Journal of Molecular Graphics and Modelling 121 (2023) 108451

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Journal of Molecular Graphics and Modelling

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Exploring the peri- and stereo- selectivities of the cycloaddition reaction of

2-(2- dimethylaminovinyl)-1-benzopyran-4-one with N-phenylmaleimide
(NPM) and dimethylacetylenedicarboxylate (DMAD) - A DFT study
Richmond Arhin a, Isaac Ofori a, Anthony Fosu a, Richard Tia a, Evans Adei a, Albert Aniagyei b, *
a
Theoretical and Computational Chemistry Laboratory, Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
b
Department of Basic Sciences, University of Health and Allied Sciences, Ho, Ghana

A R T I C L E I N F O A B S T R A C T

Keywords: The [4 + 2] cycloaddition reactions of 2-styrylchromones have been predominantly described as one of the
Xanthones efficient methods for the synthesis of xanthones-a prominent class of tricyclic molecules that occur widely in
Benzopyrone nature. These xanthones are well known for their pharmacological activities especially their role as anti-cancer
2-Styrylchromones
agents in the medicinal world. In this study, the mechanistic insight into the unusual (peri- and stereo-) selec­
N-phenylmaleimide (NPM)
Dimethylacetylenedicarboxylate (DMAD)
tivities of the reaction of 2-(2-dimethylaminovinyl)-1-benzopyran-4-one (A1) with N-phenylmaleimide (NPM)
[2 + 2] cycloaddition reaction and dimethylacetylenedicarboxylate (DMAD) has been studied using density functional theory (DFT) at the M06-
2X/6-311G (d, p) level of theory. The reaction of A1 and NPM in dimethylformamide (DMF) is periselective
towards the initial formation of a [4 + 2] cycloadduct and stereoselectively in an exo fashion with an activation
energy of 6.8 kcalmol− 1 and a rate constant of 6.43 × 107 s− 1 which occurs about 878 million times faster than the
closest competing pathway for the initial [2 + 2] cycloaddition fashion with an activation energy of
19.0 kcalmol− 1 and a rate constant of 7.32 × 10− 2 s− 1 . For the substituent effect on the reaction, the reaction
selectivity is still maintained where the exo intermediate remains the most kinetically favored cycloadduct.
However, the magnitude of the barriers increases slightly with a margin of about 0.1 − 4.8 kcalmol for the
electron-donating groups (EDGs) in the order; strong EDGs (OH < NH2 < OCH3) < weak EDGs (<Ph) and 5.3 −
6.4 kcalmol for electron-withdrawing groups in the order; strong EWGs (CF3) < weak EWGs (Cl < Br). On the
other hand, DMAD periselectively adds across the amino substituted olefinic bond of A1 via an initial [2 + 2]
stepwise cycloaddition fashion followed by an intramolecular rearrangement to form the xanthone product. The
rate constant of the rate-determining step in the pathway for the formation of the kinetically favored [4 + 2]
cycloadduct with an activation barrier of 17.3 kcalmol− 1 is 1.29 s− 1 which occurs about 373,000 times slower
than the most preferred pathway affording a [2 + 2] cycloadduct with an activation barrier of 9.7 kcalmol− 1 and
a rate constant of 4.81 × 105 s− 1 . Both reactions are normal electron-demand cycloaddition reactions and are
kinetically controlled.

1. Introduction
Natural products have always been a source of inspiration for drug
development, as evidenced by the current number of drugs on the
market and in clinical trials having been isolated or being derivatized
from natural products. Xanthones [See Fig. 1] like many others are a
group of natural products which have attracted a lot of attention from
synthetic chemists owing to their biological, pharmacological, and
biocidal activities. For example, α – mangostin [See Fig. 2] a natural
xanthonoid is obtained from the bark and dried sap of Garcinia man­
gostana L., a tropical tree belonging to the family Guttiferae [1] and its
chiral derivatives have been investigated for antioxidant,
anti-proliferative, pro-apoptotic, anti-inflammatory, anti-carcinogenic,
anti-bacterial, anti-tuberculosis, anti-fungal, anti-HIV, and enhance­
ment of the immune system, and anti-microbial activities [2]. The tri­
cyclic core of xanthones as well as the type and position of substituents
around this scaffold, are responsible for its various biological activities
making it a privileged structure in the arsenal of a medicinal chemist

* Corresponding author.
E-mail addresses: rarhin711@gmail.com (R. Arhin), iofori995@gmail.com (I. Ofori), anthonyfosu98@gmail.com (A. Fosu), richtiagh@yahoo.com (R. Tia),
eadei@yahoo.com (E. Adei), aaniagyei@uhas.edu.gh (A. Aniagyei).

https://doi.org/10.1016/j.jmgm.2023.108451
Received 12 January 2023; Received in revised form 23 February 2023; Accepted 6 March 2023
Available online 13 March 2023
1093-3263/© 2023 Elsevier Inc. All rights reserved.
R. Arhin et al.
Fig. 1. Xanthone scaffold and numbering [4].
Fig. 2. Structure of α – mangostin.
[3].
Conventional methods for the formation of the xanthone scaffold can
be traced from several reactions which include some of the oldest and
well-known routes by reaction of salicylic acids or salicylic esters with
polyphenolic compounds, catalyzed by strong acids [5]. Several acid
catalysts have been used and among them, the most successful and
commonly used is zinc chloride/phosphoryl chloride, which was named
Grover, Shah, and Shah (GSS) reaction [6]. Moreover, there is also
synthesis via diphenyl ether intermediates, Nencki reaction [7], and
other classical methods [8,9]. In the field of the syntheses of xanthones,
these methodologies are still resorted to in regard to the fact that the
reagents, in general, are cheap and accessible, and also the yields are
reasonable.
However, there are limitations associated with these traditional
methods, for instance, the common GSS reaction proceeds via a benzo­
phenone intermediate which must have one hydroxyl in the 6 or 6′
position, besides two hydroxyls in positions 2 and 2’, without that, an
additional cyclization of the benzophenone intermediate is needed to
obtain the xanthone. Also, the Nencki reaction is not so used owing to
higher reaction temperature and undesirable O-demethylations [10,11].
Such limitations and others have inspired a probe into various im­
provements to these classical methods. To improve upon these limita­
tions, several approaches have been developed toward facilitating an
efficient synthesis of these xanthone products [12,13]. Most of these
approaches involve modifications of reaction models or processes typi­
cally for Friedel–Crafts reactions and also alternations in conventional
catalytic materials. Among these developed approaches is a distinct re­
action route that is not based on the utility of two aryl derivatives as the
building blocks and the generation of the xanthonic scaffold through the
formation of ether and ketone linkages. This strategy employs the use of
chromen-4-ones (2-styrylchromones(2-SC)) [See Fig. 3] as the building
block [10].
To this end, Mustafa et al. investigated the ability of 2-styrylchro­
men-4-ones having conjugated bonds to undergo Diels Alder
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Journal of Molecular Graphics and Modelling 121 (2023) 108451
Fig. 3. Structure and numbering system of 2-styrylchromones (2-SC) [14].
cycloaddition reactions (a powerful synthetic tool) by their reaction
with some known dienophilic species. This resulted in the easy forma­
tion of xanthone derivatives [15]. On this basis, the chemical reactivity
of 2-styrylchromen-4-ones was established with reports depicting their
versatility in reacting as either a diene or a dienophile [14].
Ghosh et al. adopted this new strategic approach and reacted 2-(2-
dimethylaminovinyl)-1-benzopyran-4-one with N-phenylmaleimide
(NPM) which led to a xanthone product in one step and moderate yields.
The product outcome of the reaction was proposed to proceed via the
expected initial [4 + 2] cycloaddition (Scheme 1) where the benzo­
pyrone acts as a conjugated system (diene) due to the strong electron-
releasing effect of the amino group [16].
Moreover, the cycloaddition reactions of dimethylacetylenedi­
carboxylate (DMAD) in the [4 + 2] or Diels Alder cycloaddition fashion
has been extensively established. This reveals how the utility of this
method has become strategic in allowing the ease in the accessibility of a
variety of novel compounds most of which are known to have very
complicated biosynthetic or synthetic mechanisms [17]. A report by
Wolinsky et al. stated that this procedure complements and extends
various methods for the direct construction of benzene rings [18] Also,
the Diels Alder cycloadditions of DMAD are considered important in this
regard where subsequent intramolecular rearrangement follows the
cycloaddition to furnish various benzene rings [19] and it is very often
used as a standard to check the efficiency of various dienes [17].
In further work, the cycloaddition reaction of dimethylacetylenedi­
carboxylate (DMAD) with 2-(2-dimethylaminovinyl)-1-benzopyran-4-
one was investigated. Contrary to the expected [4 + 2] cycloaddition
observed in the reaction with NPM, a different product was isolated from
this work. Ghost et al. in attempts to rationalize this observation pro­
posed that, benzopyrone 1 behaves as an unconjugated system to give a
[2 + 2] cycloadduct (Scheme 1) which isomerizes (Scheme 3) to furnish
the xanthone product which was the observed product [16,20].
Despite the pharmacological activities of xanthone products
including those furnished by Ghosh et al., little is known about the
factors influencing such peri- and stereoselectivities of the 2-(2-dime­
thylaminovinyl)-1-benzopyran-4-one (A1) reactions with N-phenyl­
maleimide (A2) and dimethylacetylenedicarboxylate (A3).
R. Arhin et al.
Scheme 1. A proposed scheme of the reaction between 2-(2- dimethylaminovinyl)-1-benzopyran-4-one (A1) with NPM (A2) and DMAD (A3).
Scheme 2. A proposed scheme of rearrangement of [4 þ 2] cycloadduct of the reaction of A1 and A3.
Hence in this study, we report for the first time, a detailed mecha­
nism of the cycloaddition reactions of A1 with NPM (A2) and DMAD
(A3). The peri- and stereoselectivities, as well as substituent reactivity,
and electronic effect on reacting species of the title reaction have been
investigated. The effect of solvent on the reaction rate and selectivities
has also been studied.
2. Computational details and methodology
Here we present only a brief statement of the method because a fuller
description is available in Refs. [21–30]. The M06-2X hybrid functional
[31] as implemented in Gaussian 09 [30] has been employed together
with the split valence triple-ξ (TZ) basis set 6-311G (d, p) in this study.
The global electrophilicity (ω) of the various benzopyrone de­
rivatives was calculated using equation (1). The electrophilicity index
measures the ability of a reactant to accept electrons [32] and is a
function of the electronic chemical potential, μ = (EHOMO + ELUMO)/2,
and chemical hardness, η = (ELUMO - EHOMO) as defined by Pearson’s
acid-base concept [33]. Hence, species with large electrophilicity values
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Journal of Molecular Graphics and Modelling 121 (2023) 108451
are more reactive toward nucleophiles. These equations are based on the
Koopmans theory [34] originally established for calculating ionization
energies from closed-shell Hartree–Fock wavefunctions but have since
been adopted as acceptable approximations for computing electronic
chemical potential and chemical hardness.
ω = μ2/2η (1)
The nucleophilicity index of the various reagents was calculated
using equation (2). This scale of nucleophilicity is referred to as tetra­
cyanoethylene (TCE) [35].
N(nu) = EHOMO(nu) (eV) − EHOMO(TCE) (eV) (2)
The rate constants of the reaction at room temperature [k(T)] for the
cycloaddition of the benzopyrone(A1) with N-phenylmaleimide(A2)
and dimethylacetylenedicarboxylate(A3) were calculated using equa­
tion (3) with the assumption that the concentrations (c٥) of the reacting
species are 1 [36].
R. Arhin et al.
Scheme 3. A proposed scheme of rearrangement of [2 + 2] cycloadduct of the reaction of A1 and A3.
KB T −
k(T) = e Δǂ G∘ /RT
(3)
hc∘
where k = 1.380662 × 10− 23 J/K is the Boltzmann’s constant, T =
298.15 K is the reaction temperature at standard condition, h = 6.62617
× 10− 34 J s is the Planck’s constant, R = 1.987 cal/mol. K is the molar
gas constant, Δǂ G∘ is the Gibbs free energy of activation and R is the
molar gas constant, and c∘ is the concentration of the reacting species
taken as 1.
3. Results and discussion
The periselectivity of the reaction emerges from the fact that the
reactants A2 and A3 can distinctly add across the olefinic centers in A1
as clearly depicted in Schemes 4 and 5 respectively. For the reaction
between A1 and A2 in Scheme 4, path A is when the dienophile A2
Scheme 4. A proposed scheme of cycloaddition of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one with NPM.
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Journal of Molecular Graphics and Modelling 121 (2023) 108451
reacts with A1 via a [4 + 2] cycloaddition to give the products P1A
ENDO, P1A EXO, P2A ENDO, and P2A EXO through the proposed
transition states TS1A ENDO, TS1A EXO, TS2A ENDO, TS2A EXO
respectively. Path B emerges from the reaction of A1 and A2 in a [2 + 2]
cycloaddition fashion to yield P1B ENDO and P1B EXO products
through transition states TS1B ENDO and TS1B EXO respectively. From
Path A, P1A ENDO and P1A EXO are diastereomers as well as the P2A
ENDO and P2A EXO pair of products. Also, enantiomeric pairs are
observed between P1A ENDO and P2A ENDO as well as between P1A
EXO and P2A EXO.
From Scheme 5, the reaction route Path C involves two different
reaction channels, leading to the formation of P1C and P2C via TS1C
and TS2C transition states respectively. P1C and P2C form one stereo­
isomeric pair whereas P1D and P2D also form another pair of stereo­
isomers. Both P1C and P2C are formed from the cycloaddition between
A1 and the dienophile A3 in a [4 + 2] cycloaddition fashion. Path D
R. Arhin et al.
Scheme 5. A proposed scheme of cycloaddition of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one with DMAD.
emerges from the [2 + 2] cycloaddition between A1 and A3 to furnish
P1D and P2D through the transition states TS1D and TS2D respectively.
3.1. Analysis of the parent reaction of 2-(2- dimethylaminovinyl)-1-
benzopyran-4-one, (A1 R1 = NMe2) with N-phenyl maleimide (NPM)
(A2, R2 = , R3 = H) in the gas phase
In this section, the peri- and stereo-selectivities involved in the
cycloaddition reaction of 2-(2- dimethylaminovinyl)-1-benzopyran-4-
one (A1, R1 ¼NMe2) with NPM (A2, R2 ¼R3 ¼H) in the gas phase,
have been explored and results discussed. The Gibbs free energy of the
reaction of A1 and A2 at the M06-2x/6-311G (d, p) level of theory is
shown in Fig. 4.
The reaction between A1 and A2 has the formation of P2A EXO
through the transition state TS2A EXO with activation energy of
5.5 kcalmol− 1 as the most kinetically favored reaction channel in the
preferred pathway (path A in Fig. 4). In this present study, an extensive
search on the potential energy surface for the possibility of either a
stepwise or concerted mechanism for the titled reaction was conducted.
From our computations, in all cases, no minima structures were located
for a stepwise mechanism for the reaction channels in Path A, but sta­
tionary point structures (minima and first-order saddle point) were ob­
tained for the concerted mode of addition of A2 across A1 as shown in
the optimized transition state structure TS2A EXO in Fig. 4. The bond
distances of 1.88 Å and 2.62 Å depicts the concerted mode is highly
asynchronous. However, minima structures TS1B and TS1B EXO with
bond distances 2.69 Å and 2.64 Å respectively (Fig. 4) were located for
the stepwise mechanism in the reaction channel leading to the formation
of P1B EXO in path B with an activation barrier of 10.0 kcalmol− 1 for the
rate-determining step with a rate constant of 2.9 × 105 s− 1 . The reaction
energy of − 13.9 kcalmol− 1 indicates that the formation of P1B EXO is
thermodynamically feasible. However, it was observed that the dien­
ophile A2 added to the diene A1 in an asynchronous concerted fashion
leading to the formation of P1B ENDO through the transition state TS1B
ENDO as shown in the optimized transition state structure with
respective bond distances as 1.76 Å and 2.58 Å (Fig. 4). Even though, the
formation of P1B ENDO is shown to be thermodynamically feasible by a
reaction energy of − 14.8 kcalmol− 1 , it is the most kinetically unfavored
path since its activation barrier (30.4 kcalmol− 1 ) exceeds all the barrier
heights of the other reaction channels in both path A and path B. In fact,
with a rate constant of 3.2 × 10− 10 s− 1 , it is evident that the formation of
P1B ENDO proceeds about 9 × 1014 times slower than the formation of
P1B EXO in path B and also a slow reaction rate compared to the rate of
formation of the most kinetically favored product P2A EXO in path A
with a speed margin of about 1.8 × 1018 , thus indicating why no
xanthone product from the [2 + 2] pathway was isolated from the
experiment conducted by Ghosh and his coworkers.
The reaction energies with values ranging from − 13.9 to−
24.3kcalmol− 1 (Fig. 4) indicates that the reaction of A1 and A2 in both
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Journal of Molecular Graphics and Modelling 121 (2023) 108451
pathways is highly exergonic and thus a thermodynamically feasible
process. The closest competing reaction channel in Path A of the reaction
between A2 and A1 proceeds through the TS2A ENDO with an activa­
tion energy of 12.6 kcalmol− 1 to afford the P2A ENDO. The preference
for Path A associated with the formation of P2A EXO is consistent with
the experimental isolation of a xanthone product formed from an
intramolecular rearrangement of a [4 + 2] cycloadduct as products from
Path A [16]. From the energetics, it is evident the cycloadduct involved
in the rearrangement is P2A EXO. Since it has the least activation barrier
of 5.5 kcalmol− 1 and proceeds about 160 thousand times faster than the
closest competing reaction channel leading to the formation of P2A
ENDO.
From the Gibbs free energy profile shown in (Fig. 4), the reaction
energy values − 13.9kcalmol− 1 , − 14.8kcalmol− 1 , − 16.9kcalmol− 1 , −
521.7kcalmol− 1 , − 24.1kcalmol− 1 − 24.3kcalmol− 1 show that the forma­
tion of all the products is thermodynamically feasible and indicate that
the selectivity of the reactions is kinetically controlled
3.1.1. Effects of substituents on 2-(2-dimethylaminovinyl)-1-benzopyran-4-
one
This section examines the effect of substituents on benzopyranone
(A1) on the selectivities encountered in the cycloaddition reaction of
benzopyranone and N-phenylmaleimide (NPM). It ought to be stated
that attempts to locate some transition states and equilibrium geome­
tries of some intermediates in selected instances proved futile. These
include transition states and intermediate structures of most products of
P1B EXO for both electron-donating groups (EDGs) and electron-
withdrawing groups (EWGs), transition states of P1A EXO (R1¼Cl,
Br, CN) and P2A EXO (R1¼CN) for EWGs (Table 2), and transition
states of the EDGs, TS1A ENDO (R1¼OCH3), TSA ENDO (R1¼Ph),
TS2A EXO (R1¼CH3) and TS1B ENDO (R1¼Ph) (Table 1).
3.1.2. Effects of electron-donating substituents (EDGs) on the
benzopyranone
The effects of various EDGs (R1¼NH2, OH, OR, CH3, Ph) on the
mechanistic outcome of the reaction of A2 and A1 are shown in Table 1.
Evidently, from Table 1, the benzopyranone periselectively adds across
the olefinic bond in NPM via a [4 + 2] cycloaddition fashion irrespective
of the electronic influence delineated by the electron-donating groups
(EDGs) on the benzopyranone. The observed selectivities are controlled
by the electronic effects of the substituents, in all cases studied for the
EDGs on A2. The kinetically favored reaction pathway for all EDGs on
the A1 molecule is the one that leads to the formation of product P2A
EXO through TS2A EXO. The magnitude of the activation energies is
increased as compared to that of the parent reaction (R1¼NMe2) with a
margin ranging from 0.1 − 4.8 kcalmol− 1 . The extent of increase of the
activation barriers relative to the parent reaction is in the order: strong
EDGs < weak EDGs (OH < NH2 < OCH3 <Ph). Despite the variation in
the magnitude of the activation energies, selectivities of the reactions
are seen not to change and the barrier trends of activation energies of
R. Arhin et al. Journal of Molecular Graphics and Modelling 121 (2023) 108451

Table 1
Activation energies and reaction energies of the [4 þ 2]/[ 2 þ 2] cycloaddition reaction of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one with N-phenylmaleimide
in the gas phase at the M06-2X/6–311G (d, p), level of theory. All energies are in kcal/mol.
Substituents TS1A TS1A TS2A TS2A TS1B TS1B INT1BEXO TS1B P1A P1A P2A P2A P1B P1B
ENDO EXO ENDO EXO ENDO EXO EXO 2 ENDO EXO ENDO EXO ENDO EXO

R1 R2

NMe2 H 18.8 15.9 12.6 5.5 30.4 15.6 15.3 25.3 − 16.9 − 24.1 − 21.7 − 24.3 − 10.9 − 23.1
EDGs
CH3 H 23.2 17.2 14.9 – 51.2 – – – − 30.0 − 32.7 − 32.8 − 32.2 − 23.5 − 23.1
Ph H 22.5 16.5 – 10.3 – 24.2 – – − 26.6 − 30.3 − 29.7 − 30.9 − 19.3 − 19.3
NH2 H 18.5 16.0 11.4 6.4 28.7 20.0 − 39.1 – − 24.4 − 24.6 − 26.4 − 24.4 − 17.5 − 16.4
OH H 15.0 13.4 9.7 5.6 45.6 46.8 − 24.3 − 31.7 − 31.8 − 28.6 − 21.0 − 21.0
OCH3 H – 12.7 15.9 8.6 40.6 40.6 − 34.0 − 29.1 − 27.2 − 31.6 − 21.9 − 17.1

Table 2
Activation and reaction energies of the [4 þ 2]/[ 2 þ 2] cycloaddition reaction of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one with N-phenylmaleimide in the gas
phase at the M06-2X/6–311G (d, p), level of theory. All energies are in kcal/mol.
Substituents TS1A TS1A TS2A TS2A TS1B TS1B INT1B TS1B P1A P1A P2A P2A P1B P1B
ENDO EXO ENDO EXO ENDO EXO EXO EXO 2 ENDO EXO ENDO EXO ENDO EXO

R1 R2

NMe2 H 18.8 15.9 12.6 5.5 30.4 15.6 15.3 25.3 − 16.9 − 24.1 − 21.7 − 24.3 − 10.9 − 23.1
EWGs
Cl H 23.3 – 17.0 11.4 58.1 – – – − 30.3 − 38.1 − 32.8 − 35.7 − 23.9 − 23.7
Br H 23.8 – 17.5 11.9 – – – – − 30.0 − 38.5 − 32.5 − 36.5 − 23.7 − 23.7
CF3 H 26.6 16.7 17.5 10.8 – – – – − 32.5 − 39.3 − 36.1 − 38.9 − 24.5 − 24.5
CN H 21.4 – 18.1 – 61.8 – – – − 28.3 − 34.2 − 30.7 − 31.3 − 22.1 − 21.3

P2A EXO 10.3kcalmol− 1 , 6.4kcalmol− 1 , 5.6kcalmol− 1 and 8.6kcalmol− 1 temperature. The observed energetic trends do not differ from those in
for R1¼Ph, R1¼NH2, R1¼OH, and R1¼OCH3 respectively, remain the the gas phase. Also, the extensive exploration of the potential energy
same as the parent reaction where these values denote the most surface for the cycloaddition reaction of A1 and A2 reveals that
preferred pathway as compared to the barriers of the other reaction regardless of the presence of solvent (DMF), the benzopyrone (A1) adds
channels some as high as 23.2kcalmol− 1 for the competing [4 + 2] periselectively across the NPM (A2) to afford the [4 + 2] cycloadducts
pathway in path A (TS1A ENDO, R1¼CH3) and 46.8kcalmol− 1 for the from Path A.
unfavored [2 + 2] pathway in path B (TS1B EXO, R1¼OH). Similar to the gas phase computations, the reaction of A1 and A2
under experimental conditions is kinetically controlled. From Fig. 5, the
3.1.3. Effects of electron-withdrawing groups (EWGs) on the benzopyrone favorable reaction channel, again, goes through TS2A EXO to furnish
The mechanistic outcome of different electron-withdrawing groups the product P2A EXO with an activation barrier of 6.8 kcalmol− 1 . This
(R1¼CN, CF3, Br, Cl) on the benzopyrone has also been explored and selectivity is further confirmed by the rate constants for forming the
the results are displayed in Table 2. Like the EDGs, the electron- products as shown in Table 3.
withdrawing group substituted benzopyrone promotes the [4 + 2] The rate constant for the formation of P2A EXO is 6.43 × 107 s− 1 is
cycloaddition across the C–C olefinic bond present in the dienophile A2. about 4.2 × 104 times faster than the closest competing reaction channel
The obvious favorable reaction channel emerging from Path A leads to a in the Path A reaction route with a rate constant of 1.55 × 103 s− 1 . The
periselective formation of P2A EXO since low activation barriers are most kinetically favored reaction channel along Path B proceeds through
seen from this reaction channel with values ranging from 10.8 to an initial transition state TS1B to form an intermediate INT1B with a
11.9kcalmol− 1 (Table 2) in the order of R1¼CF3 < Cl < Br. The acti­ rate constant of 7.3 × 10− 2 s− 1 which is approximate 8.8 × 108 times
vation energies of the EWGs are significantly higher compared to the
activation energies of the EDGs and also higher than those of the parent
reaction (R1¼NMe2) and this is due to the electronic effects of the
substituents. Comparing the magnitude of the activation barriers to that
of the parent reaction, R1¼NMe2, the margin of increase ranges from
5.3 − 6.4 kcalmol− 1 .This shows that even R1¼CF3 which records the
least activation energy among the EWGs increases the magnitude about
53 times than the increase in magnitude by R1¼OH regarding the
preferred reaction channel leading to P2A EXO in the parent reaction,
R1¼NMe2. In all the cases considered for EWGs on the benzopyrone,
negative reaction energy values for the products from Table 2 depict that
the reactions are kinetically controlled and the selectivities are deter­
mined by the activation barriers.

3.2. Analysis of the parent reaction of 2-(2- dimethylaminovinyl)-1-

benzopyran-4-one (A1) with N-phenyl maleimide (NPM) (A2) under
experimental conditions
In this section, we explore the mechanistic effects of dime­
thylformamide (DMF) as a solvent on the parent reaction at room
Fig. 4. Gibbs free energy profile of [4 þ 2] and [2 þ 2] cycloaddition re­
actions of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one (A1, R1¼NMe2) and
N-phenylmaleimide (A2, R2¼H) in the gas phase at the M062x/6-311G (d, p)
level of theory.

6
R. Arhin et al. Journal of Molecular Graphics and Modelling 121 (2023) 108451

Fig. 5. Gibbs free energy profile of [4 þ 2] and [2 þ 2] cycloaddition re­

actions of (A1, R1¼NMe2) and (A2, R2¼R3¼H) in the dimethylformamide Fig. 6. Gibbs free energy profile of [4 þ 2] and [2 þ 2] cycloaddition re­
(DMF) solvent at the M062x/6-311G (d, p) level of theory. actions of benzopyrone (A1, R1¼NMe2) and dimethylacetylenedicarboxylate,
DMAD (A3, R2¼R3¼CO2Me) in the solvent phase at the M062x/6-311G (d, p)
level of theory.
Table 3
Rate constant (s− 1 ) at 25◦ C for the cycloaddition reaction of (A1, R1 ¼ NMe2) magnitude to a margin of about 6.0 to 9.8 kcalmol− 1 . The rate-
and NPM (A2, R2¼R3 ¼H) to form the various intermediates and products
determining step in the reaction pathway leading to the formation of
computed in DMF and gas phase.
P2D is the initial step leading to the zwitterionic intermediate INT2D
Intermediates Rate constant [k(T)] Rate constant [k(T)] which proceeds through an activation barrier of 9.7 kcalmol− 1 to afford
DMF Gas P2D. This step has a rate constant of 4.81 × 105 s− 1 which is about 856
P1A ENDO 1.14 × 10− 2
1.03 × 10− 1 times faster than the rate-determining step in the closest competing
P1A EXO 8.27 13.72 reaction channel which affords P1D. The initial step which yields the
P2A ENDO 1.55 × 103 3.60 × 103 intermediate INT1D is the rate-determining step in the reaction channel
P2A EXO 6.43 × 107 5.77 × 108 with an activation barrier of 13.7 kcalmol− 1 and a rate constant of 5.62 ×
P1B ENDO 1.08 × 10− 3 3.22 × 10− 10
P1B EXO 22.76
102 s− 1 . Considering this fact, the most kinetically favored reaction
7.32 × 10− 2
channel is that leading to the formation of P2D with its rate-determining
step having an activation barrier of 9.7 kcalmol− 1 . From Table 4, it could
slower than the formation of P2A EXO. This then explains the detection be deduced that the formation of P2C with its rate-determining step as
of a xanthone product obtained via a proposed intramolecular rear­ the initial step which affords the zwitterionic intermediate INT2C with
rangement of a [4 + 2] cycloadducts like those from Path A [16] and the an activation energy of 17.3 kcalmol− 1 and a rate constant of 1.29 s− 1 is
preference of Path A over Path B. Though the barriers slightly increase the most preferred reaction channel in terms of kinetics in the Path C
systematically under experimental conditions, the observed peri- and reaction route and is about 373000 times slower than the formation of
stereoselectivities remain the same as in the gas phase. The increase in P2D with a rate constant of 4.81 × 105 s− 1 for the rate-determining step.
magnitude in the solvent phase compared to the gas phase for the Hence, this gives an implication that the formation of the isolable
preferred pathway affording P2A EXO is by a margin of 1.3kcalmol− 1 . xanthone product is possible through the proposed intramolecular
However, the activation barrier for the reaction channel leading to the rearrangement of the [2 + 2] cycloadduct which in this case is depicted
formation of P1B ENDO is reduced from 30.4kcalmol− 1 to 21.5kcalmol− 1 from computations as P2D. The reaction under experimental conditions
but still, it records the highest activation barrier height and thus remains is kinetically controlled and the low reaction energies ranging
as the unfavored reaction channel and again depicts why no product − 25.6 kcalmol− 1 to − 40.7 kcalmol− 1 from the Gibbs free energy profile
from the [2 + 2] pathway was isolated. indicate that the reactions are highly exergonic and for that matter,
thermodynamically feasible processes. Also, all the products are ther­
modynamically stable with the products from path C being the most
3.3. Analysis of the parent reaction of 2-(2- dimethylaminovinyl)-1-
stable.
benzopyran-4-one A1 with dimethylacetylenedicarboxylate (DMAD) A3
With the formation of P2D as the most favored reaction channel, it is
under experimental conditions
seen that the computations under experimental conditions for the
This segment addresses the mechanistic effect of solvent (dime­
thylformamide (DMF)) on the cycloaddition reaction between benzo­
pyrone A1 and DMAD (A3). The various reaction channels have been Table 4
Rate constant (s− 1 ) at 25◦ C for the cycloaddition reaction of (A1, R1 ¼ NMe2)
investigated under the experimental conditions with details shown in
and DMAD (A3, R2¼R3 ¼CO2Me) to form the various intermediates and
Fig. 6. In all cases, attempts to obtain minima structures for the
products computed in DMF and gas phase.
concerted mode of addition of A3 across A1 via the [4 + 2] cycloaddi­
Intermediates Rate constant [k Intermediates/ Rate constant [k
tion fashion in the condensed phase proved futile. Thus, only the minima
(T)] Products (T)]
structures (like TS2C, TS2C2, TS2D, and TS2D2) for a stepwise
mechanism on the potential energy surface were located for the transi­ DMF (T = 25◦ C) Gas (T = 25◦ C)

tion states in both reaction pathways (path C and path D). From the INT1C 3.15 × 10 − 2 P1C 1.67 × 10− 18

energetics in Fig. 6, it is seen that all the reaction channels leading to the INT2C 1.29 P2C 3.99 × 10− 12

formation of [2 + 2] cycloadducts in the reaction path D are kinetically INT1D 5.62 × 102 INT1D 3.18 × 10− 13

INT2D 1.57 × 106 INT2D 3.13 × 10− 16

favored over the [4 + 2] cycloadducts afforded via the reaction channels
P2D 4.81 × 105
in path C with the barriers for their rate determining step lowered in

7
R. Arhin et al. Journal of Molecular Graphics and Modelling 121 (2023) 108451

cycloaddition reaction of A1 and A3 are consistent with the proposed

mechanism by Ghosh et al. for the isolated xanthone product through an
intramolecular rearrangement of a [2 + 2] cycloadduct [16].

3.3.1. Analysis of intramolecular rearrangement of cycloadduct

intermediate for the reaction between A1 and A3
Following the initial cycloaddition step, the [2 + 2] cycloadduct
formed is rationalized to proceed through a subsequent intramolecular
rearrangement process leading to the formation of the xanthone product
5. In addition to this, Ghosh et al. proposed that the process occurs under
no influence of any reagent or solvent but the cycloadduct undergoes
base-catalyzed deacylative deamination with itself functioning as the
base. This suprafacial process can also be rationalized for the rear­
rangement of the proposed [4 + 2] cycloadduct (P1C) from path C in
Scheme 5, however, it involves only 2 steps toward the final xanthone
product 6 (Scheme 2). The detailed mechanism of the base deacylative
deamination of the [2 + 2] cycloadduct (P2D) involves 4 steps to afford
the xanthone product 5. (Scheme 3). No minima structures were ob­
Fig. 8. Gibbs free energy profile of the intramolecular rearrangement of P2D
tained for the concerted mode of the rearrangement process. from the reaction of A1 and A3 in the solvent phase at the M062x/6-311G (d, p)
From Scheme 2, it is obvious that the rearrangement of P1C does level of theory.
not afford the isolable xanthone product 5. From the rearrange­
ment process, it is seen that the formation of the xanthone product
about 21.5 to 23.3 kcalmol− 1 higher than those from the solvent phase
from P1C is kinetically favored over that emanating from the pro­
calculations as shown in Table 6, the observed peri- and stereo­
posed P2D cycloadduct intermediate. This is because the rate-
selectivities differ in the gas phase.
determining step in P1C rearrangement has an activation barrier
The favored reaction channel is that which affords the product P2C
of 16.6 kcalmol− 1 (Fig. 7) and a rate constant of 4.2 s− 1 indicating about
with a reaction energy of − 23.9 kcalmol− 1 through the TS2C transition
194 billion times faster than the rearrangement step of P2D to form the
state with an activation barrier of 33.0 kcalmol− 1 . In this reaction
xanthone product 5 with a rate-determining step that has an activation
channel, A1 rather adds periselectively across DMAD (A3) through a [4
barrier of 32.0 kcalmol− 1 (Fig. 8) and a rate constant of 2.16 × 10− 11 s− 1 .
+ 2] cycloaddition manner. The rate constant of this reaction as shown
From this result, the report of no traces of the xanthone product 6 but
in Table 4 is 3.99 × 10− 12 s− 1 which is about 12.6 times faster than the
only the xanthone product 5 can be rationalized on the basis that the
most kinetically favored reaction channel in path D with a rate constant
formation of the isolable product is dependent on the initial cycload­
of 3.18 × 10− 13 s− 1 . Here too the search for the possibility of either a
dition step which in this case the kinetics of the formation of P2D is
stepwise or concerted mechanism for the reactions on the potential
favored over the rate of formation of P1C.
energy surface was conducted. Similar to the reaction of A1 with A2, the
reaction of A1 and A3 depicts only minima structures for the concerted
3.4. Analysis of the parent reaction of 2-(2- dimethylaminovinyl)-1-
mechanism for the transition states in the path C reaction route. How­
benzopyran-4-one (A1) with dimethylacetylenedicarboxylate (DMAD)
ever, all the transition state geometries located in the path D reaction
(A3) in the gas phase calculation
route constitute the minima structures for the stepwise mode of addition
of A3 across the amino substituted olefinic center in A1.
From Table 5, an analysis of the energetics depicts that, except for
From Table 6, the reaction energy values depict that the thermody­
the reaction channel leading to the formation of P2C, all the reaction
namic feasibility of the reactions is still maintained. Also, it depicts that
channels leading to the formation of products in the reaction route path
the reactions are kinetically controlled, and the products formed are
D have lower activation barriers as compared to those in the reaction
thermodynamically stable and unlikely to revert to the reactants.
route path C. From the gas phase calculation, the observed energetic
trends differ from those obtained under the experimental conditions.
Also, apart from the barriers significantly increased with a range of 3.5. Interactions of frontier molecular orbitals

According to the linear combination of atomic orbitals (LCAO)

Fig. 7. Gibbs free energy profile of the intramolecular rearrangement of P1C
from the reaction of A1 and A3 in the solvent phase at the M062x/6-311G (d, p)
level of theory.
approximation, atomic orbitals make up molecular orbitals. When these
molecular orbitals pair up in a pericyclic reaction such as cycloadditions,
the coupling between the diene and the dienophile occurs such that
electrons flux from the HOMO of the diene to the LUMO of the dien­
ophile. Alternatively, the cycloaddition may be significantly controlled
by the HOMO of the dienophile, where electrons are promoted from the
HOMO of the dienophile to the LUMO of the diene during the reaction.
This mode of the pairing of frontier molecular orbitals is described as
inverse electron demand cycloaddition. Hence frontier interactions
provide a means to rationalize the flow of electron density.
Figs. 9 and 10 represent the graphical illustration of the frontier
molecular interactions between A1 and A2. From this illustration, it is
seen that the energy required to promote an electron from the HOMO of
A1 (R1¼NMe2) to the LUMO of A2 (R2¼R3¼H) is 5.13 ev whereas the
energy required to promote an electron from the HOMO of A2
(R2¼R3¼H) to the LUMO of A1 (R1¼NMe2) is 8.26 ev. With the rela­
tive minimal energy required to promote an electron from the HOMO of
A1 (R1¼NMe2) to the LUMO of A2 (R2¼R3¼H), there is an implication

8
R. Arhin et al. Journal of Molecular Graphics and Modelling 121 (2023) 108451

Table 5
Activation energies of the [4 þ 2]/[ 2 þ 2] cycloaddition reaction of 2-(2- dimethylaminovinyl)-1-benzopyran-4-one with dimethylacetylenedicarboxylate in the gas
phase at the M06-2X/6-311G (d, p), level of theory. All energies are in kcal/mol.
Gas Phase TS1C TS2C TS1D TS2D INT1D INT2D TS1D2 TS2D2

Gas 41.0 33.0 38.6 34.5 31.1 31.7 – 36.7

cycloaddition reaction since evidently the energy needed to transfer an

Table 6
electron from the HOMO of A1 (R1¼NMe2) to the LUMO of A3
Reaction energies of the [4 þ 2]/[ 2 þ 2] cycloaddition reaction of 2-(2-
(R1¼R2¼CO2Me) is lower than that required to promote an electron
dimethylaminovinyl)-1-benzopyran-4-one with dimethylacetylenedicarbox­
ylate in the gas phase at the M06-2X/6-311G (d, p), level of theory. All energies
from the HOMO of A3 (R1¼R2¼CO2Me) to the LUMO of A1
are in kcal/mol. (R1¼NMe2) with values of 6.43 ev and 9.50 ev respectively.
The effect of substituents on A1(R1¼NMe2) on the electron demand
Gas Phase P1C P2C P1D P2D
is shown in Table 7. The substitution of EDGs (-CH3, -Ph, -NH2, -OH,
Gas − 24.6 − 23.9 − 5.2 − 7.5 -OCH3) on A1(R1¼NMe2) results in a normal electron demand cyclo­
addition reaction whereas the EWGs cause the reaction between A1
(R1¼ -Br, -CN, CF3) and A2 (R2¼R3¼H) to proceed through an inverse
electron demand cycloaddition reaction except for a Cl substituted de­
rivative of A1. Therefore, derivatives of A1 containing EDGs act as
nucleophiles whiles those with EWGs acts as electrophiles. From this
analysis, we can rationalize through the lower activation barriers be­
tween the ranges of 5.6 to 46.8 kcalmol− 1 for both strong EDGs (OH,
NH2, and OCH3) and EWGs (CF3) than their weak counterparts (CH3,
Ph, Cl, Br) with activation energies between the range of 10.3 to
58.1 kcalmol− 1 as observed in Tables 1 and 2

3.6. Analysis of the global reactivity indices

The intrinsic reactivity in cycloadditions is effectively described

Fig. 9. Graphical illustration of HOMO-LUMO interactions of A1 (R1 ¼ NMe2)
and A2, (R2 ¼ R3 ¼ H).
using the global reactivity indices within the conceptual density func­
tional theory (CDFT) analysis. Thus, in this section, we deploy concep­
tual tools to examine the chemical reactivity and selectivity of reactant
molecules. Characteristics of Diels Alder reactions and other cycload­
ditions are essentially modulated by charge transfer (CT) processes be­
tween the two reactants (i.e., diene and dienophile or dipole and
dipolarophile) [37]. This forms the basis for employing global reactivity
descriptors such as chemical potential (μ), hardness (η), and softness (s)
to qualitatively describe the reactivity of molecules in this work. Mol­
ecules with a high electrophilicity index (ω) value are the best electro­
philes within a group of molecules. Those with larger (ω) have highly
inclined reactivity toward nucleophilic molecules. Also, for a set of
molecules, the one described as highly nucleophilic and most reactive
towards electrophiles is that which has the highest nucleophilicity index
(N) value.

3.6.1. Global reactivity indices analysis of cycloaddition between A1 and

A2
The computed global reactivity indices for A2 (R2¼R3¼H) and A1
derivatives are shown in Table 8. The electronic chemical potential (μ)
of A2 (R2¼R3¼H) is − 3.14 eV which is slightly higher than that of A1
(R1¼NMe2) which is − 3.20eV, thus the reaction between A1 and A2 is
expected to have a slight polar character. For A1 (R1¼NMe2), Ph and
CN substituents on the A1 molecule increases the μ value thus making
the A1 a better nucleophile. Apart from these substituents, all the other
substituents including both EDGs and EWGs used in this study on A1
decrease the value of μ thus reducing the nucleophilic nature of the A1
molecule. This observation is consistent with the observed activation
Fig. 10. Graphical illustration of HOMO-LUMO interactions of A1 (R1 ¼
NMe2) and A3 (R1¼R2¼CO2Me).
barriers of the A1 derivatives with slightly increased values relative to
that of the parent reaction A1 (R1¼NMe2).
According to the electrophilicity scale, any chemical species with an
that the reaction proceeds through a normal electron demand cycload­
index ω < 0.8 eV, 0.8 ≤ ω ≤ 1.5eV, ω > 1.5 eV is classed a marginal,
dition reaction in that A1 (R1¼NMe2) acts as a nucleophile and A2
moderate and strong electrophile respectively and species with nucle­
(R2¼R3¼H) reacts as an electrophile.
ophilicity index (N), N > 3.0 eV, 2.0 ≤ N ≤ 3.0 eV, N < 2.0 eV as strong,
Also, from the frontier molecular interactions between the HOMO
moderate and marginal nucleophile respectively. Considering this fact,
and LUMO of orbitals of A1 (R1¼NMe2) and A3 (R1¼R2¼CO2Me), as
A1 (R1¼NMe2) has a ω value of 0.80 eV and an N value of 3.91 eV
shown in Fig. 10, the reaction proceeds via a normal electron demand
allowing its classification as moderately electrophilic and strongly

9
R. Arhin et al. Journal of Molecular Graphics and Modelling 121 (2023) 108451

Table 7
HOMO-LUMO gaps for the interaction of A1 (R1 = S) and A2 (R2 = R3 = H).
Substituent, S = R1 A1 A2 (R2 = R3 = H)

HOMO(H) LUMO(L) HOMO(H) LUMO(L) L (A2)-H (A1) L (A1)-H (A2) Electron Demand

CH3 − 7.91 − 0.94 − 8.06 − 1.77 6.14 7.14 Normal

Ph − 7.63 − 1.45 − 8.06 − 1.77 5.86 6.61 Normal
NH2 − 7.20 − 0.57 − 8.06 − 1.77 5.43 7.49 Normal
OCH3 − 7.64 − 0.78 − 8.06 − 1.77 5.87 7.28 Normal
OH − 7.75 − 0.78 − 8.06 − 1.77 5.98 7.28 Normal
CN − 8.45 − 2.06 − 8.06 − 1.77 6.68 6.00 Inverse
CF3 − 8.36 − 1.62 − 8.06 − 1.77 6.59 6.44 Inverse
Br − 8.16 − 1.33 − 8.06 − 1.77 6.39 6.73 Inverse
Cl − 8.19 − 1.30 − 8.06 − 1.77 6.42 6.76 Normal

4. Conclusion
Table 8
Global reactivity indices for A1 (R1 = NMe2), A2 (R2 = R3 = H) and for the
The results from this computational study depict that the benzo­
derivatives of benzopyrone A1 in eV.
pyrone (A1) adds periselectively across the C–C olefinic bond of NPM
Substituent, S = R1 М Н ω N (A2) in a [4 + 2] cycloaddition fashion. In this manner, the preferential
Parent = NMe2 − 3.20 0.80 6.39 3.91 addition occurs in such a way that the reaction stereoselectively yields
CH3 − 3.48 0.87 6.97 2.91 the cycloadduct P2A EXO which is capable of undergoing an intra­
Ph 3.09 0.77 6.18 3.19
−
molecular rearrangement to yield the isolable xanthone product 2 from
NH2 − 3.32 0.83 6.63 3.62
OCH3 − 3.43 0.86 6.86 3.18 the experiment. The formation of the preferred cycloadduct P2A EXO
OH − 3.48 0.87 6.97 3.07 under experimental conditions has a rate constant of 6.43 × 107 s− 1
CN − 3.20 0.80 6.39 2.37 which is about 41500 fold faster than the closest competing reaction
CF3 3.37 0.84 6.74 2.46
−
route with a rate constant of 1.55 × 103 s− 1 .
Br − 3.42 0.86 6.83 2.66
Cl − 3.44 0.86 6.88 2.63 Both EDGs and EWGs substituted on the benzopyrone (A1) irre­
A2, (R2 = R3 = H) − 3.14 0.79 6.28 2.77 spective of their electronic effect maintain the peri- and stereo­
selectivities of the reaction. However, the rate of the reaction decreases
gradually due to an increase in activation barriers from EDGs to the
nucleophilic respectively. On the other hand, A2 (R2¼R3¼H) also de­ EWGs in the order; strong EDGs (OH < NH2 < OCH3) < weak EDGs
picts marginal electrophilic and moderate nucleophilic characteristics (<Ph), strong EWGs (CF3) < weak EWGs (Cl < Br). Also, the substituents
since its ω and N values are 0.79 eV and 2.77 eV respectively. Hence, affect whether the addition proceeds via a normal or inverse electron
electron density will flux from A1 (R1¼NMe2) indicating that it behaves demand cycloaddition reaction. Reactions with EDGs substituted on A1
as a nucleophile whereas A2 (R2¼R3¼H) plays the electrophilic role in proceed via a normal electron demand cycloaddition mechanism while
the reaction of A1 and A2. Again, this indicates the consistency with the reactions with EWGs substituted A1 derivatives proceed through an
HOMO-LUMO interactions shown in (Fig. 9) where there is a normal inverse electron demand cycloaddition mechanism. The EDGs
electron demand cycloaddition reaction with electron density fluxing substituted derivatives of the benzopyrone A1 behave as nucleophiles in
from A1 (R1¼NMe2) (nucleophile) with minimum HOMO-LUMO gap the cycloaddition across the C–C olefinic bond in NPM (A2) whiles the
energy of 5.13 eV to A2 (R2 = R3 = H) (electrophile). EWGs substituted benzopyrone derivatives behave as electrophiles. In
all the cases for this study, the diene adds across the C–C olefinic center
3.6.2. Global reactivity indices analysis of A1 cycloaddition with A3 of A2 via a concerted asynchronous mechanism but a stepwise zwit­
Table 9 summarizes the electronic chemical potential (μ), chemical terionic mechanism has been found for the reaction channel leading to
hardness (η), global electrophilicity (ω), and nucleophilicity index P1B EXO. DMF solvent has no significant effect on the energetic trends
values. For the parent reaction, A3 (R1¼R2¼CO2Me) has a chemical observed for the cycloaddition between A1 and A2 at room temperature
potential (μ) value of − 4.77 eV, and that for the benzopyrone A1 but has slightly increased activation barriers as compared to those in the
(R1¼NMe2) as shown in Table 8 is − 3.20 eV. These values show a gas phase. It can also be concluded that the observed selectivities in the
significant difference of 1.57 eV approximately 36.21 kcalmol− 1 and reaction are kinetically controlled.
151.48 kJmol− 1 of energy. This indicates a high polar character of the From the results obtained for the reaction between A1 and A3 under
reaction. The 1.19 ev (ω) and 0.81 ev (N) values classify A3 experimental conditions (at room temperature with dimethylforma­
(R1¼R2¼CO2Me) as moderate electrophile and marginal nucleophile mide, DMF solvent) it can be concluded that here, the benzopyrone (A1)
respectively. Therefore, within the course of the cycloaddition reaction acts rather as an unconjugated diene system which adds periselectively
between A1 (R1¼NMe2) and A3 (R1¼R2¼CO2Me), we expect a high to DMAD (A3) via the initial [2 þ 2] cycloadduct P2D. Even though,
propensity of electron density fluxing from A1 (R1¼NMe2) which best the rearrangement process of the proposed [4 þ 2] cycloadduct inter­
behaves as a nucleophile whereas A3 (R1¼R2¼CO2Me) acts as an mediate P1C proceeds about 194 billion times faster, the preference for
electrophile the formation of xanthone product 8 from the intramolecular rear­
rangement of P2D emanates from the fact that the overall rate of for­
mation of the xanthone products (6 and 8) isolated from the reaction of
A1 and A3 is significantly dependent on the initial cycloaddition to
afford the cycloadduct intermediates. And in this case, the rate of for­
Table 9
mation of P2D occurs about 15.3 million times faster than the rate of
Global reactivity indices for A1 (R1 ¼ NMe2) A2, (R2 ¼ R3 ¼ H) and for the formation of P1C with respective activation barriers of their rate-
derivatives of A3 in eV. determining steps as 9.7 kcalmol− 1 and 19.5 kcalmol− 1 and correspond­
Substituent μ Н Ω N
ing rate constants as 4.81 × 105 s− 1 and 3.15 × 10− 2 s− 1 respectively.
Moreover, this study also depicts that the base-catalyzed deacylative
A3 (R1 = R2 = CO2Me) − 4.77 9.54 1.19 0.81
amination is a suprafacial process regarding the intramolecular

10
R. Arhin et al.
rearrangement of the proposed [4 þ 2] cycloadduct intermediate,
hence the preference for P1C over P2C in the subsequent step. More­
over, there is no way the rearrangement of P2C can afford the xanthone
product 6 and thus confirms the rationalization of the mechanism for the
formation of the product via the [2 þ 2] initial cycloaddition by Ghosh
and his co-workers since the formation of P1C is the most kinetically
unfavored reaction channel with the highest barrier height of
19.5 kcalmol− 1 . The results also depict that the most predominant
stepwise mechanism for thermal [2 þ 2] cycloaddition is valid since all
the transition states under experimental conditions proceed through a
stepwise zwitterionic mechanism to give the [2 þ 2] cycloadducts (P1D
and P2D).
Ethical approval
Not applicable.
Authors’ contributions
SA, JAK and CHB conceived the idea and planned the study. SA ran
computations and wrote the manuscript. JAK, RT, EA, and AA analyzed
data. All authors approved the manuscript before submission.
Funding
The authors are very grateful to the National Council for Tertiary
Education, Republic of Ghana, for a research grant under the Teaching
and Learning Innovation Fund (TALIF/KNUST/3/0008/2005) and
South Africa’s Centre for High-Performance Computing for access to
additional computing resources on the lengau cluster.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
Data will be made available on request.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jmgm.2023.108451.
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