Computational and Theoretical Chemistry 1225 (2023) 114138

Contents lists available at ScienceDirect

Computational and Theoretical Chemistry

journal homepage: www.elsevier.com/locate/comptc

[3 + 2] Cycloaddition reaction of disubstituted-3-benzylidene succinimide

with C, N-disubstituted nitrile imines for synthesizing spiro-heterocycles: A
computational study
Gabriel Amankwah *, Caroline R. Kwawu, Elliot S. Menkah, Evans Adei
Theoretical and Computational Chemistry Laboratory, Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

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

Keywords: The relevance of spiro heterocycles in the biomedical sector is enormous. This computational work extensively
Heterocycles investigates the stereo-, regio-, chemo-, and site- selectivities of the [3 + 2] cycloaddition reaction of
Spiropyrazolines disubstituted-3-benzylidene succinimide (3-BS) with C, N-disubstituted nitrile imines derivatives for the for­
Computations
mation of spiro heterocycles. This study employs the B3LYP, B3LYP-D3, M06, M06-2X, and MPWB1K hybrid
Selectivity
density functional calculations with the 6-311G(d, p) basis sets. Various computations show that the attachment
of the nitrile imine across the olefinic functionality of the disubstituted-3-BS has relatively lower barriers
compared to the carbonyl functionalities present. Generally, electron-releasing groups on disubstituted-3-BS
increase the activation barriers, whereas electron-withdrawing groups significantly reduce the activation barrier.
The GEDT values predicts a low polar character for the [3 + 2] Cycloaddition reaction. Results from local and
global parr functions calculations are in accordance with the selectivities and energetic trends observed.

1. Introduction
In recent decades, cycloaddition reactions have been discovered to
be an essential synthetic technique for the production of complex spiro
heterocyclic compounds from their root monomers. Under the scope of
cycloadditions, the [3 + 2] cycloaddition (32CA) of ethylene derivatives
(EDs) in reaction with three-atom components (TACs) provides a handy
way to access such compounds [1–4]. In adopting the 32CA reaction,
controlling the regio-, chemo-, site- and stereo-selectivity has been the
key challenge in routine synthetic practice. The selectivities can be
manipulated using appropriate substitutes on reacting species or by
catalytic control. In the 32CA reactions, various theoretical and
computational studies have proven how substitutes with different
electronic and stearic properties show diverse degrees of alterations in
energy trends, rate, and thermodynamics of reactions [5–10].
Nitrile imines and diazoalkanes are TACs used in synthesizing most
spiro heterocyclic compounds, including spiropyrazolines, through a
one-step binding of the TAC with an ED in a cycloaddition manner.
Spiropyrazoline [11] is a five-membered spiro heterocycle with two
neighboring atoms of nitrogen fused by a single atom. Pyrazoline
compound is the source of their base structure, with a unique spiro
fusion that shows significant anticancer and anti-inflammatory proper­
ties [12–14]. Spiro heterocycles are difficult to synthesize; nevertheless,
they comprise an underexposed section in the field of chemistry with
significant drug design potential [15].
32CA reaction has also been refined into a valuable tool for con­
structing such spiro heterocyclic compounds [11,16]. The distinctive
regio- and stereoselectivity linked with its mechanism [17] is the most
noticeable feature of spiropyrazoline. Dhar et al. in 1982 reported the
first reaction of 1,3-diphenylnitrilimine with fulvene for the synthesis of
spiropyrazoline. From their findings, the spiropyrazoline cycloadduct
synthesized was dependent on substituent on the substrates [3]. A report
by Raghunathan and co-workers on the formation of 1,3-diphenyl-4-aryl
spiropyrazolines [5.3′ ]4′ -chromanones through a 32CA of phenyl
disubstituted nitrile imine to arylidene-4-chromanones [17] indicates
that steric effect played a key role than electronic effect in the formation
of the regioselective compounds observed. Other works on metal-free [3
+ 2][18–20] and metal-assisted [3 + 2][21–23] CA reactions have also
been explored.
Recent advances in the efficient synthesis of spiropyrazolines

Abbreviations: DFT, Density Functional Theory; TAC, Three Atom Component; GEDT, Global Electron Density Transfer; 3-BS, 3-Benzylidene Succinimide.
* Corresponding author.
E-mail addresses: gabrielamankwah170@gmail.com (G. Amankwah), kwawucaroline@gmail.com (C.R. Kwawu), esmenkah@knust.edu.gh (E.S. Menkah), eadei@
yahoo.com (E. Adei).

https://doi.org/10.1016/j.comptc.2023.114138
Received 20 January 2023; Received in revised form 14 March 2023; Accepted 25 April 2023
Available online 29 April 2023
2210-271X/© 2023 Elsevier B.V. All rights reserved.
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Scheme 1. 32CA reaction of 3-Benzylidene Succinimide (3-BS, 1) with nitrile imines (2).

Scheme 2. Proposed reaction path A for the 32CA of disubstituted-3-benzylidene Succinimides (X1) and nitrile imines (X2).

2
G. Amankwah et al.
Scheme 3. Proposed reaction paths B and C for the 32CA of disubstituted-3-benzylidene Succinimides (X1) and nitrile imines (X2).
compounds have also proven to be remarkable [24–26]. In addition to
these advances, Chen’s group, in 2017, for the first time, described an
alternative cycloaddition reaction in the synthesis of Spiropyrazolines.
An in situ 1,2-diaza-1, 3-dienes was formed to react with 3-bromooxin­
doles in a base-mediated formal (4 + 1) annulation reaction[27]. In
2018, Guo et al. described the [4 + 2] cycloaddition (42CA) reaction of
azo–o-quinone with arylcarbohydrazonoyl chlorides to generate
2,3–dihydro-1H-benzo[e][1,2,4]triazepine [28]. Su and co-workers
2019 reported the efficient 32CA reaction of para-quinone methides
with nitrile imine molecule to generate spiropyrazoline-
cyclohexadienones [29]. A computational study on this experimental
work for the formation of these spiropyrazolines compounds by Sol­
eymani and Jahanparvar ruled out the formation of intermediates. The
study showed a one-step reaction mechanism [2] for the reaction.
Most recently, Yuan et al. [30] reported the diastereoselectivity in
32CA reaction of nitrile imines (2) with 3-Benzylidene Succinimide (1)
to yield 80 % of functionalized spiropyrazolines (3) in the presence of
dichloromethane (DCM). Yuan et al. [30] proposed a reaction mecha­
nism where a hydrazonoyl chloride dehydrochlorination forms an in-
situ nitrile imine and then subsequently reacts with 1 to generate the
spiropyrazoline product 3, as illustrated in Scheme 1. Generated spi­
ropyrazoline compounds occupy a prime position in medicinal chemis­
try, where it is also recognized as a potent antimicrobial [24] and an
anticancer agent [31].
However, the detailed molecular reaction mechanism of the 32CA of
C, N- disubstituted nitrile imines with disubstituted-3-BS has not been
reported. Likewise, solvent effect, substrate influence, and driving fac­
tors of the observed stereo- chemo-, regioselectivities of this reaction
(see Schemes 1, 2 and 3) remain unreported despite the relevance of the
reaction.
In the present research, a complete computational analysis of the
32CA of disubstituted-3- Benzylidene Succinimide with nitrile imines
derivatives has been conducted using density functional theory (DFT)
calculations supported with DFT-based reactivity indices and global
electron density transfer to provide a thorough insight into the observed
selective chemo-, regio- and stereo-spiro cycloadduct. This study aims to
provide computational guidance for correlative experiments on various
spiropyrazoline scaffolds.
3
Computational and Theoretical Chemistry 1225 (2023) 114138
2. Computational details and methodology
2.1. DFT calculations and geometry optimizations
Guess structures of all the considered molecules (reactants, products,
and transition states (TS)) were generated and visualized with Avogadro
[32] molecule editor and visualizer. The Sybyl force field was used for
the geometry minimization of each molecule [33]. The internal co­
ordinates of the molecules (bond lengths, bond angles, and dihedral
angles) were constrained to obtain guess input structures, and the
remaining internal values were then fully optimized [34–37]. This
process gives appropriate guess transition state-input geometries, which
are then submitted for full transition state calculations without geome­
try constraints [38–40].
The Gaussian ‘09 [41] package was employed to perform all the DFT
geometry optimizations. In computation for the effects of solvent on the
reactions, the polarizable continuum model was employed [42] in
dichloromethane (DCM) All quantum-chemical calculations were per­
formed with the Gaussian ‘09 [43] computational chemistry software
suite at the hybrid DFT B3LYP level of theory with 6-311G(d,p) basis set
[44,45]. The Becke, Lee, Yang, and Parr functional (B3LYP) is a
gradient-corrected functional for exchange and correlation, which is an
excellent functional for studying reactions consisting of lower activation
energies [35,46]. The reaction of methyl disubstituted-3-BS and C, N-
dimethyl nitrile imine were also computed (full optimization and energy
calculations) at B3LYP-D3/6-311G(d, p), M06/6-311G(d,p), M06 2X/6-
311G(d,p) and MPWB1K/6-311G(d,p) level of theory to investigate the
suitability of the level of theory chosen [36,47].
Full harmonic vibrational frequency computations were done to
ensure that every transition state structure has a Hessian matrix with just
one negative eigenvalue, represented by an imaginary vibrational fre­
quency along the corresponding reaction coordinates. The intrinsic re­
action coordinate calculations [48,49] was done to make sure that every
favorable transition state connected the reactants and products along
the reaction coordinate smoothly [8,50–52] CYL view was used to make
graphical representations of the optimized structures [53].
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Table 1
Activation energies (kcal/mol) of transition states for the 32CA reaction of disubstituted-3-BS (X1) with C, N-disubstituted nitrile imine (X2) at B3LYP/6-311G(d, p)
level of theory.
SUBSTITUENT(S) TS1A TS2A TS3A TS4A TS1B TS2B TS1C TS2C

R1, R2, R3, R4 = S

–H 8.0 8.0 10.1 10.4 19.8 29.0 20.1 28.0

–CH3 8.9 11.6 10.0 11.2 19.1 26.1 17.5 24.9
–CH2CH3 9.7 11.9 10.7 11.9 20.2 27.2 18.8 19.7
–OCH3 5.6 10.5 9.1 12.3 23.2 23.8 21.8 22.9
–NH2 9.2 6.3 10.9 9.0 19.0 10.5 15.9 9.9
–OH 7.6 12.5 9.1 12.6 21.1 21.2 22.9 19.2
–Br 9.8 15.3 12.3 16.0 23.2 30.5 24.5 30.4
–CN 10.8 15.5 13.4 17.3 13.5 33.1 15.1 33.8
–NO2 10.8 19.9 14.2 22.1 18.5 21.6 11.1 34.1
–CHO 8.7 8.2 12.3 13.1 14.9 30.1 10.9 18.7
–COOH 9.7 15.6 13.5 18.5 17.4 34.0 – 38.0
–Ph 10.4 15.7 – 17.8 – 32.7 17.4 –

2.2. Reactivity indices
Eqs. (1) and (2) were used to determine the global electrophilicity
(ω) [54] and maximum electronic charge (ΔNmax) of the different
disubstituted-3-BS and nitrile imine derivatives. The electrophilicity
index measures a reactant’s propensity to take in electrons [55] and is in
relation with the chemical hardness, η = (ELUMO - EHOMO) and electronic
chemical potential, μ = (EHOMO + ELUMO)/2, as described by Pearson’s
acid-base concept [56]. Therefore, the moieties with greater electro­
philicity values are the most reactive species toward nucleophiles. These
equations are based on the Koopmans theory [57], it was initially
developed to calculate the ionization energies from closed-shell Hartree-
Fock wavefunctions, but it has subsequently been accepted as a reliable
approximation for estimating chemical hardness and the electronic
chemical potential.
ω = μ2 /2η
ΔNmax = − μ/η
The maximum electronic charge transfer (ΔNmax) calculates the
maximum electronic charge that the electrophile may accept. Therefore,
the molecules with the highest ΔNmax index would be the best elec­
trophile in a given series of chemicals. With the aid of single-point en­
ergy calculations across the optimized neutral geometries and the
unrestricted UB3LYP formalism for the radical species, the electrophilic
- observations were made for M06-2X/6-311G (d,p) and B3LYP-D3/6-
(P+
k ) and nucleophilic (Pk) Parr functions of the radical anion and the
radical cation were determined [58,59]. Equation (3) was used for the
calculation of the nucleophilicity index of the various molecules. Tet­
racyanoethylene (TCE) was used as the scale of nucleophilicity [60].
N(nu) = EHOMO(nu) (eV) − EHOMO(TCE) (eV)
The global electron density transfer [61] (GEDT) was calculated by
the sum of the natural atomic charges, resulting from the Natural Pop­
ulation Analysis [62,63] (NPA), of the atoms in each framework at the
transition states. An indication of the direction of the electron density
flux was determined using the sign where positive values indicated a
flux from the considered framework to the other one.
stereoisomers. In addition, P1A is a regioisomer of P3A, while P2A is
also a regioisomer of P4A. Path B emanates from the 32CA of X2 along
the hindered carbonyl bond in X1, which yields two regioisomeric spi­
rocycloadducts, P1B and P2B, through TS1A and TS2A. The 32CA of X2
across the less hindered carbonyl in X1 also describes path C, which
leads to the furnishing of spirocycloadducts P1C and P2C via TS1C and
TS2C (see Scheme 2). Reaction energies are attached to their corre­
sponding cycloadducts in parenthesis. All energies in the figures are
reported in kcal/mol.
3.1. Analysis of the 32CA reaction of methyl disubstituted-3-BS (X1) with
C, N - dimethyl nitrile imine (X2) at different computational levels
We employed different computational methods with similar basis
sets i.e., B3LYP/6-311G (d,p), B3LYP-D3/6-311G (d,p), M06/6-311G (d,
(1) p), M06-2X/6-311G (d,p), and MPWB1K/6-311G (d,p) to compute the
optimized geometries and activation energies of the stationary points
(2) (reactants, and transition states) for the reaction of C, N-dimethyl nitrile
imine (X2, R3, R4 = CH3) with methyl disubstituted-1-phenyl-3-
benzylidenepyrrolidine-2,5-dione (X1, R1, R2 = CH3) and shown in
Table S1. In all instances, the addition of nitrile imine across the olefinic
bond through TS1A was the preferred pathway (see Table S3).
The computations were initially carried out with M06/6-311G (d,p),
which was observed to underestimate the activation energies. Similar
311G (d,p), which will lead to the challenge of recording near or
negative activation energies. On the other hand, the results for B3LYP
and MPWB1K functional at the same basis sets proved promising and
reliable for this study as they recorded activation energies that were
neither very high nor near negatives as noted elsewhere [36,47,64–67].
The difference in energy between the two functional was almost 3 kcal/
mol. Subsequent computations were performed at the B3LYP/6-311G
(d,p).
From the bond lengths analysis of the optimized geometries dis­
played in Figs. 3 and 5, there is an observed asynchronous one-step bond
formation process which is pronounced in all reaction pathways.

3. Results and discussion
Considering the various reactive centers in disubstituted-3-BS (X1),
the reaction between X1 and C, N-disubstituted nitrile imines (X2) has
been proposed to go through three distinct 32CA reactive, path A, path
B, and path C (Scheme 2). Due to the molecular orientations of the re­
actants, Path A emerges from the 32CA reaction of X2 along the olefinic
bond of X1 through transition states (TSs) TS1A, TS2A, TS3A, and TS4A
to afford four spiro cycloadducts P1A, P2A, P3A, and P4A accordingly.
With regards to the structures of the products, P1A and P2A are
3.2. Analysis on the 32CA reaction of Disubstituted-3-BS (X1) with C, N-
disubstituted nitrile imine (X2)
This segment investigates the effect of the presence and absence of
electron-releasing groups (ERGs = OH, NH2, OCH3, CH3, CH2CH3),
electron-withdrawing groups (EWGs = NO2, COOH, CHO, CN, Br),
phenyl and hydrogen on the observed site-, chemo-, regio-, and stereo-
selectivities on the X1 and X2. These computations are carried out to
give us information on the type of substituents to be accommodated on
the species to influence a particular product outcome. Efforts to identify
some transition states were unsuccessful; however, the possibility of

4
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Table 2
Reaction energies of products for the 32CA reaction of disubstituted-3-BS (X1) with C, N-disubstituted nitrile imine (X2) at B3LYP/6-311G(d, p) level of theory.
SUBSTITUENT(S) P1A P2A P3A P4A P1B P2B P1C P2C

R1, R2, R3, R4 = S

–H − 44.6 − 44.6 − 44.6 − 43.2 –23.2 9.5 − 25.6 7.2

–CH3 − 39.8 − 39.4 − 43.4 − 41.9 − 21.4 8.6 − 24.7 5.9
–CH2CH3 – – − 41.4 − 38.6 − 19.8 11.0 –23.1 –
–OCH3 − 39.9 − 34.9 − 45.0 − 43.1 − 18.1 6.0 − 19.4 3.3
–NH2 − 30.5 − 5.7 − 36.1 − 35.7 − 19.9 7.8 − 26.7 2.2
–OH – − 21.2 − 46.5 − 43.1 − 21.2 5.5 – 3.8
–Br –33.7 − 31.4 − 36.7 – − 9.1 14.7 − 11.3 12.9
–CN − 34.2 − 31.6 –33.5 − 30.4 − 17.7 17.3 − 18.9 16.4
–NO2 − 45.1 − 42.8 − 46.7 − 44.8 − 20.0 7.6 − 19.0 9.5
–CHO − 42.4 − 42.8 − 43.5 − 35.1 − 20.1 9.2 – 7.3
–COOH − 41.9 − 41.3 − 43.6 − 40.5 − 20.5 9.8 − 21.8 13.0
–Ph − 31.9 − 30.6 –33.7 – − 13.3 20.6 − 18.9 16.2

Fig. 1. Gibbs free energy (kcal/mol) profile for the gas phase reaction of hydrogen disubstituted-3-BS with hydrogen C, N-disubstituted nitrile imine at B3LYP/6-
311G (d, p) level of theory.

such pathways being present cannot be excluded. Reaction energies for
respective products have been placed in brackets.
Following the results displayed in Tables 1 and 2 for the titled re­
action above, the following deductions can be made: (i)The computed
activation energies suggest the regioselective attachment of C, N-
disubstituted nitrile imines across the olefinic bond of the 3-BS to afford
corresponding spirocycloadducts as the most kinetically favorable
pathway. (ii) In all cases of study, the generation of P1 via TS1A is the
most favored reaction route which is consistent with Yuan et al. [30]
observation except NH2 where there is a competition between the
regioisomers P1A to P4A. (iii) Higher activation energies are witnessed
for the reaction across the carbonyls in the X1 compared to the reactions
at the olefinic center. (iv) Stripping off all substituents and forming
hydrogen substituents on ED (H-X1) and TAC (H-X2) results in lost
stereoisomerism in Path A with the formation of P1A (-46.6 kcal/mol)
and P2A (-46.6 kcal/mol) through TS1A and TS2A having similar
activation energy of 8.0 kcal/mol. Generation of cycloadducts P3A
(-44.6 kcal/mol) and P4A (-43.2 kcal/mol) through TS3A and TS4A also
tend to have an almost similar activation energy of 10.1 kcal/mol and
10.4 kcal/mol, respectively. (v) The highest recorded activation barrier
in the reaction of H-X1 and H-X2 is 29.0 kcal/mol. Considering the
energetics, Path B and C are observed to have higher selectivity in

5
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Fig. 2. Gibbs free energy (kcal/mol) profile for the gas phase reaction of methyl disubstituted-3-BS with C, N-dimethyl nitrile imine at B3LYP/6-311G (d, p) level of
theory and results for the solvent (DCM) phase computations at the same level of theory are in parenthesis.

TS1A TS2A TS3A TS4A

TS1B TS2B TS1C TS2C

Fig. 3. Views of optimized favorable transition states’ structures with geometrical parameters for the gas phase 32CA reaction of C, N-dimethyl nitrile imine with
methyl disubstituted-3-BS.

6
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Table 3
Activation energies (kcal/mol) of transition states for the 32CA reaction of 3-BS with C, N – disubstituted nitrile imine at B3LYP/6–311(d, p) level of theory.
SUBSTITUENT(S) TS1A TS2A TS3A TS4A TS1B TS2B TS1C TS2C

R3, R4 = S

–H 11.8 15.6 13.5 17.1 23.9 31.3 22.9 29.3

–CH3 8.2 13.0 10.4 14.1 20.3 25.5 – 24.2
–CH2CH3 8.7 13.6 10.7 14.5 21.0 25.9 20.2 24.6
–OCH3 5.4 9.4 9.3 13.2 24.5 19.2 20.2 18.5
–NH2 3.0 – 6.5 8.8 21.2 12.4 19.2 12.0
–OH 4.2 7.3 8.7 8.3 20.9 17.6 20.1 17.0
–Br 9.2 14.0 11.5 14.3 21.1 – 21.6 30.2
–CN 11.0 15.3 11.9 15.0 10.6 – 9.6 38.4
–NO2 9.5 – – 12.9 – 36.9 – 34.0
–CHO 8.6 11.2 10.5 13.7 8.4 40.2 8.1 39.7
–COOH 12.9 15.8 15.1 17.2 14.3 41.8 – 41.2
–Ph 10.4 15.7 – 17.8 – 32.7 17.4 –

forming spiro cycloadducts P1B to P1C than Path A, generating P1A to
P4A. The Gibbs free energy profile for gas phase computations of the
32CA reaction of hydrogen-disubstituted nitrile imine with hydrogen-
disubstituted-3-BS at the B3LYP/6-311G level of theory is shown in
Fig. 1. (vi) ERGs and EWGs replacing hydrogens on the X1 and X2 have
the same energetic trends as hydrogen substituent. An increase in acti­
vation energies varying from 0.5 kcal/mol to 3.0 kcal/mol of the re­
actions, precisely the preferred reaction route, is observed for the
formation of P1A through TS1A. (vii) The activation and reaction en­
ergies observed indicate that kinetics plays a leading role in the gener­
ation of the cycloadducts. (viii) From the gas-phase energetics shown in
Tables 1 and 2, the most kinetically favored route in the reaction of X1
(R1, R2 = Ph) with X2 (R3, R4 = Ph) is the reaction route where X2
chemo- and regioselectively add across the olefinic functionality in X1.
This favored pathway leads to the generation of product P1A (-31.9
kcal/mol) via TS1A with an activation energy of 10.4 kcal/mol. The
creation of P1A is irreversible because of the product’s enhanced exer­
gonic nature and stability.
The Gibbs free energy profile for the gas phase of 32CA reaction of C,
N-dimethyl nitrile imine (X2, R3, R4 = CH3) with methyl disubstituted 1-
phenyl-3-benzylidenepyrrolidine-2,5-dione (X1, R1, R2 = CH3) at the
B3LYP/6-311G level of theory is shown in Fig. 2. In Fig. 2, the solvent
phase (Dichloromethane (DCM)) computations are displayed in paren­
thesis for the activation and reaction energies of 32CA reaction of X2
(R3, R4 = CH3) with X1 (R1, R2 = CH3). From Fig. 1., computations on
the reaction of X2 (R3, R4 = CH3) with X1 (R1, R2 = CH3) at the solvent
phase indicate similar energetic trends but with a higher magnitude of
activation energies.
The optimized geometries of the stationary points for studying the
reaction of X2 (R3, R4 = CH3) with X1 (R1, R2 = CH3) are shown in Fig. 3.
Once more, the obtained bond lengths for all structures are prominent
features of the transition state geometry. From Fig. 3, asynchronicity is
noticeable in the transition states TS1A since the C, N-dimethyl nitrile
imine moiety adds across the methyl disubstituted-3-BS through an
asynchronous one-step mechanism.
3.3. GEDT Analysis
The global electron density transfer [61] (GEDT) values of the
transition states (TS1A, TS2A, TS3A, and TS4A) of the [3 + 2] cyclo­
addition reaction of X2 (R3, R4 = CH3) with X1 (R1, R2 = CH3) were
computed to investigate the polarity of the reaction. Cycloaddition re­
actions with GEDT values greater than 0.20 e correspond to a polar
process, whereas values near 0.05 e indicate a non-polar process. The
GEDT values in the gas phase computations and experimental condition
(DCM solvation) are 0.14 e (0.18 e) at TS1A, 0.14 e (0.19 e) at TS2A,
0.14 e (0.17 e) at TS3A and 0.13 e (0.17 e) at TS4A with parenthesis
containing the experimental conditions GEDT values. This further
analysis of the experimental conditions was done to analyze the influ­
ence of the conditions on the polarity. The GEDT values obtained indi­
cate a low polar character for the reaction of X2 with X1. Hence, the
32CA of X2 (R3, R4 = CH3) across the olefinic bond of X1 (R1, R2 = CH3)
proceeds via a forward electron density flux (FEDF), that is the electron
flux from X2 to X1.
3.4. The reaction of 3-BS with C, N – Disubstituted nitrile imine
The exclusive influence of different substituents on the C, N -
disubstituted nitrile imine (X2, R3, R4 = H, Ph, ERGs, EWGs) molecule in
reaction with 3-BS (X1, R1, R2 = Ph) has been examined in this section.
Tables 3 and 4 show the various stationary point energies of X2 (R3, R4
= H, ERGs, EWGs) in reaction with X1 (R1, R2 = Ph). It ought to be
mentioned that attempts to identify certain transition states were un­
successful in some cases. Fig. 4 shows the Gibbs free-energy profile of X1
(R1, R2 = Ph) and C, N - dimethyl nitrile imine (X2, R3 R4 = CH3) from
the gas phase at B3LYP/6-311G level of theory.

Table 4
Reaction energies (kcal/mol) of the products for the 32CA reaction of 3-BS with C, N – disubstituted nitrile imine at B3LYP/6–311(d, p) level of theory.
SUBSTITUENT(S) P1A P2A P3A P4A P1B P2B P1C P2C

R3, R4 = S

–H − 38.3 − 35.3 − 40.3 − 37.5 − 16.2 14.4 − 21.3 11.2

–CH3 − 37.8 − 36.4 − 42.2 − 39.6 − 18.0 11.0 –22.7 7.2
–CH2CH3 − 36.6 –33.2 − 39.0 − 38.4 − 17.1 12.0 − 21.9 8.2
–OCH3 − 41.3 − 38.7 − 43.4 − 42.1 − 15.2 7.4 − 20.5 3.1
–NH2 − 37.1 –33.9 − 38.6 − 34.8 − 13.2 – − 18.5 7.7
–OH − 42.1 − 16.0 − 43.8 − 42.6 − 16.1 7.4 − 21.2 2.9
–Br –33.0 − 30.8 − 36.8 − 35.2 − 5.8 17.5 − 11.0 12.8
–CN – − 36.6 − 39.2 − 37.4 − 13.3 22.7 − 17.4 19.2
–NO2 − 47.4 − 46.2 − 48.3 − 46.9 − 19.5 12.5 –23.3 8.5
–CHO − 41.2 − 39.7 − 45.5 − 43.4 − 18.7 – – − 14.3
–COOH − 40.7 − 39.2 − 42.7 − 40.6 − 16.2 20.1 − 20.6 14.6
–Ph − 31.9 − 30.6 –33.7 – − 13.3 20.6 − 18.9 16.2

7
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Fig. 4. Gibbs free energy profile of gas phase reaction of C, N-dimethyl nitrile imine with methyl disubstituted-3-BS at B3LYP/6-311G (d, p) level of theory.

TS1A TS2A TS3A TS4A

TS1B TS2B TS1C TS2C

Fig. 5. Views of optimized favorable transition states’ structures with geometrical parameters for the gas phase 32CA reaction of C, N-dimethyl nitrile imine with 3-
benzylidene Succinimide (3-BS).

8
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Table 5
Activation energies (kcal/mol) of transition states for the 32CA reaction of disubstituted-3-BS (X1) derivatives and C, N - dimethyl nitrile imine (X2) at B3LYP/6–311
(d, p) levels of theory.
SUBSTITUENT(S) TS1A TS2A TS3A TS4A TS1B TS2B TS1C TS2C

R1, R2 = S

–H 5.1 5.1 7.1 7.3 15.6 23.0 15.8 22.2

–CH3 8.9 11.6 10.0 11.2 19.1 26.1 17.5 24.9
–CH2CH3 9.1 11.4 10.2 11.1 – 26.5 18.1 25.3
–OCH3 – 17.0 10.5 14.5 – 28.8 20.8 28.9
–NH2 15.1 15.2 12.5 10.6 18.5 21.8 14.3 –
–OH 11.3 16.6 9.6 13.9 20.6 26.9 19.6 24.6
–Br 6.6 12.2 8.7 13.3 17.7 23.2 18.5 23.2
–CN − 2.3 2.1 0.1 4.2 4.1 10.6 7.5 11.0
–NO2 − 1.6 8.4 − 0.1 8.3 9.8 14.8 14.1 17.2
–CHO 0.2 2.4 3.1 4.8 11.3 – 7.8 12.6
–COOH 1.7 11.0 3.0 10.8 14.5 17.1 – 18.6
–Ph 8.2 13.0 10.4 14.1 20.3 25.5 – 24.2

From Tables 3 and 4 and Fig. 4, the C, N – disubstituted X2 chemo
and regioselectively adds across the olefinic functionality irrespective of
the electronic ability of the substituent on the X2 molecule. These ob­
servations can be related to the reduced steric at the olefinic bond and
the distant position of substitutes on X2 and X1. This high regiose­
lectivity in the reaction analyzed for the ERG, EWG, Ph, H on X2, for the
generation of P1A to P4A through transition state TS1A to TS4A then
leads to a kinetically favored stereospecific cycloadduct P1A via TS1A in
all cases.
Evidently, from Table 3, the ERGs - X2 (R3, R4 = CH2CH3, OH, NH2,
OCH3) generally lowers activation energies for the favored pathway
when reacted with X1 (R1, R2 = Ph) at the gas phase. OH – X2 and NH2 –
X2 are observed to have the lowest activation energies of 4.2 kcal/mol
and 3.0 kcal/mol, respectively, thereby increasing the rate of the reac­
tion compared to the reaction of CH3 – X2 with X1 (R1, R2 = Ph) which
has a high activation energy of 8.2 kcal/mol (Fig. 4). This outcome can
be partially attributed to the rise in the electronic density of X2, making
it a stronger nucleophile.
On the other hand, higher activation energies of about 0.4 kcal/mol
to 4.6 kcal/mol increase are observed for the reaction of EWGs - X2 (R3,
R4 = NO2, COOH, CHO, CN, Br) with X1 (R1 R2 = Ph) compared to ERGs
specifically CH3 – X2 in reaction with X1 (R1, R2 = Ph) (Fig. 4). Carboxyl
disubstituted X2 records the highest activation barrier of 12.9 kcal/mol
for TS1A to furnish product P1A (-40.7 kcal/mol) due to its high
strength of electron redrawing making X2 a poor nucleophile, therefore,
slowing down the reaction by increasing its activation barrier. The order
in which the activation barrier increase is CHO > Br > NO2 > CN >
COOH.
From Table 3, an in-depth investigation of the reaction of ERGs and
EWGs on X2 indicates a slight change in the magnitude of the energetics;
however, the trends in the regio and stereoselectivity remain the same as
the energetic patterns of reaction of C, N – diphenyl nitrile imine (X2, R3,
R4 = Ph) with X1 (R1, R2 = Ph). An illustration of the gas phase B3LYP
optimized favorable transition state structures for the reaction of X2 (R3,
R4 = CH3) with X1 (R1, R2 = Ph) is displayed in Fig. 5. These observed
bond lengths once again confirm the one-step asynchronous reaction
mechanism for the reaction of disubstituted-3-BS with C, N – dimethyl
nitrile imine, where the formation of one bond is more pronounced than
the other. The carbon–carbon bond formation is more pronounced than
the carbon–nitrogen bond in the preferred pathway, which leads to the
cycloadduct P1A.
3.5. The reaction of C, N - dimethyl nitrile imine with Disubstituted-3-
Benzylidene Succinimide (3-BS, X1)
This segment reports on the mechanistic influence of substituents
with different electronic and steric on the energetics of disubstituted-3-
BS (X1, R1, R2 = H, Ph, ERGs, EWGs) as it reacts with C, N - dimethyl
nitrile imine (X2, R3, R4 = CH3). A surrogate for X2 (R3, R4 = CH3) that
is X2 (R3, R4 = CH3) as literature on related organic reactions indicates
that methyl nitrile imine can be employed as a minimized model for
phenyl nitrile imine used in experimental works [36,50,51]. Tables 5
and 6 show the outcome of the gas phase computations for the 32CA
reaction of X1 (R1, R2 = H, Ph, EWGs, EDGs) with X2 (R3, R4 = CH3) at
the B3LYP level of theory and 6-311G (d, p) basis sets.
Generally, from Tables 5 and 6, the generation of spiro cycloadducts
via Path A is noticed to be relatively lower than the activation energies
of cycloadducts emerging via path B and Path C (Scheme 2). From the
energetics displayed, the chemoselectivity (attachment to olefinic
functionality on X1) trend observed is similar to the reaction of H-X1

Table 6
Reaction energies (kcal/mol) of products for the [3 + 2] cycloaddition reaction of disubstituted-3-BS (X1) derivatives and C, N - dimethyl nitrile imine (X2) at B3LYP/
6–311(d, p).
SUBSTITUENT(S) P1A P2A P3A P4A P1B P2B P1C P2C

R1, R2 = S

–H − 45.2 − 45.2 − 46.8 − 45.0 − 26.7 4.3 − 28.8 − 14.7

–CH3 − 39.8 − 39.4 − 43.4 − 41.9 − 21.4 8.6 − 24.7 5.9
–CH2CH3 − 39.1 − 37.5 − 42.8 − 41.1 − 19.0 9.2 –23.1 –
–OCH3 − 36.9 –33.5 − 42.3 − 38.3 − 20.4 8.0 –23.8 6.6
–NH2 –33.1 − 31.3 − 39.2 − 38.0 − 24.7 5.3 − 31.5 − 1.0
–OH − 38.7 − 38.1 − 43.9 − 44.8 –22.5 6.6 − 26.0 4.7
–Br − 42.9 − 41.2 − 50.6 − 43.0 –23.3 6.5 − 25.1 5.1
–CN − 44.6 − 40.2 − 45.9 − 41.9 –33.6 3.6 − 34.5 − 4.4
–NO2 − 44.2 − 41.6 − 48.1 − 46.4 − 28.1 2.0 − 27.8
–CHO − 38.4 − 40.0 − 42.8 − 42.1 –32.4 3.3 − 29.3 0.9
–COOH − 39.4 − 38.6 − 43.5 − 41.7 – 2.7 − 26.2 3.6
–Ph − 37.8 − 36.4 − 42.2 − 39.6 − 18.0 7.2 –22.7 7.2

9
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Fig. 6. Gibbs free energy profile of the gas phase reaction of C, N-dimethyl nitrile imine with carbonyl disubstituted-3-BS (X1).

Table 7 Table 8
Values for global reactivity indices (in eV) for the various derivative of 3-BS Values of global reactivity indices (in eV) for the various derivatives of nitrile
(X1). imine (X2).
Substrate μ Ƞ ω N Substrate μ Ƞ ω N

–H − 4.65 5.59 1.94 1.92 –H − 3.68 5.89 1.15 2.74

–CH3 − 4.38 5.75 1.67 2.11 –CH3 − 3.09 5.36 0.89 3.60
–CH2CH3 − 4.37 5.72 1.67 2.14 –CH2CH3 − 3.10 5.33 0.90 3.61
–OCH3 − 4.10 5.47 1.54 2.53 –OCH3 − 3.90 4.66 1.63 3.13
–NH2 − 3.53 5.14 1.21 3.27 –NH2 − 3.17 4.57 1.10 3.91
–OH − 4.25 5.29 1.71 2.47 –OH − 4.02 4.80 1.68 2.95
–Br − 5.00 5.35 2.34 1.69 –Br − 5.43 3.74 3.95 2.07
–CN − 6.18 4.95 3.86 0.71 –CN − 5.76 4.28 3.87 1.47
–NO2 − 6.40 4.64 4.42 0.64 –NO2 − 6.38 4.90 4.15 0.54
–CHO − 5.73 4.28 3.83 1.5 –CHO − 5.52 4.45 3.43 1.62
–COOH − 5.51 4.92 3.08 1.4 –COOH − 5.03 5.01 2.53 1.84
X1 (R1, R2 = Ph) − 4.43 4.33 2.27 2.77 X2 (R3, R4 = Ph) − 3.46 3.53 1.69 4.15

with X2 (R3, R4 = CH3) (Fig. 3). ERGs - disubstituted X1 molecules have
higher activation energies of about 3.8 kcal/mol to 6.8 kcal/mol
compared to the activation energies of H-X1 in reaction with X2 (R3, R4
= CH3) in the gas phase. This outcome can be linked to the rise in
electron density of X1 as ERGs are replaced on it, making it a poor
electrophile.
The energetics shown in the table shows an observed competition for
stereoselectivity and regioselectivity when strong ERGs (R1, R2 = NH2,
OH) are placed on X1. For NH2 - X1, the most favored reaction channel is
the route that leads to the formation of the spiro cycloadduct P4A (-38.0
kcal/mol) through TS4A with an activation energy of 10.6 kcal/mol.
Considering OH - X1, the preferred reaction channel is the generation of
product P3A (-43.9 kcal/mol) through TS3A with an activation energy of
9.6 kcal/mol.
However, for EWGs-disubstituted X1, the activation energies are
observed to decrease significantly except for Br - X1, which has an
activation energy of 1.5 kcal/mol higher than that of the activation
energy of the favored pathway in H - X1 in reaction with X2 (R3, R4 =
CH3) (Table 5). The furnishing of product P1A via TS1A is observed to be
the preferred reaction pathway which is similar to the H - X1 in reaction
with X2 (R3, R4 = CH3). CHO - X1 and COOH - X1 recorded activation
energies of 0.2 kcal/mol and 1.7 kcal/mol. These respective energies are
4.9 kcal/mol and 3.4 kcal/mol lower than H - X1 in reaction with X2
(R3, R4 = CH3) (Table 5). Fig. 6 illustrates the Gibbs free energy profile
of the CHO - X1 in reaction with X2 (R3, R4 = CH3) at the B3LYP/6-311G
(d.p) in the gas phase.
In all instances, the chemo selectivity observed in the reaction of X2
(R3, R4 = Ph) with X1 (R1, R2 = Ph) is maintained. The formation of
cycloadduct P2B was observed to be thermodynamically unstable. The
kinetics of the reaction is the controlling factor for the selectivity noticed
in the reaction of C, N disubstituted X1 with X2 (R3, R4 = CH3).
3.6. Conceptual density functional theory reactivity indices analysis
3.6.1. Global descriptors
In this segment, the inherent reactivity of the disubstituted-3-BS
(X1) and C, N-disubstituted nitrile imine (X2) are investigated using the
global reactivity parameters, and the results are shown in Tables 7 and 8.
The electronic chemical potential (μ) value indicates the pattern of
electron density flow, whether its fluxes from the X2 to X1 (forward

10
G. Amankwah et al. Computational and Theoretical Chemistry 1225 (2023) 114138

Table 9 whereas EWG increases the nucleophilic character.

Mulliken atomic spin densities of 3-BS (X1) and C, N - diphenyl nitrile imine
(X2). 3.6.2. Local descriptors
-
X1 X2 Employing the local electrophilic (P+ k ) and nucleophilic (Pk) Parr

Mulliken Mulliken
functions established by Domingo et al. [58], the origin of selectivity
observed in the reaction of the nitrile imine and 3-BS (X1, R1, R2 = Ph)
P-k Pþ P-k Pþ
k k
have been computed and the outcome displayed in Table 9. Fig. 7 shows
C1 − 0.023 0.124 C1 0.155 0.254 the atomic labels of X1 (R1, R2 = Ph) and X2 (R3, R4 = Ph). The atomic
O7 − 0.022 0.124 N1 − 0.081 0.148 species in the ethylene derivative with the highest electron densities are
C2 0.129 0.087 N2 0.382 0.056
C6 0.021 0.317
the targets of the TAC in the Parr function designs. A quantitative
C4 − 0.022 0.005 measure of the electron density at respective atomic centers is analyzed
O8 0.064 0.007 with the Mulliken atomic spin densities (ASD) and summarized in
Table 9.
Analysis of reactive centers of X1 molecule, which includes C1 =
electron demand flux (FEDF)) or the otherwise (reverse electron demand
0.124, O7 = 0.124, C2 = 0.087, C6 = 0.317, C4 = 0.005, and O8 = 0.007,
(REDF)).
shows that for the electrophilic Mulliken atomic spin densities, C2 =
The μ value of X2 (R3, R4 = Ph) is − 3.46, which is higher than that of
0.095 and C6 = 0.287 has the largest electron densities for the attack of
X1 (R1, R2 = Ph) having μ of − 4.43 hence infers a fluxing of electrons
X2. Therefore, due to the greater Parr function coefficient noticed in C2
from X2 to X1 (FEDF). EWGs (NO2, COOH, CHO, CN, Br) on X1 mole­
and C6, the most favorable interactions are predicted to occur along the
cule decreases the μ value, thus making X1 a strong nucleophile relative,
C2 and C6 olefinic bond of the 1-phenyl-3-benzylidenepyrrolidine-2,5-
and EDG (OH, NH2, OCH3, CH3, CH2CH3) on X1 molecule instead in­
dione molecule to give the P1A, P2A, P3A and P4A which is consis­
crease the μ value making X1 a poor nucleophile relative to C, N-
tent with the higher chemoselectivity observed in the energetic trends.
dimethyl nitrile imine. This outcome is coherent with the observed
The nucleophilic NBO atomic spin densities of the X2, C1 = 0.254
lower and higher activation barriers for the analyzed reactions of X1 and
and N2 = 0.056, as displayed in Table 9, the nucleophilic C1 atom of the
X2, as shown in Tables 1-6.
X2 molecule prefers to bind preferentially to the electrophilic C6 atom
In the concept of CDFT, the electrophilicity reactivity descriptor (ɷ)
while the nucleophilic N2 binds to the comparatively electrophilic C2 to
helps to determine organic molecules which act as the best electrophile in
afford product P1A as observed by Yuan et al [30]. This analysis is
a given reaction[55]. From Table 7, the order for ɷ for C, N-disubstituted
consistent with the observed chemo and regioselectivity.
nitrile imine is given as; NH2 < OCH3 < CH2CH3 < CH3 < OH < H < Br <
Ph < CN < COOH < CHO < NO2. X1 (R1, R2 = NH2) has the least value of
4. Conclusion
1.21 eV, making X1 a poor electrophile, while X1 (R1, R2 = NO2, CN) have
the highest ɷ values of 4.42 eV and 3.83 eV making them the most
The results of the extensive computational study show that in the [3
electrophilic derivatives in the series. These results in EWGs on X1 as most
+ 2] cycloaddition reaction of disubstituted nitrile imine (X2) with
electrophilic accounts for its lowest activation energy observed thereby
disubstituted-3-Benzylidene succinimide (3-BS, X1), the plausible re­
promoting a faster occurrence of the reaction at the preferred pathway
action pathway proceeds through Path A (addition across the olefinic
(see Table 5). These observations are consistent with the reactions of X2
functionality) leading to the formation of a regio-, chemo-, and a ster­
(R3, R4 = CH3) with disubstituted-3-BS.
eoselective spiroheterocyclic compound. The C, N-disubstituted nitrile
Considering the nucleophilicity values (N) from Table 8, X2 (R3, R4
imine chemoselectively add across the olefinic functionality present in
= NH2) has an N value of 3.91 eV, which is the highest of all the N
the disubstituted-3-BS to yield P1A through path A.
values, thus making NH2-X2 the best nucleophile amongst the nitrile
Reactions along Path A have a comparatively lower activation bar­
imine derivatives. However, X2 (R3, R4 = NO2) has the least computed N
rier resulting in a lower magnitude of regioselectivity as compared to the
value of 0.64 eV, making NO2-X2 the poorest nucleophile. From the
other pathways, path B and C (addition across the carbonyl
results in Table 8, EDG on X2 decreases the nucleophilic character,

Fig. 7. Atomic labels of the 3-BS (X1) and C, N - diphenyl nitrile imine (X2).

11
G. Amankwah et al.
functionalities) have a higher magnitude of regioselectivity ranging
from 2 kcal/mol to 15 kcal/mol.
The five-membered spiro heterocyclic products P1A is generated not
only due to the higher barriers for the cycloreversion steps but also
because the spiro cycloadducts furnished are relatively more stable than
the other formed cycloadducts. Various substitute effects suggest the
formation of product P1A.
From the findings, there is always a selective addition across the
olefinic functionality irrespective of the electron-influencing ability of
the substituent on the nitrile imine. Dichloromethane has no substantial
effect on the energetic trend and selectivity of the reaction. The results
are in good agreement with the experimental data. The selectivities and
energetic trends of the cycloaddition reaction of disubstituted-3-BS with
other TACs are attractive research areas for future works.
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Availability of data and materials
The data on which this manuscript is based is reported in this
manuscript and the attached supplementary information.
Funding
This work was funded by the National Council for Tertiary Educa­
tion, Ghana, through the Teaching and Learning Innovation Fund
(TALIF/KNUST/3/0008/2005).
Author contributions
Gabriel Amankwah: Conceptualization, Simulations, Project
administration, Data curation, Formal analysis, Investigation, Method­
ology, Writing - original draft, Writing - review & editing. Caroline R.
Kwawu: Conceptualization, Formal analysis, Methodology, Funding
acquisition, Writing - review & editing, Resources. Elliot S. Menkah:
Formal analysis, Software, Writing - review & editing. Evans Adei:
Formal analysis, Resources, Methodology, Funding acquisition, Writing
- review & editing.
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
The data supporting this work are provided within the article and the
supporting information.
Acknowledgments
Authors acknowledge 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 to South Africa’s
Centre for High-Performance Computing for access to additional
computing resources on the lengau cluster. The authors are also very
grateful for funding from The World Academy of Sciences (grant 18-032
RG/CHE/AF/AC_I and 22-004 RG/PHYS-CHE/AF/AC_CG). CRK ac­
knowledges the UK Royal Society and Leverhulme Trust for a research
grant under the Royal Society-Leverhulme Africa Postdoctoral Fellow­
ship Award Scheme (grant LAF\R1\180013).
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.comptc.2023.114138.
12
Computational and Theoretical Chemistry 1225 (2023) 114138
References
[1] I. Ofori, G.B. Pipim, R. Tia, E. Adei, A DFT study of the double (3 + 2)
cycloaddition of nitrile oxides and allenoates for the formation of
spirobiisoxazolines, J. Mol. Graph. Model. 109 (2021), 108033, https://doi.org/
10.1016/j.jmgm.2021.108033.
[2] M. Soleymani, S. Jahanparvar, A computational study on the [3+2] cycloaddition
of para-quinone methides with nitrile imines: a two-stage one-step mechanism,
Monatshefte Fur Chemie. 151 (2020) 51–61, https://doi.org/10.1007/s00706-019-
02531-2.
[3] D.N. Dhar, R. Ragunathan, Synthesis of spiro-pyrazolines: reaction of 1,3-diphe­
nylnitrilimine with fulvenes, Tetrahedron. 40 (1984) 1585–1590, https://doi.org/
10.1016/S0040-4020(01)91808-3.
[4] S. Dadiboyena, E.J. Valente, A.T. Hamme, Synthesis and tautomerism of spiro-
pyrazolines, Tetrahedron Lett. 55 (2014) 2208–2211, https://doi.org/10.1016/j.
tetlet.2014.02.052.
[5] E. Opoku, R. Tia, E. Adei, Computational studies on [4 + 2] / [3 + 2] tandem
sequential cycloaddition reactions of functionalized acetylenes with
cyclopentadiene and diazoalkane for the formation of norbornene pyrazolines,
J. Mol. Model. 25 (2019) 168, https://doi.org/10.1007/s00894-019-4056-x.
[6] G.B. Pipim, R. Tia, E. Adei, Quantum chemical investigation of the formation of
spiroheterocyclic compounds via the (3 + 2) cycloaddition reaction of 1-methyl-3-
(2,2,2-trifluoroethylidene) pyrrolidin-2-one with diazomethane and nitrone
derivatives, Tetrahedron. 94 (2021), 132306, https://doi.org/10.1016/j.
tet.2021.132306.
[7] G.B. Pipim, E. Opoku, R. Tia, E. Adei, Peri-, Chemo-, Regio-, Stereo- and Enantio-
Selectivities of 1,3-dipolar cycloaddition reaction of C, N-Disubstituted nitrones
with disubstituted 4-methylene-1,3-oxazol-5(4H)- one: A quantum mechanical
study, J. Mol. Graph. Model. 97 (2020), 107542, https://doi.org/10.1016/j.
jmgm.2020.107542.
[8] E. Opoku, R. Tia, E. Adei, [ 3 + 2 ] versus [ 2 + 2 ] Addition : A Density Functional
Theory Study on the Mechanistic Aspects of Transition Metal-Assisted Formation of
1 , 2-Dinitrosoalkanes, J. Chem. 2016 (2016) 10 pages. 10.1155/2016/4538696.
[9] D.A. Akuamoah, E. Opoku, R. Tia, E. Adei, 1,3-Dipolar cycloaddition reaction of
indoles with tosyl azide, subsequent dehydroaromatization and ring-opening
cascade: a computational study, Theor. Chem. Acc. 139 (2020) 1–16, https://doi.
org/10.1007/s00214-020-02653-5.
[10] E. Opoku, G. Baffour Pipim, R. Tia, E. Adei, Mechanistic study of the tandem
intramolecular (4 + 2)/intermolecular (3 + 2) cycloaddition reactions for the
formation of polyaza- and polyisoxazolidine-steroids, J. Heterocycl. Chem. 57
(2020) 1748–1758, https://doi.org/10.1002/jhet.3900.
[11] Z. Sadiq, S. Naz, H.S. Akbar, Spiropyrazolines: Insights into Recent Strategies and
Synthetic Applications, 2018. 10.2174/1570178615666181022141147.
[12] L.S.S. Reddy, M.B. Raju, C. Sridhar, Novel pyrazolines: Synthesis and evaluation of
their derivatives with anticancer and anti-inflammatory activities, Int. J. Pharm.
Pharm. Sci. 8 (2016) 247–254.
[13] A. Burmudžija, J. Muškinja, Z. Ratković, M. Kosanić, B. Ranković, S.B. Novaković,
G.A. Bogdanović, Pyrazoline derivatives of acryloyl substituted ferrocenyl ketones:
Synthesis, antimicrobial activity and structural properties, Inorganica Chim. Acta.
471 (2018) 570–576, https://doi.org/10.1016/j.ica.2017.11.061.
[14] X. Wang, Y.M. Pan, X.C. Huang, Z.Y. Mao, H.S. Wang, A novel methodology for
synthesis of dihydropyrazole derivatives as potential anticancer agents, Org.
Biomol. Chem. 12 (2014) 2028–2032, https://doi.org/10.1039/c3ob42432d.
[15] T.A. King, H.L. Stewart, K.T. Mortensen, A.J.P. North, H.F. Sore, D.R. Spring,
Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for
Fragment-Based Drug Discovery, European J. Org. Chem. 2019 (2019) 5219–5229,
https://doi.org/10.1002/ejoc.201900847.
[16] R. Fusco, L. Garanti, G. Zecchi, Intramolecular 1,3-Dipolar Cycloadditions of Aryl
Azides Bearing Alkenyl, Alkynyl, and Nitrile Groups, J. Org. Chem. 40 (1975)
1906–1909, https://doi.org/10.1021/JO00901A007/ASSET/JO00901A007.FP.
PNG_V03.
[17] R. Raghunathan, M. Shanmugasundaram, S. Bhanumathi, E.J. Padma Malar,
Synthesis of Spiropyrazoline [5.3] 4-Chromanones, Heteroat. Chem. 9 (1998)
327–332. 10.1002/(SICI)1098-1071(1998)9:3.
[18] M.M. Efremova, A.S. Novikov, R.R. Kostikov, T.L. Panikorovsky, A.V. Ivanov, A.
P. Molchanov, Regio- and diastereoselectivity of the cycloaddition of nitrones with
N-propadienylindole and pyrroles, Tetrahedron. 74 (2018) 174–183, https://doi.
org/10.1016/j.tet.2017.11.056.
[19] E.V. Sirotkina, M.M. Efremova, A.S. Novikov, V.V. Zarubaev, I.R. Orshanskaya, G.
L. Starova, R.R. Kostikov, A.P. Molchanov, Regio- and diastereoselectivity of the
cycloaddition of aldonitrones with benzylidenecyclopropane: An experimental and
theoretical study, Tetrahedron. 73 (2017) 3025–3030.
[20] M.M. Efremova, A.P. Molchanov, A.S. Novikov, G.L. Starova, A.A. Muryleva, A.
V. Slita, V.V. Zarubaev, 1,3-Dipolar cycloaddition of N-allyl substituted polycyclic
derivatives of isoindole-1,3-dione with nitrones and nitrile oxides: An experimental
and theoretical investigation, Tetrahedron. 76 (2020), 131104, https://doi.org/
10.1016/j.tet.2020.131104.
[21] A.S. Novikov, M.L. Kuznetsov, Theoretical study of Re(IV) and Ru(II) bis-
isocyanide complexes and their reactivity in cycloaddition reactions with nitrones,
Inorganica Chim. Acta. 380 (2012) 78–89, https://doi.org/10.1016/j.
ica.2011.08.016.
[22] A.A. Melekhova, A.S. Smirnov, A.S. Novikov, T.L. Panikorovskii, N.A. Bokach, V.
Y. Kukushkin, Copper(I)-Catalyzed 1,3-Dipolar Cycloaddition of Ketonitrones to
Dialkylcyanamides: A Step toward Sustainable Generation of 2,3-Dihydro-1,2,4-
oxadiazoles, ACS Omega. 2 (2017) 1380–1391, https://doi.org/10.1021/
acsomega.7b00130.
G. Amankwah et al.
[23] M.A. Kinzhalov, A.S. Legkodukh, T.B. Anisimova, A.S. Novikov, V.V. Suslonov, K.
V. Luzyanin, V.Y. Kukushkin, Tetrazol-5-ylidene Gold(III) Complexes from
Sequential [2 + 3] Cycloaddition of Azide to Metal-Bound Isocyanides and N4
Alkylation, Organometallics. 36 (2017) 3974–3980, https://doi.org/10.1021/acs.
organomet.7b00591.
[24] A.K. Gupta, N.K. Vaishanv, R. Kant, K. Mohanan, Rapid and selective synthesis of
spiropyrazolines and pyrazolylphthalides employing Seyferth-Gilbert reagent, Org.
Biomol. Chem. 15 (2017) 6411–6415, https://doi.org/10.1039/c7ob01417a.
[25] H. Liu, H. Jia, B. Wang, Y. Xiao, H. Guo, Synthesis of Spirobidihydropyrazole
through Double 1,3-Dipolar Cycloaddition of Nitrilimines with Allenoates, (2017)
19–22. 10.1021/acs.orglett.7b01961.
[26] G. Utecht, G. Mlostoń, M. Jasiński, A Straightforward Access to
Trifluoromethylated Spirobipyrazolines through a Double (3+2)-Cycloaddition of
Fluorinated Nitrile Imines with Alkoxyallenes, Synlett. 29 (2018) 1753–1758,
https://doi.org/10.1055/s-0037-1610454.
[27] D.Z. Chen, W.J. Xiao, J.R. Chen, Synthesis of spiropyrazoline oxindoles by a formal
[4 + 1] annulation reaction between 3-bromooxindoles and: In situ -derived 1,2-
diaza-1,3-dienes, Org. Chem. Front. 4 (2017) 1289–1293, https://doi.org/
10.1039/c7qo00163k.
[28] Z. Guo, H. Jia, H. Liu, Q. Wang, J. Huang, H. Guo, A [4 + 3] Annulation Reaction
of aza- o-Quinone Methides with Arylcarbohydrazonoyl Chlorides for Synthesis of
2,3-Dihydro-1 H-benzo[e][1,2,4]triazepines, Org. Lett. 20 (2018) 2939–2943,
https://doi.org/10.1021/acs.orglett.8b00990.
[29] Y. Su, Y. Zhao, B. Chang, X. Zhao, R. Zhang, X. Liu, D. Huang, K.H. Wang, C. Huo,
Y. Hu, Cycloaddition of para-Quinone Methides with Nitrile Imines: Approach to
Spiro-pyrazoline-cyclohexadienones, J. Org. Chem. 84 (2019) 6719–6728, https://
doi.org/10.1021/acs.joc.9b00434.
[30] C. Yuan, X. Ning, T. Gao, Z. Zeng, K. Lee, Y. Xing, S. Sun, G. Wang, [3+2]
Cycloaddition of Nitrile Imines with 3-Benzylidene Succinimides: A Facile Access
to Functionalized Spiropyrazolines, Asian, J. Org. Chem. 11 (2022) 1–4, https://
doi.org/10.1002/ajoc.202100699.
[31] Â. Monteiro, L.M. Gonçalves, M.M.M. Santos, Synthesis of novel spiropyrazoline
oxindoles and evaluation of cytotoxicity in cancer cell lines, Eur. J. Med. Chem. 79
(2014) 266–272, https://doi.org/10.1016/j.ejmech.2014.04.023.
[32] M.D. Hanwell, D.E. Curtis, D.C. Lonie, T. Vandermeerschd, E. Zurek, G.
R. Hutchison, Avogadro: An advanced semantic chemical editor, visualization, and
analysis platform, J. Cheminform. 4 (2012) 17, https://doi.org/10.1186/1758-
2946-4-17.
[33] M. Clark, R.D. Cramer, N. Van Opdenbosch, Validation of the general purpose
tripos 5.2 force field, J. Comput. Chem. 10 (1989) 982–1012, https://doi.org/
10.1002/jcc.540100804.
[34] J. Atta, K. George, B. Pipim, R. Tia, E. Adei, Investigating the site -, regio -, and
stereo - selectivities of the reactions between organic azide and 7 -
heteronorbornadiene: a DFT mechanistic study, J. Mol. Model. (2021), https://doi.
org/10.1007/s00894-021-04857-3.
[35] G.B. Pipim, E. Opoku, Unveiling the molecular mechanisms of the cycloaddition
reactions of aryl hetaryl thioketones and C, N-disubstituted nitrilimines, J. Mol.
Model. 27 (2021) 84, https://doi.org/10.1007/s00894-021-04706-3.
[36] H. Abdullah, E. Opoku, Quantum chemical study on the mechanism and selectivity
of [3 + 2] cycloaddition reactions of aryl nitrile oxides with furanone, Theor.
Chem. Accounts 2022 14110. 141 (2022) 1–14. 10.1007/S00214-022-02915-4.
[37] A. Tawiah, G.B. Pipim, R. Tia, E. Adei, Exploring the chemo-, regio-, and
stereoselectivities of the (3 + 2) cycloaddition reaction of 5,5-dimethyl-3-methy­
lene-2-pyrrolidinone with C,N-diarylnitrones and nitrile oxide derivatives: a DFT
study, J. Mol. Model. 2021 2710. 27 (2021) 1–13. 10.1007/S00894-021-04911-0.
[38] A.R. Umar, B. Donkor, E. Opoku, Mechanistic details of domino [3+2]
cycloaddition/[3,3] sigmatropic shift reactions of N-vinyl nitrones with
isocyanates, Comput. Theor. Chem. 1210 (2022), 113643, https://doi.org/
10.1016/j.comptc.2022.113643.
[39] G.B. Pipim, R. Tia, E. Adei, (3 + 2) cycloaddition reaction of 7-isopropylidene­
benzonorbornadiene and diazomethane derivatives: A theoretical study, J. Mol.
Graph. Model. 101 (2020), 107713, https://doi.org/10.1016/j.
jmgm.2020.107713.
[40] G. Baffour Pipim, E. Opoku, Catalyst-free [3 + 2] cycloaddition reaction of oxa-,
aza-, and thio-bicyclic alkenes with cyclic and acyclic nitrones: A mechanistic
study, Comput. Theor. Chem. 1214 (2022), 113790, https://doi.org/10.1016/j.
comptc.2022.113790.
[41] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M. a. Robb, J.R. Cheeseman,
G. Scalmani, V. Barone, G. a. Petersson, H. Nakatsuji, X. Li, M. Caricato, a. V.
Marenich, J. Bloino, B.G. Janesko, R. Gomperts, B. Mennucci, H.P. Hratchian, J. V.
Ortiz, a. F. Izmaylov, J.L. Sonnenberg, Williams, F. Ding, F. Lipparini, F. Egidi, J.
Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V.G. Zakrzewski, J. Gao,
N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K.
Throssell, J. a. Montgomery Jr., J.E. Peralta, F. Ogliaro, M.J. Bearpark, J.J. Heyd,
E.N. Brothers, K.N. Kudin, V.N. Staroverov, T. a. Keith, R. Kobayashi, J. Normand,
K. Raghavachari, a. P. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, J.M.
Millam, M. Klene, C. Adamo, R. Cammi, J.W. Ochterski, R.L. Martin, K. Morokuma,
O. Farkas, J.B. Foresman, D.J. Fox, G09, (2009) Gaussian 09, Revision E.01,
Gaussian, Inc., Wallington.
[42] J. Tomasi, B. Mennucci, R. Cammi, Quantum mechanical continuum solvation
models, Chem. Rev. 105 (2005) 2999–3093, https://doi.org/10.1021/cr9904009.
13
Computational and Theoretical Chemistry 1225 (2023) 114138
[43] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, Gaussian 09, revision b. 01,
Gaussian, Inc., Wallingford, CT. 6492 (2009).
[44] K.N. Houk, B.R. Beno, M. Nendel, K. Black, H.Y. Yoo, S. Wilsey, J.K. Lee,
Mechanical methods : competing concerted and stepwise mechanisms’, 399 (1997)
169–179.
[45] J. Tirado-Rives, W.L. Jorgensen, Performance of B3LYP density functional methods
for a large set of organic molecules, J. Chem. Theory Comput. 4 (2008) 297–306,
https://doi.org/10.1021/ct700248k.
[46] B. Donkor, A.R. Umar, E. Opoku, Mechanistic elucidation of the tandem
Diels–Alder/(3 + 2) cycloadditions in the design and syntheses of heterosteroids,
J. Mol. Model. 28 (2022) 1–16, https://doi.org/10.1007/s00894-022-05063-5.
[47] A.R. Umar, E. Opoku, Mechanistic studies on stereoselective domino [4 + 2]/retro
[3 + 2]/[3 + 2] cycloaddition reactions of oxadiazoles with strained and
unstrained cycloalkenes, Theor. Chem. Acc. 141 (2022) 1–16, https://doi.org/
10.1007/s00214-022-02872-y.
[48] H.P. Hratchian, H.B. Schlegel, Using Hessian Updating To Increase the Efficiency of
a, (2005) 61–69.
[49] H.P. Hratchian, H.B. Schlegel, H.P. Hratchian, H.B. Schlegel, Accurate reaction
paths using a Hessian based predictor – corrector integrator Accurate reaction
paths using a Hessian based predictor – corrector integrator, 9918 (2004).
10.1063/1.1724823.
[50] D. Roland, J.N. Haleegoah, E. Opoku, R. Tia, E. Adei, Mechanistic studies on
tandem cascade [4 + 2]/ [3 + 2] cycloaddition of 1,3,4-oxadiazoles with olefins,
J. Mol. Graph. Model. 93 (2019) 2–11, https://doi.org/10.1016/j.
jmgm.2019.107452.
[51] E. Opoku, R. Tia, E. Adei, Quantum chemical studies on the mechanistic aspects of
tandem sequential cycloaddition reactions of cyclooctatetraene with ester and
nitrones, J. Mol. Graph. Model. 92 (2019) 17–31, https://doi.org/10.1016/j.
jmgm.2019.06.019.
[52] E. Opoku, R. Tia, E. Adei, DFT mechanistic study on tandem sequential [4 + 2]/[3
+ 2] addition reaction of cyclooctatetraene with functionalized acetylenes and
nitrile imines, J. Phys. Org. Chem. 32 (2019) e3992.
[53] C.Y. Legault, C. Y. CYLview, 2009. http://www.cylview.org.
[54] L.R. Domingo, M.J. Aurell, P. Pérez, R. Contreras, Quantitative characterization of
the global electrophilicity power of common diene/dienophile pairs in Diels-Alder
reactions, Tetrahedron. 58 (2002) 4417–4423, https://doi.org/10.1016/S0040-
4020(02)00410-6.
[55] L.R. Domingo, M.J. Aurell, P. Pérez, R. Contreras, Quantitative characterization of
the local electrophilicity of organic molecules. Understanding the regioselectivity
on Diels-Alder reactions, J. Phys. Chem. A. 106 (2002) 6871–6875, https://doi.
org/10.1021/jp020715j.
[56] R.G. Parr, L. v. Szentpály, S. Liu, Electrophilicity Index, J. Am. Chem. Soc. 121
(1999) 1922–1924. 10.1021/ja983494x.
[57] T. Koopmans, Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den
Einzelnen Elektronen Eines Atoms, Physica. 1 (1934) 104–113, https://doi.org/
10.1016/S0031-8914(34)90011-2.
[58] L.R. Domingo, P. Pe, P. Pérez, J.A. Sáez, Understanding the local reactivity in polar
organic reactions through electrophilic and nucleophilic Parr functions, RSC Adv. 3
(2013) 1486–1494, https://doi.org/10.1039/c2ra22886f.
[59] L.R. Domingo, P. Pérez, J.A. Sáez, Obtaining the Electrophilic and Nucleophilic
Parr Functions, RSC Adv. 3 (2013) 1486–1494.
[60] L.R. Domingo, E. Chamorro, P. Pérez, Understanding the Reactivity of Captodative
Ethylenes in Polar Cycloaddition Reactions. A Theoretical Study, J. Org. Chem. 73
(2008) 4615–4624, https://doi.org/10.1021/jo800572a.
[61] L.R. Domingo, A new C-C bond formation model based on the quantum chemical
topology of electron density, RSC Adv. 4 (2014) 32415–32428, https://doi.org/
10.1039/c4ra04280h.
[62] A.E. Reed, L.A. Curtiss, F. Weinhold, Intermolecular Interactions from a Natural
Bond Orbital, Donor—Acceptor Viewpoint, Chem. Rev. 88 (1988) 899–926,
https://doi.org/10.1021/cr00088a005.
[63] A.E. Reed, R.B. Weinstock, F. Weinhold, Natural population analysis, J. Chem.
Phys. 83 (1985) 735–746, https://doi.org/10.1063/1.449486.
[64] A.I. Adjieufack, J. Moto Ongagna, A. Pouyewo Tenambo, E. Opoku, I.
N. Mbouombouo, How a Chromium Tricarbonyl Complex Catalyzes the [3 + 2]
Cycloaddition Reaction of N-Substituted Phenylnitrones with Styrene: A Molecular
Electron Density Theory Analysis, Organometallics. 41 (2022) 3809–3822, https://
doi.org/10.1021/acs.organomet.2c00394.
[65] B. Donkor, E. Opoku, A. Aniagyei, Theoretical studies on cycloaddition reactions of
N-allyl substituted polycyclic Isoindole-1,3-dione with nitrones and nitrile oxides,
Comput. Theor. Chem. 1208 (2022), 113574, https://doi.org/10.1016/j.
comptc.2021.113574.
[66] G. Arhin, A.H. Adams, E. Opoku, R. Tia, E. Adei, 1, 3-Dipolar cycloaddition
reactions of selected 1,3-dipoles with 7-isopropylidenenorbornadiene and follow-
up thermolytic cleavage: A computational study, J. Mol. Graph. Model. 92 (2019)
267–279, https://doi.org/10.1016/j.jmgm.2019.08.004.
[67] E. Opoku, G. Arhin, G. Baffour, P. Anita, H. Adams, R. Tia, E. Adei, Site -, enantio -
and stereo - selectivities of the 1, 3 - dipolar cycloaddition reactions of
oxanorbornadiene with C, N - disubstituted nitrones and dimethyl nitrilimines : a
DFT mechanistic study, Theor. Chem. Acc. (2020) 1–15, https://doi.org/10.1007/
s00214-019-2529-8.