation of an
open intermediate, which, subsequently, reacts in an intramolecular
cycloaddition process to afford the lapachone derivative.
Solvent effect was also taken into consideration for three representative
cases: ethene, cyanoethene and methoxyethene (Tables 2 and 3). Dioxane
was first considered, as it is the experimental solvent used. Water was also
considered as solvent, in an attempt to investigate the effect of solvents with
higher polarity than dioxane on the transition state structures. In general, we
observed that the solvent decreases the activation energies for the hetero-
Diels-Alder process, especially when solvent of higher polarity is used, an
expected result considering the high polarity of the transition structures. The
ΔΔE ‡
SCF varies from -2.08 to -1.51 kcal mol-1 for α-lapachone formation and from -
3.20 to -1.75 kcal mol-1 for β-lapachone formation.
The concertedness or, conversely, the asynchronicity, was quantified in
terms of the ∆d parameter (Table 3), which is the difference between the C–O
and C-C distances in the transition structure24, with a higher ∆d value indicating
a higher asynchronicity. Observe that although the oxygen atom is smaller than
the carbon atom, the C-C distance in the transition structures for all reactions is
smaller than the C-O distance, a clear indication that the C-C bond is formed
earlier than the C-O bond. Interestingly, the solvents have a strong effect on the
∆d parameter. In all cases, we observed an increase in the ∆d parameter when
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solvent is taken into account, with the effect increasing in the more polar solvent
water. This is consistent with the highly polar character of the transition
structures, as discussed before12,25. The polar character of the reaction, and
consequent asynchronicity, increases when increasing the medium polarity.
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Table 2. Solvation effect on the activation energies for the hetero-Diels-Alder reaction of 4H with
ethene, methoxyethene and cyanoethene in the ortho approaching mode.
Solvent
횫퐄퐒‡퐂퐅
횫퐇 ‡
횫퐆 ‡
Regioselectivit
y
Dienophile
(IEFPCM)
(kcal mol-1)
(kcal mol-1)
(kcal mol-1)
-
17.93
17.18
15.85
19.87
18.85
17.08
21.09
20.53
19.58
23.19
22.47
21.44
5.71
17.65
16.89
15.62
19.60
18.58
16.85
20.71
20.09
19.27
22.77
22.08
21.24
5.74
21.75
20.86
19.42
23.68
22.64
20.53
24.87
23.97
24.10
26.57
25.88
26.14
9.70
α
β
α
β
α
β
Dioxane
Water
-
Ethene
Dioxane
Water
-
Dioxane
Water
-
Cyanoethene
Dioxane
Water
-
Dioxane
Water
-
4.90
4.94
8.90
4.07
3.77
6.40
Methoxyethene
7.30
7.14
10.86
9.02
Dioxane
Water
5.78
5.64
4.10
3.83
6.70
The experimental α/β regioselectivity observed for the reaction with 4H is
also nicely reproduced by our theoretical calculations. For all reactions
computed, the transition state structure for formation of α-lapachone has lower
energy than the corresponding one for formation of β-lapachone. This occurs for
all considered reaction pathways and in the formation of all considered regio-
and diastereoisomers, even including the implicit solvation effect. The reason
for preferential formation of the α isomer is not so obvious22. In trying to find a
rationalization for this preference, we decided to explore in detail the energy
profile for the reaction of 4H with ethene.
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Table 3. Interatomic distances of Cdienophile-Cdiene and Cdienophile-Odiene obtained in the optimized
transition state structures and asynchronicity measurement (Δd).
5
6
Interatomic distances (Å)
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Dienophile
Ethene
isomer
Solvent effect Cdienophile-Cdiene Cdienophile-Odiene Δd (Å)
Gas phase
Dioxanea
Watera
2.027
2.009
1.984
1.970
1.956
1.941
1.945
1.864
1.907
1.860
2.090
2.146
2.233
2.033
2.100
2.223
1.932
1.927
1.920
1.901
1.897
1.883
2.052
2.044
1.864
1.844
2.293
2.343
2.435
2.302
2.356
2.455
2.498
2.556
2.823
2.941
2.792
2.889
3.013
2.856
2.966
3.047
2.269
2.286
2.312
2.273
2.288
2.318
2.865
2.906
0.266
0.334
0.448
0.333
0.400
0.514
0.553
0.692
0.916
1.081
0.720
0.743
0.780
0.823
0.866
0.824
0.337
0.359
0.392
0.372
0.391
0.435
0.813
0.862
-
α
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Gas phase
Dioxanea
Watera
β
α
β
α
β
Gas phase
Gas phase
Gas phase
Gas phase
Gas phase
Dioxanea
Watera
Propene
Styrene
α
β
α
β
Methoxyethene
Cyanoethene
Gas phase
Dioxanea
Watera
Gas phase
Dioxanea
Watera
Gas phase
Dioxanea
Watera
α
β
α
β
Gas phase
Gas phase
Gas phase
Gas phase
Cyclopentadiene
Ethynylbenzene
b
-
b
-
-
aIEFPCM solvation model; bFormation of Michael addition intermediate.
The reaction between 4H and ethene along a generic reaction coordinate
The origin of the α/β-regioselectivity observed for the hetero-Diels-Alder
reactions between 4H and ethene was investigated by analysis of the Potential
Energy Surfaces (PES) leading from the pre-reactive complexes (IC) to the
transition structures (TSα and TSβ, respectively) for both reactions. We
computed a set of points along the IRC going from the transition structure to the
pre-reactive complex and analyzed them according to the Activation Strain
Model (ASM) and the Energy Decomposition Analysis (EDA). For the purpose
of comparing equivalent points along both (α and β) reaction coordinates, we
had to develop an alternative description of the progress of the reaction as it
progresses from the pre-reactive complex to the transition structure.
Based on the Activation Strain Model (ASM), we wanted to quantify the
deformation in the geometry as the reaction advanced from the reactants to the
transition structure. Observe that the reorganization energy, which has been
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usually taken as a measurement of the reaction coordinate, is not suitable in the
present case, as it is not possible to define a unique and simultaneous
reorganization energy for both reactions, leading either to the α- or the β
derivatives. The starting point was then to define a new generic reaction
coordinate that could take into account the most relevant structural changes
occurring in both, the dienophile and in the quinone methide and that could be
measured in equivalent positions for both reactions. Therefore, we defined a
new reaction coordinate, qsz, which is computed considering two components:
contributions from deformations in dihedral angles and in bond lengths. From
these we took the most relevant ones, i.e. the six lengths of changing/forming
bonds involved in the cycloaddition reaction and the C-C-H(H) dihedral angles
of the three methylene groups - two methylene groups of ethene and the
methylene group of 4H (Figure 6a). The weight of each of these components to
the final value of qsz was determined by the contribution of each of them to the
overall reorganization energy along the IC → TSα process, according to the
Activation Strain Model (Figure 6b). We observed that roughly 70% of the
reorganization energy (13.2 kcal mol-1 in a total of 19.4 kcal mol-1) is due to the
distortion of the dihedral angles and that distortion of the bond length
contributed to circa 30% (6.18 kcal mol-1).
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Figure 6. Illustration of the mapped structural parameters for the definition of the reaction
coordinate qsz (a): six lengths of changing/forming bonds involved in the cycloaddition reaction
(red lines) and the C-C-H(H) dihedral angles of the three methylene groups (blue circles).
Decomposition of the activation energy into interaction and reorganization energy and
contributions of dihedral angles and bond lengths deformation for the reorganization energy (b).
The changes in bond lengths and dihedral angles were mapped and the
corresponding s and z reaction coordinate components (Equations 1 and 2)
were calculated for each point obtained along the IRC curve. In Equation 1, dR
and dP correspond to the individual bond lengths mapped in the pre-reactive
complex and final product, respectively, whereas di corresponds to the
individual bond lengths mapped in each point of the IRC curve. Similarly, ai, aR,
and aP correspond to the dihedral angles mapped in each point of the IRC
curve, in the pre-reactive complex, and in the final product.
Next, the s and z parameters for the reaction forming the α derivative were
normalized against the range of values between the pre-reactive complex (IC)
and the transition structure (TSβ) for the reaction forming the β derivative, the
one with the highest reorganization energy. The normalization was done using
Equations 3 and 4, in which s100 and z100 are the normalized parameters, s and
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z are the parameters calculated by Equations 1 and 2 for each point along the
IRC curve, and s(TSβ) and z(TSβ) are the corresponding parameters calculated
for the transition structure TSβ. According to Equations 1 and 2, s(TSβ) and
z(TSβ) are equal to 0.706 and 0.200, respectively.
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When taken together, and considering the weights determined previously,
we quantified the generic reaction coordinate qsz according to Equation 5. In
Equation 5, s100 and z100 are those obtained from Equations 3 and 4,
respectively. It is important to mention that the pre-reactive complex (IC)
considered here has adequate symmetry and orientation for following both
reaction paths, being therefore an equivalent initial point for both reactions.
∑
|풅풊 ― 풅푹|
s = ∑
(Equation 1)
(Equation 2)
(Equation 3)
(Equation 4)
|풅푷 ― 풅푹|
∑
|풂풊 ― 풂푹|
z = ∑
|풂푷 ― 풂푹|
퐬
s100 =
z100 =
퐬(퐓퐒훃)
퐳
퐳(퐓퐒훃)
(Equation 5)
퐪퐬퐳 = ퟎ.ퟑ ×
+ ퟎ.ퟕ × 퐳ퟏퟎퟎ
퐬ퟏퟎퟎ
For the plots in Figure 7 it is necessary to associate the qsz reaction
coordinate with labels that identifies the points along the reaction coordinate
and the α- or β-lapachone PES. For this, we use qsz(x,y), where qsz represents
the reaction progress and is the value plotted in the abscissa of the energy
profiles, x labels the key points along the reaction coordinate (usually indicating
TSα or TSβ) and y indicates the referred PES as belonging to α- or β-lapachone
(α or β, respectively). For instance, the qsz point corresponding to the transition
state of α-lapachone is written as qsz(TSα,α); the transition state of β-lapachone
is written as qsz(TSβ,β); and the point on the PES of β-lapachone that
corresponds to the transition state of α-lapachone is written as qsz(TSα,β).
Following the PES for β-lapachone in Figure 7(a), TSβ is located at
qsz(TSβ,β) = 1 (as defined by our normalization process), whereas following the
PES for α-lapachone, TSα is located at qsz(TSα,α) = 0.95. Following this
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procedure, we found the point on the β-lapachone PES corresponding to TSα
qsz(TSα,β) = 0.95. Therefore, when taken on the same basis, the transition state
of β-lapachone (TSβ, qsz(TSβ,β) = 1.00) is, indeed, more lately formed than TSα,
in connection with the Hammond postulate26. Having defined equivalent
reaction coordinates for both PES, the points qsz(TSα,β) can now be compared
to qsz(TSα,α) and the Activation Strain Model (ASM) and Energy Decomposition
Analysis (EDA) can be used to rationalize and identify the origin of the lateness
of TSβ.
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At qsz(TSα,α) and qsz(TSα,β), the computed reorganization energy (EReorg
)
is roughly identical in both cases (Figure 7(a)), varying only by 0.4 kcal mol-1.
This is quite reasonable, as according to our reaction coordinate model, at
qsz(TSα,α) and qsz(TSα,β) the reaction progress and the distortion of the
reactants for formation of the α- and β-derivatives should be identical. On the
other hand, the interaction energy (EInt) is significantly different for qsz(TSα,α)
and qsz(TSα,β), reaching -7.0 kcal mol-1 at qsz(TSα,α), but only -4.8 kcal mol-1 at
qsz(TSα,β).
It is interesting to notice that if equivalent points on both PES were not
considered, but instead the two transition state structures were directly
compared, the energy barrier difference for both reactions would be erroneously
attributed to the distortion energy for forming these transition states: EReorg(TSα)
= 19.4 kcal mol-1 and EReorg(TSβ) = 21.6 kcal mol-1. However, as it will be shown
next, this is the result of distinct interaction energies acting at each point of both
PES. The reorganization energy curves for both reactions Figure 7(a) present
very small energy differences, which become quite evident when EReorg is
computed at qsz(TSα,α) and qsz(TSα,β), 19.4 and 19.0 kcal mol-1, respectively.
The Energy Decomposition Analysis (EDA) was additionally used to
decompose the computed interaction energies at qsz(TSα,α) and qsz(TSα,β) into
electrostatic, Pauli repulsion, polarization, exchange and dispersion energy
terms (EES, EREP, EPOL, EEX and EDISP, respectively). As shown in Figure 7(b),
the dispersion energy term is roughly identical at these points (∆EDISP = -0.24
kcal mol-1). Electrostatic, polarization and exchange energy terms present more
negative values for qsz(TSα,β) (∆EES = -1.94 kcal mol-1, ∆EPOL = -1.36 kcal mol-1
and ∆EEX = -3.18 kcal mol-1). Finally, the Pauli repulsion term is much more
destabilizing at qsz(TSα,β) than at qsz(TSα,α) (∆EREP = +8.92 kcal mol-1) and the
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overall effect is the observed lower interaction energy at qsz(TSα,β) than at
qsz(TSα,α), ∆EInt being equal to +2.19 kcal mol-1. The higher increase of the
Pauli repulsion term on the β PES results that TSβ is achieved in a later stage
than TSα, where the stabilizing terms (dispersion, electrostatic, polarization and
exchange energies) are able to overcome the destabilizing Pauli repulsion term.
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Figure 7. Activation Strain Model (ASM) and Energy Decomposition Analysis (EDA) of all IRC
points obtained from TSα and TSβ towards the initial complex. The abscissa describes the
advances of the reaction according to the qsz coordinate.
Within the EDA scheme for the decomposition of the interaction energy
between two fragments, the Pauli repulsion term (EREP) accounts for energy
increase necessary for going from the superposition of the unperturbed electron
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density of the separated fragments to the antisymmetrized and renormalized
individual wavefunctions of the fragments before Kohn-Sham orbital
relaxation27,28. This term has been frequently associated with the repulsion
between closed shell orbitals and is an indicator of the steric repulsion between
the fragments27,28. For the hetero-Diels-Alder reaction investigated here,
however, the repulsion between the closed shell sp2 orbitals within the quinone
methide fragment 4H may be the major source for the EREP differences observed
for the α- and β-lapachone PES.
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The destabilizing interaction between sp2 orbitals of neighboring carbonyl
groups in the 1,2-quinone derivatives is clearly seen when their energy is
compared to their 1,4-isomer (Table 4). Considering three common quinones
isomer pairs (1,2-/1,4-quinone, 1,2-/1,4-naphtoquinone and 2-/4-lawsone), as
well as α-/β-lapachone, we always find the 1,4 (or α-derivative) as the most
stable species (Table 4). In trying to find a connection between the relative
stability of these species and their structure we broken each of them into their
respective triplet acrolein diradicals, as shown by the dashed lines over each
structure of Figure 3. The interaction energy (Eint) between the two fragments
were then computed.
Table 4. Relative energy difference for bringing together the corresponding triplet acrolein
diradicals shown below (separated by dashed lines) for formation of 1,2-/1,4-quinone, 1,2-/1,4-
naphtoquinone, 2-/4-lawsone and α-/β-lapachone.
ΔE
ΔE
-
ESCF,Relative
Eint
7.23
-202.90
0.00
-209.40
-
7.40
-204.75
0.00
-212.12
-6.50
-7.38
ΔE
-
-3.34
ΔE
-
ESCF,Relative
Eint
3.89
-205.18
0.00
-208.62
4.44
-203.94
0.00
-208.32
-4.38
Method: M06-2X/6-31+G(d,p)
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A direct correlation between the relative stability of these isomers and the
interaction energy between the acrolein diradicals can be observed.
Additionally, for lawsone and lapachone, the relative energy between isomers,
as well as the interaction energy difference between the radicals, decrease
significantly when compared to 1,2-/1,4-quinone and 1,2-/1,4-naphtoquinone.
This is a direct effect of the additional oxygen atom bonded to the quinone core,
which results in a smaller relief of the electronic repulsion between sp2 orbitals
when going from 4-lawsone to 2-lawsone or from β-lapachone to α-lapachone.
The same repulsion can be expected within 4H between C1=O and C2=O,
which must decrease as the reaction proceeds towards the formation of TSα
and the rehybridization of the oxygen at C2 takes place. For formation of TSβ,
on the other hand, such electronic repulsion remains throughout the reaction
path, resulting in the steepest increase of the EREP curve observed in Figure 7.
Overall, these results show that the α-selectivity of the hetero-Diels-Alder
reactions involving the quinone methide 4H is due to the Pauli repulsion of its
C1=O and C2=O carbonyl groups and consequent higher reactivity of the α-
moiety when compared to the β-moiety towards the relaxation of such
destabilizing interaction.
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CONCLUSIONS
The
hetero-Diels-Alder
reaction
between
3-methylene-1,2,4-
naphthotriones (4H) and a set of dienophiles (ethene, propene, styrene,
methoxyethene, cyanoethene, cyclopentadiene and ethynyl benzene) has been
investigated. Throughout this investigation, endo/exo, ortho/meta and α/β
selectivity was taken into account considering eight approaching modes of the
dienophiles over 4H. Discreet endo/exo diastereoselectivity was computed for
‡
these reactions (
ΔΔG
< 4 kcal mol-1) and pronounced ortho/meta
regioselectivity for dienophile containing an electron releasing groups, achieving
of circa 19 kcal mol-1. In all cases, the lowest energy barriers were
ΔΔG ‡
computed for the ortho-endo approaching mode.
Solvent effect over the hetero-Diels-Alder process was also take into
ΔES‡CF
consideration, revealing a decrease of the energy barriers, with
varying
from - 2.08 to -1.51 kcal mol-1 for α-lapachone formation and from -3.20 to -1.75
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kcal mol-1 for β-lapachone formation. The concertedness of the transition state
structure for the hetero-Diels-Alder reaction was also observed to decrease,
with the asynchronicity measurement (Δd) increasing significantly with the
polarity of the solvent.
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The experimentally observed α-selectivity was thoroughly investigated by
means of the Activation Strain Model (ASM) and Energy Decomposition
Analysis (EDA) approaches. Comparison of equivalent points on α- and β-
lapachone Potential Energy Surfaces revealed that lower Pauli Repulsion is
observed over the reaction path for formation of α-lapachone when compared to
β-lapachone. The reduction of repulsive interaction between sp2-like orbitals of
C1=O and C2=O groups within 4H during the formation of TSα is considered to
be the major origin for this effect. For reaction forming the β derivatives the
C1=O and C2=O groups remain unaltered and therefore there is no release on
the steric interaction.
EXPERIMENTAL SECTION
Experimental details.
Analytical grade solvents were used. Reagents were purchased from
Aldrich or Acros Chemical Co. Column chromatography was performed on silica
gel 60 (Merck 70-230 mesh). Yields refer to chromatographically and
spectroscopically homogeneous materials. Reactions were monitored by thin-
layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates
(60F-254) using UV light as visualizing agent and/or with ethanol solution of 3%
vanillin in sulfuric acid followed by heating. Infrared spectra were recorded on a
Perkin-Elmer FT-IR Spectrum One spectrophotometer, calibrated relative to the
1601.8 cm-1 absorbance of polystyrene; values are reported in cm-1. Melting
points were observed on a Fischer-Johns melting point apparatus. NMR spectra
were recorded on a Varian Unity Plus VXR (300 MHz) equipment in DMSO-d6
or CDCl3 solutions and tetramethylsilane as the internal standard (δ = 0 ppm).
In case of multiplets, the signals were reported as intervals. Signals were
abbreviated as s, singlet; d, doublet; t, triplet; m, multiplet. High-resolution mass
spectra (HRMS) were recorded on an MICROMASS Q-TOF MICRO Mass
spectrometer using ESI-TOF (electrospray ionization-time of flight). Purity of
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final compounds was established using elemental analysis. All compounds were
ascertained based on their elemental analysis.
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General Procedure for preparation of pyran naphthoquinones. To a round-
bottom flask equipped with a magnetic stirring bar, lawsone was dissolved (1
mmol) in dioxane (20 mL), followed by addition of formaldehyde (8 mmol). The
dienophile (3 mmol) was added dropwise and the reaction mixture was stirred
under reflux until consumption of the starting material. The solvent was
removed under reduced pressure; ethyl acetate was added in the residue and
the mixture was washed with saturated sodium bicarbonate aqueous solution.
The combined organic extract was washed with water, dried over anhydrous
sodium sulfate, filtered and concentrated under vacuum. The residual mixture of
products was purified by flash chromatography employing gradient n-
hexane/EtOAc as eluent, furnishing the desired 1,2 and 1,4-naphthoquinones.
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2-ethoxy-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (5).29 Compound 5
0
was obtained as a yellow solid in 80% yield (140 mg). m.p.= 168-170 C; IR
1
(film, CHCl3) cm-1): 3418, 2929, 1713, 1595, 1269, 1251, 1014, 941, 736; H
NMR (CDCl3, 300 MHz): δ 1.19 (3H, t, J = 7.0 Hz, CH3), 1.79-1.90 (2H, m, H-4),
2.12 (2H, t, J = 2.4 Hz, H-3), 5.47 (1H, t, J = 2.4 Hz, H-2), 3.72 (1H, ddd, J =
4.3, 7.0 and 9.7 Hz, OCH2), 3.92 (1H, ddd, J = 4.3, 7.0 and 9.7 Hz, OCH2), 7.68
(2H, dddd, J = 1.7, 7.3, 9.2 and 11.0 Hz, H-8 and H-7), 8.08 (2H, dddd, J = 1.7,
7.3, 9.2 and 11.0 Hz, H-9 and H-6); 13C{1H} NMR (CDCl3, 75 MHz): δ 14.5
(CH3), 15.2 (CH2), 25.2 (CH2), 65.0 (OCH2CH3), 98.4 (C-2), 122.9 (C-4a), 126.3,
126.4, 133.2 and 134.1 (C-Har), 131.2 (C-9a), 132.1 (C-5a), 152.8 (C-10a),
184.4 (C=O). HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for C15H14O4Na
281.0892; Found 281.0886. Anal. Calcd for C15H14O4: C, 69.76; H, 5.46. Found:
C, 69.73; H, 5.40.
2-butoxy-3,4-dihydro-2H-benzo [g]chromene-5,10-dione (6).29 Compound 6
0
was obtained as a yellow solid in 70% yield (120 mg). M.p.= 168-170 C; IR
(film, CHCl3) (cm-1):3436, 2924, 2854, 1770,1713, 1596, 1280, 1064, 940, 723;
1H NMR (CDCl3, 300 MHz): δ 0.86 (3H, t, J = 7.3 Hz, CH3); 1.25-1.38 (1H, m,
CH2); 1.50-1.60 (1H, m, CH2); 1.79-1.90 (2H, m, CH2); 2.09-2.17 (2H, m, CH2);
3.65 (1H, ddd, J = 3.1; 6.5 and 9.7 Hz, OCH2); 3.88 (1H, ddd, J = 3.1; 6.5 and
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9.7 Hz, OCH2); 5.47 (1H, t, J = 2.6 Hz, H-2); 7.70 (2H, dddd, J = 1.7; 7.3; 9.2;
11.0 Hz, H-8 and H-7); 8.09 (2H, dddd, J = 1.7; 7.3; 9.0; 10.9 Hz, H-9 and H-6);
13C{1H} NMR (CDCl3, 75 MHz): δ 14.1 (CH3); 13.5 (CH2CH3); 18.9 (C-4); 24.8
(C-3); 31.3 (CH2CH2CH3); 68.9 (OCH2CH3); 98.2 (C-2); 122.5 (C-4a); 125.9;
126.0; 130.8 and 132.8 (C-Har); 131.7 (C-9a); 133.7 (C-5a); 152.2 (C-10a);
184.0 (C=O). HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for C17H18O4Na
309.1205; Found 309.1210. Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found:
C, 71.20; H, 6.40.
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2-isobutoxy-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (7). Compound 7
0
was obtained as a yellow solid in 67% yield (117 mg). M.p.= 145-148 C; IR
1
(film, CHCl3) (cm-1): 3340, 2957, 1678, 1651, 1387, 1301, 1259, 957, 720; H
NMR (CDCl3, 300 MHz): δ 0.85 (6H, t, J = 6.7 Hz, 2CH3), 1.79-1.91 (2H, m, H-
3), 2.15 (1H, t, J = 6.7 Hz, CH(CH3)2), 2.53-2.76 (2H, m, H-4), 3.43 (1H, dd, J =
6.7 and 9,5 Hz, OCH2), 3.66 (1H, dd, J = 6.7 and 9.5 Hz, OCH2), 5.46 (1H, t, J =
2.5 Hz, H-2), 7.69 (2H, dddd, J = 1.8, 7.5, 9.2 and 10.9 Hz, H-8 and H-7), 8.09
13
(2H, dddd, J = 1.8, 7.5, 9.2 and 10.9 Hz, H-9 and H-6); C{1H} NMR (CDCl3,
75 MHz): δ 14.1 (C-4), 18.9 (CH3), 24.8 (C-3), 28.2 (CH (CH3)2), 75.6
(OCH2CH(CH3)2), 98.2 (C-2), 122.6 (C-4a), 125.8, 126.0, 132.8 and 133.7 (C-
Har), 130.8 (C-9a), 131.7 (C-5a), 152.5 (C-10a), 184.0 (C=O); HRMS (ESI/Q-
TOF) m/z: [M + Na]+ Calcd for C17H18O4Na 309.1205; Found 309.1215. Anal.
Calcd for C17H18O4: C, 71.31; H, 6.34. Found: C, 71.40; H, 6.38.
(±)-11,11a-dihydrobenzo[g]cyclopenta[b]chromene-5,10(1H,3aH)-dione
(8a). 29 Compound 8a was obtained as a yellow solid in 88% yield (153 mg).
0
M.p.= 140-142 C; IR (film, CHCl3) (cm-1): 2885, 2851, 1676, 1643, 1386,
1
1198, 1011, 932, 725; H NMR (CDCl3, 300 MHz): δ 2.30-2.29 (1H, m, H-4a),
2.50-2.62 (3H, m, H-4 and H-5), 2.97-2.89 (1H, m, H-5), 5.32 (1H, d, J = 2.6 Hz,
H-1a), 6.11-6.15 (1H, m, H-3), 6.23-6.27 (1H, m, H-2), 7.85-7.94 (2H, m, H-9
13
and H-8), 8.04-8.08 (2H, m, H-10 and H-7); C{1H} NMR (CDCl3, 75 MHz): δ
19.7 (C-4), 34.0 (C-4a), 37.5 (C-5), 83.2 (C-1a), 119.7 (C-5a), 125.6, 125.9,
130.9 and 137.0 (C-Har), 130.6 (C-6a), 131.6 (C-10a), 133.5 (C-2 or C-3),
134.3 (C-2 or C-3), 155.8 (C-11a), 178.8 and 183.5 (C=O); HRMS (ESI/Q-TOF)
m/z: [M + Na]+ Calcd for C16H12O3Na 275.0786; Found 275.0795. Anal. Calcd
for C16H12O3: C, 76.18; H, 4.79. Found: C, 76.09; H, 4.73.
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(±)-7a,8-Dihydrobenzo[h]cyclopenta[b]chromene-5,6(7H,10aH)-dione
(8b).11 Compound 8b was obtained as a orange solid in (21mg) 12% yield.
M.p.= 146-147 0C; IR (film, CHCl3) (cm-1): 2975, 2931, 1738,1716, 1599, 1284,
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959, 927, 720; H NMR (DMSO-d6, 300 MHz): δ 2.23-2.32 (1H, m, H-5), 2.47-
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2.54 (1H, m, H-5), 2.66-2.95 (3H, m, H-4 and H-4a), 5.48-5.50 (1H, m, H-1a),
6.28-6.31 (1H, m H-3), 6.18-6.21 (1H, m H-2), 7.68 – 7.73 (1H, m, ArH), 7.85-
13
7.87 (2H, m, ArH), 8.01-8.08 (1H, m, ArH); C{1H} NMR (DMSO-d6, 75 MHz):
δ 19.7 (C-5), 34.5 (C-4a), 37.9 (C-4), 85.0 (C-1a), 112.5 (C-5a), 124.4 (C-3),
135.7 (C-2), 128.5, 131.2, 131.5 and 135.7 (C-ar), 130.3 (C-7a), 132.6 (C-11a),
163.6 (C-11b), 178.4 and 179.8 (2C=O); HRMS (ESI/Q-TOF) m/z: [M + Na]+
Calcd for C16H12O3Na 275.0786; Found 275.0785. Anal. Calcd for C16H12O3: C,
76.18; H, 4.79. Found: C, 76.10; H, 4.76.
(±)-3,4,4a,5-tetrahydrobenzo[g]pyrano[2,3-b]chromene-6,11(2H,12aH)-
dione (9a).29 Compound 9a was obtained as a yellow solid in 75% yield (130
mg). M.p.= 163-165 0C; IR (film, CHCl3) (cm-1): 2936, 1678, 1645, 1623, 1348,
1
1194, 1145, 954, 721; H NMR (CDCl3, 300 MHz): δ 1.53-1.64 (2H, m, H-6),
1.71-1.79 (2H, m, H-4), 2.19-2.29 (1H, m, H-5), 2.65 (1H, d, J = 2.5, H-5a),
3.74-3.81 (1H, m H-3), 3.97-4.05 (1H, m H-3), 5.44 (1H, d, J = 2.5, H-1a), 7.67-
7.73 (2H, m, H-10 and H-9), 8.05 (2H, m, H-11 and H-8); 13C{1H} NMR (CDCl3,
75 MHz): δ 23.4 (C-4), 23.7 (C-5 and C-6), 30.3 (C-5a), 62.5 (C-3), 97.9 (C-1a),
119.4 (C-6a), 125.8, 126.1, 132.9 and 133.7 (C-Har), 130.8 (C-7a), 131.7 (C-
11a), 153.0 (C-12a), 184.1 (2C=O); HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd
for C17H14O3Na 289.0943; Found 289.0930. Anal. Calcd for C17H14O3: C, 76.68;
H, 5.30. Found: C, 76.65; H, 5.28.
(±)-7,7a,8,9-Tetrahydro-5H-benzo[c]xanthene-5,6(11aH)-dione
(9b).11
Compound 9b was obtained as a orange solid in (44mg) 25% yield. M.p.= 142-
143 0C; IR (film, CHCl3) (cm-1): 2021,1694, 1604, 1570, 1392, 1262, 955, 784;
1H NMR (CDCl3, 300 MHz): δ 1.62-1.69 (3H, m, H-4 and H-5), 2.17-2.30 (2H,
m, H-5 and H-5a), 2.66 (1H, dd, J =6.5 and 10.9 Hz, H-6), 2.50 (1H, dd, J =6.5
and 11.0 Hz, H-6), 4.77 (1H, t, J =3.9 Hz, H-1a), 5.93-5.99 (1H, m, H-3), 6.04-
6.09 (1H, m, H-3), 7.49 (1H, ddd, J = 1.2, 7.5 and 8.7 Hz,H-8), 7.63 (1H, ddd, J
= 1.2, 7,5 and 9.0 Hz, H-9), 7.80 (1H, dd, J = 0.9 and 7.5 Hz, H-10), 8.05 (1H,
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dd, J = 0.9 and 7.5 Hz, H-7); 13C{1H} NMR (CDCl3, 75 MHz): δ 22.5 (C-4), 23.6
(C-5), 24.7 (C-6), 29.3 (C-5a), 73.8 (C-1a), 112.2 (C-6a), 124.3 (C-3), 124.7 (C-
2), 128,8, 130.8, 134.1 and 135.0 (C-ar), 130.2 (C-8a), 132.4 (C-12a), 161.6 (C-
12b), 179.9 (2C=O); HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for C17H14O3Na
289.0943; Found 289.0932. Anal. Calcd for C17H14O3: C, 71.10; H, 5.22. Found:
C, 71.09; H, 5.20.
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2-phenyl-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (10a).22 Compound
10a was obtained as a yellow solid in 80% yield (140 mg). M.p.= 168-170 0C; IR
1
(film, CHCl3) (cm-1): 1679, 1649, 1617, 1260, 1202, 1063, 958, 910, 721; H
NMR (CDCl3, 300 MHz): δ 2.15 (1H, dddd, J = 2.6, 3.2, 5.7 and 14.0 Hz, H-3a),
2.30 (1H, dddd, J = 2.2, 6.2, 6.5 and 14.0 Hz, H-3b), 2.63 (1H, ddd, J = 3.2, 6.2
and 13.7 Hz, H-4a), 2.77 (1H, ddd, J = 2.2, 5.7, and 13.7 Hz, H-4b), 5.22 (1H,
dd, J = 2,6 e 6,5 Hz, H-2), 7.32 – 7.40 (5H, m, 2-phenyl), 7.68 (2H, dddd, J =
2.0, 7.5, 9.2 and 11.0 Hz, H-8 e H-7), 8.10 (2H, dddd, J =2.0, 7.5, 9.2 and 10.9
13
Hz, H-9 e H-6); C{1H} NMR (CDCl3, 75 MHz): δ 18.3 (C-4), 27.6 (C-3), 78.8
(C-2), 121.4 (C-4a), 125.6 (C-4’-phenyl), 125.8 (C-6), 126.1 (C-9), 128.1 (C-2’-
phenyl), 128.4 (C-3’-phenyl), 130.8 (C-9a), 131.7 (C-5a), 132.9 (C-7, C-8),
133.7 (C-Har), 139.1 (C-1’), 152.2 (C-10a), 184.0 (C-5 and C-10); HRMS
(ESI/Q-TOF) m/z: [M + Na]+ Calcd for C19H14O3Na 313.0943; Found: 313.0936.
Anal. Calcd for C19H14O3: C, 78.61; H, 4.86. Found: C, 78.70; H, 4.94.
2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (10b).22 Compound
10b was obtained as an orange solid in 20% yield (35 mg). M.p.= 161-163 0C;
IR (film, CHCl3) (cm-1): 1696, 1647, 1605,1573, 1397, 1300, 1280, 1232, 1158,
1093, 922, 700; 1H NMR (CDCl3, 300 MHz): δ 2.08 (1H, dddd, J = 2.7, 3.2, 5.6
and 13.8 Hz, H-3a), 2.33 (1H, dddd, J = 3.4, 6.3, 7.4 and 13.8 Hz, H-3b), 2.60
(1H, ddd, J = 3.2, 6.3 and 8.8 Hz, H-4a), 2.76 (1H, ddd, J = 3.4, 5.6 and 8.8 Hz,
H-4b), 5.27 (1H, dd, J = 2.7 and 7.4 Hz, H-2), 7.39-7.46 (5H, m, 2-phenyl), 7.53
(1H, ddd, J = 1.0, 7.4 and 8.6 Hz, H-8), 7.64 (1H, ddd, J = 1.4, 7.6 and 9.1 Hz,
H-9), 7.83 (1H, dd, J = 1.0 and 7.6 Hz, H-10), 8.01 (1H, dd, J = 1.4 and 7.6 Hz,
H-7). 13C{1H} NMR (CDCl3, 75 MHz): δ 18.2 (C-4), 28.2 (C-3), 79.9 (C-2), 113.8
(C-4a), 123.9 (C-10), 125.6 (C-7), 125.7 (C-4’-phenyl), 128.4 (C-8), 128.5 (C-2’-
phenyl), 128.6 (C-3’-phenyl), 129.8 (C-6a), 130.6 (C-9), 131.9 (C-1’-phenyl),
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139.2 (C-10a), 162.7 (C-10b), 178.7 and 179.0 (C-5 and C-6); HRMS (ESI/Q-
TOF) m/z: [M + Na]+ Calcd for C19H14O3Na 313.0943; Found: 313.0944. Anal.
Calcd for C19H14O3: C, 78.61; H, 4.86. Found: C, 78.67; H, 4.91.
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2-(4-fluorophenyl)-3,4-dihydro-2H-benzo[g]chromene-5,10-dione
(11a).29
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Compound 11a was obtained as a yellow solid in 75% yield (130 mg). M.p.=
0
171-173 C; IR (film, CHCl3) (cm-1): 1678, 1647, 1618, 1513, 1260, 1201,
1065, 958, 835, 720; 1H NMR (CDCl3, 300 MHz): δ 2.15 (1H, dddd, J = 2.4, 3.3,
6.5 and 13.0 Hz, H-3a), 2.30 (1H, dddd, J = 2.1, 6.2, 7.0 and 13.0 Hz, H-3b),
2.75 (1H, ddd, J = 3.3, 6.2 and 12.5 Hz, H-4a), 2.80 (1H, ddd, J = 2.1, 6.5, and
12.5 Hz, H-4b), 5.16 (1H, dd, J = 2.4 and 7.0 Hz, H-2), 7.08 (2H, t, J = 8.7,
2Char-F), 7.36 – 7.41 (2H, m, 2ArH), 7.70 (2H, dddd, J = 1.5, 7.5, 9.2 and 11.0
Hz, H-8 and H-7), 8.10 (2H, dddd, J = 1.5, 7.5, 9.2 and 10.9 Hz, H-9 and H-6);
13C{1H} NMR (CDCl3, 75 MHz): δ 18.5 (C-4), 27.8 (C-3), 78.3 (C-2), 115.3 and
115.6 (d, J = 21.4 Hz, 2Char-F), 121.4 (C-4a), 125.9 (C-6), 126.2 (C-9), 127.5
(C-7), 127.6 (C-8), 133.0 (C-2’), 133.8 (C-3’), 130.8 (C-9a), 131.8 (C-5a), 135.0
(C-4’), 155.1 (C-10a), 179.1 and 184.0 (C-5 and C-10); HRMS (ESI/Q-TOF)
m/z: [M + Na]+ Calcd for C19H13FO3Na 331.0849; Found: 331.0838. Anal. Calcd
for C19H13FO3: C, 74.02; H, 4.25. Found: C, 74.09; H, 4.31.
2-(4-fluorophenyl)-3,4-dihydro-2H-benzo[h]chromene-5,6-dione
(11b).11
Compound 11b was obtained as an orange solid in 25% yield (44 mg). M.p.=
0
142-147 C; IR (film, CHCl3) (cm-1): 1573, 1607, 1513, 1394, 1280, 1229,
1
1156, 922; H NMR (CDCl3, 300 MHz): δ 2.07 (1H, dddd, J = 2.4, 3.2, 5.6 and
12.8 Hz, H-3a), 2.34 (1H, dddd, J = 3.1, 6.5, 7.8 and 12.8 Hz, H-3b), 2.61 (1H,
ddd, J = 3.2, 6.5 and 8.7 Hz, H-4a), 2.75 (1H, ddd, J = 3.1, 5.6 and 8.7 Hz, H-
4b), 5.24 (1H, dd, J = 2.4 and 7.8 Hz, H-2), 7.15 (2H, t, J = 8.5 Hz, 2Char-F),
7.39-7.44 (2H, m, H-ar), 7.53 (1H, ddd, J = 1.2, 7.2 and 8.7 Hz, H-8), 7.64 (1H,
ddd, J = 1.4, 7.8 and 9.2 Hz, H-9), 7.83 (1H, dd, J = 1.1 and 6.5 Hz, H-10), 8.01
(1H, dd, J = 1.1 and 6.3 Hz, H-7). 13C{1H} NMR (CDCl3, 75 MHz): δ 18.3 (C-4),
28.3 (C-3), 79.4 (C-2), 113.8 (C-4a), 115.4 and 115.7 (d, J = 21.4 Hz, C-3’),
123.8 (C-10), 127.5 (C-7), 127.6 (C-8), 128.6 (C-1’), 129.8 (C-6a), 130.7 (C-3’),
131.8 (C-2’), 134.7 (C-9’), 135.7 (C-4’), 137.7 (C-10a), 162.6 (C-10b), 178.4 and
179.2 (C-5 and C-6); HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for
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C19H13FO3Na 331.0849; Found: 331.0845. Anal. Calcd for C19H13FO3: C, 74.02;
H, 4.25. Found: C, 74.00; H, 4.25.
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2-(4-chlorophenyl)-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (12a).29
Compound 12a was obtained as a yellow solid in 80% yield (140 mg). M.p.=
130-132 0C; IR (film, CHCl3) (cm-1): 3068, 2929,1677, 1650, 1620, 1597, 1260,
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1202, 1065, 911, 823, 720; H NMR (CDCl3, 300 MHz): δ 1.97-2.10 (1H, m, H-
3); 2.26-2.35 (1H, m, H-3); 2.59-2.80 (2H, m, H-4); 5.17 (1H, dd, J = 2.6 and 6.8
Hz, H-2); 7.29 – 7.39 (4H, m, ArH); 7.70 (2H, dddd, J = 2.1; 7.8; 9.2; 11.0 Hz, H-
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8 and H-7); 8.10 (2H, dddd, J = 2.0; 7.8; 9.2; 10.9 Hz, H-9 and H-6); C{1H}
NMR (CDCl3, 75 MHz): δ 18.8 (C-4); 28.1 (C-3); 78.5 (C-2); 121.8 (C-4a);
126.3; 126.6; 127.5; 129.1; 133.4 and 134.2 (C-Har); 131.2 (C-9a); 132.1 (Car-
Cl); 134.4 (C-5a); 138.1 (Cquat.ar); 155.4 (C-10a); 184,4 (C=O); HRMS (ESI/Q-
TOF) m/z: [M + Na]+ Calcd for C19H13ClO3Na 347.0553; Found: 347.0542. Anal.
Calcd for C19H13ClO3: C, 70.27; H, 4.03. Found: C, 70.10; H, 4.08.
2-(4-chlorophenyl)-3,4-dihydro-2H-benzo[h]chromene-5,6-dione
(12b).11
Compound 12b was obtained as an orange solid in 20% yield (35 mg). M.p.=
143-145 C; IR (film, CHCl3) (cm-1): 3068, 2928, 1697, 1647, 1607, 1393,
0
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1281, 1092, 923, 774; H NMR (CDCl3, 300 MHz): δ 1.97-2.11 (1H, m, H-3);
2.27-2.36 (1H, m, H-3); 2.54-2.65 (1H, m, H-4); 2.74 (1H, ddd, J = 3.1; 5.6 and
8.7 Hz H-4); 5.24 (1H, dd, J = 2.4 and 7.8 Hz, C-2); 7.36-7.45 (4H, m, H-ar);
7.53 (1H, ddd, J = 1.2, 7.5 and 8.5 Hz,H-8); 7.64 (1H, ddd, J = 1.4, 7.5 and 9.0
Hz, H-9), 7.83 (1H, dd, J = 1.2 and 7.8 Hz, H-10), 8.01 (1H, dd, J = 1.9 and 8.0
Hz, H-7); 13C{1H} NMR (CDCl3, 75 MHz): δ: 18.2 (C-4), 28.2 (C-3), 79.2 (C-2),
113.8 (C-4a), 123.8; 127.1; 128.6; 128.8; 130.7 and 134.8 (C-ar); 129.8 (C-6a);
131,9 (Cquart C-2); 134.2 (Car-Cl); 137.7 (C-10a); 162.5 (10b); 178.3 and 179,2
(2C=O); HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for C19H13ClO3Na 347.0553;
Found: 347.0542. Anal. Calcd for C19H13ClO3: C, 70.27; H, 4.03. Found: C,
70.10; H, 4.08.
2-(4-methylphenyl)-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (13a).29
Compound 13a was obtained as a yellow solid in 70% yield (122 mg). M.p.=
135-137 0C; IR (film, CHCl3) (cm-1): 2920,1677, 1645, 1617, 1595, 1258, 1200,
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1065, 958, 826, 720; H NMR (CDCl3, 300 MHz): δ 2.01-2.14 (1H, m, H-3);
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2.26-2.33 (1H, m, H-3); 2.36 (1H, s, CH3); 2.59-2.79 (2H, m, H-4); 5.18 (1H, dd,
J = 2.6 and 6.3 Hz, H-2); 7.18 – 7.29 (4H, m, ArH); 7.69 (2H, dddd, J = 1.0; 7.3;
9.0; 10.7 Hz, H-8 and H-7); 8.09 (2H, dddd, J = 1.0; 7.3; 9.0; 10.7 Hz, H-9 and
H-6); 13C{1H} NMR (CDCl3, 75 MHz): δ 18.8 (C-4); 21.4 (CH3); 28.0 (C-3); 79.2
(C-2); 121.8 (C-4a); 126.1; 126.2; 126.5; 129.5; 133.7 and 134.1 (C-Har); 131.3
(C-9a); 136.3 (C-5a); 138.3 (Cquat.ar); 155.8 (C-10a); 179.6 and 184,0 (2C=O);
HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for C20H16O3Na 327.1099; Found:
327.1103. Anal. Calcd for C20H16O3: C, 78.93; H, 5.30. Found: C, 78.90; H,
5.28.
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2-(4-methylphenyl)-3,4-dihydro-2H-benzo[h]chromene-5,6-dione
(13b).29
Compound 13b was obtained as an orange solid in 30% yield (52 mg). M.p.=
165-167 0C; IR (film, CHCl3) cm-1): 2924, 1697, 1647, 1590, 1572, 1393, 1280,
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1151, 922, 771; H NMR (CDCl3, 300 MHz): δ: 2.00-2.14 (1H, m, H-3); 2.27-
2.35 (1H, m, H-3); 2.40 (3H, s, CH3) 2.53-2.64 (1H, m, H-4); 2.77 (1H, ddd, J =
3.1; 5.6 and 8.7 Hz H-4); 5.24 (1H, dd, J = 2.4 and 7.8 Hz, C-2); 7.24-7.33 (4H,
m, H-ar); 7.51 (1H, ddd, J = 1.4, 7.5 and 8.7 Hz, H-8); 7.62 (1H, ddd, J = 1.4,
7.5 and 9.0 Hz, H-9), 7.81 (1H, dd, J = 1.2 and 7.8 Hz, H-10); 8.01 (1H, dd, J =
1.4 and 7.5 Hz, H-7); 13C{1H} NMR (CDCl3, 75 MHz): δ: 18.7 (C-4); 21.4 (CH3);
28.6 (C-3); 80.4 (C-2); 114.3 (C-4a); 124.3; 126.1; 128.9; 129.7; 131.0 and
135.1 (C-ar); 130.2 (C-6a); 132.4 (Cquart-C-2); 136.7 (Car-CH3); 138.7 (C-10a);
163.2 (10b); 178.8 and 179.8 (2C=O); HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd
for C20H16O3Na 327.1099; Found: 327.1095. Anal. Calcd for C20H16O3: C,
78.93; H, 5.30. Found: C, 78.90; H, 5.28.
2-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (14a).
29
Compound 14a was obtained as a yellow solid in 80% yield (140 mg). M.p.=
o
165-166 C; IR (film, CHCl3) (cm-1): 1681, 1645, 1612, 1245, 1194, 1062,
1021, 953, 720; 1H NMR (CDCl3, 300 MHz): δ 2.10 (1H, dddd, J = 2.6, 3.5, 6.4
and 13.0 Hz, H-3°), 2.28 (1H, dddd, J = 2.0, 6.1, 6.3 and 13.0 Hz, H-3b), 2.59
(1H, ddd, J = 3.5, 6.1 and 12.2 Hz, H-4a), 2.76 (1H, ddd, J = 2.0, 6.4, and 12.2
Hz, H-4b), 5.14 (1H, dd, J = 2.6 and 6.3 Hz, H-2), 6.89 (2H, d, J = 8.3 Hz, ArH),
7.30 (2H, d, J = 8.3 Hz, ArH), 7.69 (2H, dddd, J = 1.5, 7.5, 9.0, 11.0 Hz, H-8 and
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H-7), 8.09 (2H, dddd, J = 1.5, 7.5, 9.0, 10.9 Hz, H-9 and H-6). C{1H} NMR
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(CDCl3, 75 MHz): δ 19.0 (C-4), 28.0 (C-3), 55.5 (OCH3), 79.1 (C-2), 114.3 (C-
4a), 126.2 (C-6), 126.5 (C-9), 133.5 (C-7), 134.1 (C-8), 131.3 (C-9a), 131.7 (C-
5a), 155.8 (C-10a), 159.9 (C-4’), 179.7 and 184.5 (C-5 and C-10); HRMS
(ESI/Q-TOF) m/z: [M + Na]+ Calcd for C20H16O4Na 343.1049; Found: 343.1041.
Anal. Calcd for C20H16O4: C, 74.99; H, 5.03. Found: C, 74.89; H, 5.07.
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2-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (14b).11
Compound 14b was obtained as a yellow solid in 20% yield (35 mg). M.p.= 155-
157 0C; IR (film, CHCl3) (cm-1): 1605, 1572, 1525, 1280, 1249, 1170, 921, 774;
1H NMR (CDCl3, 300 MHz): δ 2.11 (1H, dddd, J = 2.4, 3.6, 5.7 and 13.0 Hz, H-
3a); 2.31 (1H, dddd, J = 3.2, 6.2, 7.8 and 13.0 Hz, H-3b); 2.61 (1H, ddd, J = 3.6,
6.2 and 8.7 Hz, H-4a), 2.76 (1H, ddd, J = 3.2, 5.7 and 8.7 Hz H-4b), 3.85 (3H, s,
OCH3), 5.20 (1H, dd, J = 2.4 and 7.8 Hz, C-2), 6.96-6.99 (2H, m, H-ar), 7.34-
7.37 (2H, m, H-ar), 7.51 (1H, ddd, J = 1.4, 7.5 and 8.7 Hz,H-8), 7.60 (1H, ddd, J
= 1.4, 7.5 and 9.0 Hz, H-9), 7.80 (1H, dd, J = 1.2 and 7.8 Hz, H-10), 8.08 (1H,
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dd, J = 1.4 e 7.5 Hz, H-7). C{1H} NMR (CDCl3, 75 MHz): δ: 18.4 (C-4), 28.0
(C-3), 55.2 (OCH3), 79.9 (C-2), 113.8 (C-4a), 114.0 (C-10), 123.9 (C-7), 127.2
(C-8), 128.5 (C-2’), 129.8 (C-6a), 130.6 (C-3’), 131.2 (C-9’), 132.0 (C-10a),
134.7 (C-1’), 159,6 (C-4’), 162.9 (C-10b), 178.4 and 179.4 (C-5 and C-6).
HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for C20H16O4Na 343.1049; Found:
343.1054. Anal. Calcd for C20H16O4: C, 74.99; H, 5.03. Found: C, 74.97; H,
5.01.
2-phenyl-4H-benzo[g]chromene-5,10-dione (15). Compound 15 was obtained
0
as a yellow solid in 60% yield (104 mg). M.p.= 157-163 C; IR (film, CHCl3)
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(cm-1): 3401, 2918, 1673, 1651, 1625, 1245, 1206, 1101, 998, 758; H NMR
(CDCl3, 300 MHz): δ 3.36 (2H, d, J = 3.7 Hz, H-4), 5.68 (1H, t, J = 3.7 Hz, H-3),
7.35-7.43 (3H, m, H-8 and H-7 and H-para at C-2), 7.68-7.75 (4H, m, ArH),
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8.09-8.16 (2H, m, H-9 and H-6); C{1H} NMR (CDCl3, 75 MHz): δ 21.9 (C-4),
100.5 (C-3), 121.6 (C-4a), 126.9, 128.5, 128.9, 131.0, 131.4, 135.9 and 136.6
(C-Har), 133.4 (C-5a), 134.2 (C-9a), 135.0 (C-quat. Ar), 150.7 (C-10a), 154.5
(C-2), 186.6 (C-5 and C10); HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for
C19H12O3Na 311.0786; Found: 311.0775. Anal. Calcd for C19H12O3: C, 79.19; H,
4.20. Found: C, 79.10; H, 4.20.
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Procedure for preparation of 10a/10b at large scale. To a round-bottom flask
equipped with a magnetic stirring bar, 5 grams (28.71 mmols) of lawsone was
dissolved in dioxane (100 mL), followed by addition of 6.89 grams of
formaldehyde (229.68 mmol). The 8.97 grams of styrene (86.13 mmols) was
added dropwise and the reaction mixture was stirred under reflux until
consumption of the starting material. The solvent was removed under reduced
pressure; ethyl acetate was added in the residue and the mixture was washed
with saturated sodium bicarbonate aqueous solution. The combined organic
extract was washed with water, dried over anhydrous sodium sulfate, filtered
and concentrated under vacuum. The residual mixture of products was purified
by flash chromatography employing gradient n-hexane/EtOAc as eluent,
furnishing the desired 1,2-naphthoquinone (10a) and 1,4-naphthoquinone (10b)
in 75% (3.7 grams) and 25% (1.3 grams) yields, respectively.
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Computational details.
Full geometry optimizations were carried out using the hybrid DFT M06-2X
functional30 together with the 6-31+G(d,p) basis set. For each optimized
stationary point, the second-order Hessian matrix was computed at the same
level to confirm the stationary point as a minimum on the potential energy
surface, in which all eigenvalues are 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, the distorted transition state structure obtained during the
animation was optimized towards products and pre-reactive complexes. The
normal mode calculations were also useful for computing the thermodynamic
parameters at 298 K using standard statistical thermodynamic equations for an
ideal gas31. Apart from the gas-phase calculations, solvation effects were also
accounted for by using water and dioxane as implicit solvent within the
polarized continuum solvation model (IEFPCM)32,33. All computations were
performed with the G09 software package using default convergence criteria34.
For the reaction between 4H and ethene, IRC calculations35-37 from the
transition state structures TSα and TSβ towards products (α- and β-lapachone,
respectively) and pre-reactive complexes (IC) were performed. The transient
structures obtained at each IRC point were decomposed into two fragments (4H
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