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\DOI{10.5802/crchim.340}
\datereceived{2024-03-03}
\daterevised{2024-05-31}
\datererevised{2024-07-02}
\datererevised{2024-09-06}
\dateaccepted{2024-09-10}
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\begin{document}

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\begin{noXML}

\CDRsetmeta{articletype}{research-article}

\title{Studies of axially chiral atropisomers of an indole-substituted
phthalonitrile derivative\vspace*{-2pt}}

\alttitle{\'{E}tudes des atropisom\`{e}res axialement chiraux d'un
d\'{e}riv\'{e} de phthalonitrile substitu\'{e} par l'indole}

\author{\firstname{Sami} \lastname{Ayari}\CDRorcid{0000-0002-1505-1922}\IsCorresp}
\address{University of Tunis El Manar Faculty of Sciences of Tunis,
Laboratory of Structural Organic Chemistry and Macromolecular LR99ES14,
University Campus, 2092 Tunis, Tunisia}
\address{Laboratory of Microorganisms and Active Biomolecules LR03ES03,
Department of Biology, Faculty of Sciences of Tunis, University of
Tunis-El Manar, 2092 El Manar I Tunis, Tunisia}
\email[S. Ayari]{sami.ayari@fst.utm.tn}

\author{\firstname{Haitham} \lastname{Elleuch}\CDRorcid{0000-0003-2373-6427}\IsCorresp}
\addressSameAs{1}{University of Tunis El Manar Faculty of Sciences of Tunis,
Laboratory of Structural Organic Chemistry and Macromolecular LR99ES14,
University Campus, 2092 Tunis, Tunisia}
\email[H. Elleuch]{haitham.elleuch@cst.rnu.tn}

\author{\firstname{Amal} \lastname{Thebti}\CDRorcid{0000-0002-5544-8086}}
\addressSameAs{2}{Laboratory of Microorganisms and Active Biomolecules LR03ES03,
Department of Biology, Faculty of Sciences of Tunis, University of
Tunis-El Manar, 2092 El Manar I Tunis, Tunisia}

\author{\firstname{Hadda-Imene} \lastname{Ouzari}\CDRorcid{0000-0002-3237-554X}}
\addressSameAs{2}{Laboratory of Microorganisms and Active Biomolecules LR03ES03,
Department of Biology, Faculty of Sciences of Tunis, University of
Tunis-El Manar, 2092 El Manar I Tunis, Tunisia}

\shortrunauthors

\keywords{\kwd{DFT}
\kwd{HOMO--LUMO}
\kwd{Indole}
\kwd{Phthalonitrile}
\kwd{Atropisomers}
\kwd{Chirality}
\kwd{Transition state energy}}

\altkeywords{\kwd{DFT}
\kwd{HOMO-LUMO}
\kwd{Indole}
\kwd{Phthalonitrile}
\kwd{Atropisom\'{e}rie}
\kwd{Chiralit\'{e}}
\kwd{\'{E}tat de transition \'{e}nerg\'{e}tique}}

\begin{abstract}
A synthesis and theoretical study of
3-(2-methyl-1\textit{H}-indol-3-yl)-6-nitrophthalonitrile (\textbf{1}) are
presented in this study. Structural confirmation of the molecule was
achieved using \textsuperscript{1}H, \textsuperscript{13}C NMR and mass spectroscopy. The
determination of the atropisomer rotational barrier for compound
\textbf{1} revealed its classification as a class 1 atropisomer.
Additionally, a comprehensive analysis was conducted, encompassing
HOMO--LUMO evaluation of the transition states, examination of their
structure, and calculation of the activation energy.
\vspace*{-3pt}
\end{abstract}

\begin{altabstract}
Une synth\`{e}se et \'{e}tude th\'{e}orique du
3-(2-m\'{e}thyl-1\textit{H}-indol-3-yl)-6-nitrophthalonitrile (\textbf{1})
sont pr\'{e}sent\'{e}es dans cette \'{e}tude. La confirmation
structurelle de la mol\'{e}cule a \'{e}t\'{e} obtenue par RMN \textsuperscript{1}H,
\textsuperscript{13}C et spectroscopie de masse. La d\'{e}termination de la
barri\`{e}re de rotation de l'atropisom\`{e}re pour le compos\'{e}
\textbf{1} a r\'{e}v\'{e}l\'{e} sa classification en tant
qu'atropisom\`{e}re de classe 1. De plus, une analyse compl\`{e}te a
\'{e}t\'{e} men\'{e}e, comprenant l'\'{e}valuation HOMO-LUMO des
\'{e}tats de transition, l'examen de leur structure et le calcul de
l'\'{e}nergie d'activation.
\end{altabstract}

\maketitle

\vspace*{-1pt}

\twocolumngrid

\end{noXML}

\let\rmmu\upmu

\section{Introduction}\label{sec1}

Indole derivatives are prominently and extensively distributed in
diverse ecosystems within the natural environment~\cite{1,2,3}. They play
a pivotal role in numerous biological and clinical applications. These
versatile compounds exhibit a spectrum of activities, including
antiviral~\cite{4}, anti-inflammatory, and analgesic
properties~\cite{5}; anticancer potential~\cite{6,7,8,9,10}; anti-HIV
activity~\cite{11,12,13}; antioxidant effects~\cite{14}; antimicrobial
attributes~\cite{15,16,17,18}; antitubercular functions~\cite{19}; and
anticholinesterase capabilities~\cite{20,21}. Additionally, they
demonstrate noteworthy antimalarial activity~\cite{22,23}.

\begin{scheme*}
\includegraphics{sc01}
{\vspace*{6pt}}
\caption{\label{sch1}Mechanism for coupling reaction of
3-nitrophthalonitrile with 2-methylindole.}
{\vspace*{-8pt}}
\end{scheme*}

In the pursuit of designing innovative organic compounds featuring
atropisomers, a strategic approach involves, among others, the
\mbox{synergistic} \mbox{coupling} of indole moieties with phthalonitrile
derivatives~\cite{24,25,26,27}. This method not only increases the
structural diversity of the resultant compounds but also holds
significant promise for expanding the repertoire of bioactive
molecules~\cite{28}. 

The impact of chirality on a drug's biological activity is exemplified by
the significant complications arising from enantiomers in racemic
mixtures. A classic illustration of this phenomenon is thalidomide.
Consequently, atropisomerism manifests when a rotational barrier takes
place due to steric hindrance, leading to the separation of individual
conformers when axial chirality is established~\cite{29,30}.
Atropisomerism emerges in various molecular frameworks in drug
discovery, encompassing biaryls, diaryl ethers, and other structural
motifs~\cite{31}. This emphasizes the relevance of considering
atropisomerism in the design and development of pharmaceutical
compounds with enhanced biological efficacy and reduced complications\break
associated with stereochemistry. According to LaPlante et~al.,
atropisomers are classified into three categories based on the amount
of energy required for their racemization by rotation of the chiral
axis~\cite{32,33}. Class 1 atropisomers have barriers of rotation,
around the chiral axis, of ${<}$20~kcal/mol and racemize in a minute or
faster; class 2 atropisomers have a barrier to rotation between 
20 and 28~kcal/mol and racemize in 1 h to a month; and class 3
atropisomers possess a barrier to rotation ${>}$28~kcal/mol and
racemize in 1 year or greater.

An intriguing observation emerges concerning atropisomerism in
small-molecule drugs, where the prevalence is notably dominated by
unstable class 1 atropisomers. Despite these molecules possessing
distinct biological functions and exhibiting atroposelective binding to
proteins, they are frequently categorized as achiral~\cite{33,34}.

In fact, rapidly interconverting atropisomers or class 1 atropisomers
interact with their biological receptors in configurations that are
biologically irrelevant,
which can cause side effects~\cite{35,36}. Interconverting atropisomers
are shown to bind their respective targets
atroposelectively~\cite{37,38,39}. Therefore, atropisomers should be
taken into account when designing new medicinal drugs.\looseness=-1

In a previous work~\cite{24}, we have synthesized an atropisomeric
phthalonitrile-3-yl (PN3) substituted indole derivative with a N--C
chiral axis. A dihedral angle of 42.17(8)$''$ exists between the indole and the phthalonitrile
due to steric repulsion. Theoretical studies revealed
that the rotational barrier of PN3 was 8.82~kcal${\cdot}$mol$^{-1}$~at 
room temperature (RT)  and,
according to LaPlante et~al.~\cite{34}, PN3 is classified as a class 1
atropisomer.\break


\begin{scheme*}
\includegraphics{sc02}
{\vspace*{7pt}}
\caption{\label{sch2}Mesomeric forms of 3-nitrophthalonitrile.}
\vspace*{-3pt}
\end{scheme*}

\begin{figure*}
\includegraphics{fig01}
\caption{\label{fig1}The geometries of the transition states of the
studied reaction with different bases.}
\end{figure*}


In this study, we report the synthesis of a new indole 
derivative,~3-(2-methyl-1${H}$-indol-3-yl)-6-nitrophthalonitrile 
\textbf{(1)}.~Compound \textbf{1} was synthesized, and theoretical
calculations were performed to investigate the structure of the
transition state of \textbf{1} and its activation energy as well as its
rotational transition states. Additionally, highest occupied molecular
orbital  (HOMO)--lowest unoccupied molecular orbital (LUMO) analyses
were conducted. Compound \textbf{1} exhibits axial chirality. It was
structurally characterized and has been studied theoretically and
spectroscopically. 

{\vspace*{-2pt}}

\section{Results and discussion}\label{sec2}

{\vspace*{-2pt}}

\subsection{Synthesis and characterization of compound~1}\label{sec21}

{\vspace*{-2pt}}

A transition-metal-free nucleophilic attack to form a C--C bond
between phthalonitrile-3-yl (PN3) and 2-methylindole in the presence of
NaH as the base, in DMSO at room temperature, was achieved. The
${\upalpha}$- and ${\upbeta}$-position are suitable for C--N and C--C
cross-coupling, but the presence of the methyl group in the
${\upalpha}$-position makes the ${\upbeta}$-position favorable for the
C--C coupling. No reaction occurred when using
K$_{2}$CO$_{3}$ as the base and DMF as the solvent.
To achieve the coupling reaction, NaH was used as the base and DMSO as
the solvent at RT. The reaction provided compound
\textbf{1} in 69\% yield. The mechanism of the coupling reaction is
presented in Scheme~\ref{sch1}. 


The electron-withdrawing nitro group orients
the addition to the \textit{ortho} position. This molecule presents
three mesomeric forms, with form \textbf{IV} being the most stable and
least sterically congested. For this reason, 2-methylindole in its form
\textbf{II} preferentially adds to the nitro group (Scheme~\ref{sch2}).

The protonation of indole occurs at C3 rather than N1. The
deprotonation of the indole moiety starts when the N--H group reacts
with NaH leading to 2-methylindol-1-ide \textbf{I}, which was converted
to 2-methylindol-3-ide \textbf{II} via resonance (Scheme~\ref{sch1}).
The nucleophilic attack of \textbf{II} on 6-nitrophthalonitrile would
lead to compound \textbf{1}~\cite{40}. Nuclear magnetic resonance 
(NMR, $^{1}$H and $^{13}$C) and
mass spectroscopy spectra analysis were used to confirm the structure
of target compound \textbf{1}. As shown in the Supporting
Information, the analyses were consistent with the predicted
structures~(SI, Figure~\ref{fig1}--\ref{fig3}).

\subsection{Transition state energy}\label{sec22}

\vspace*{-2pt}

As shown in Figure~\ref{fig1}A, K$_{2}$CO$_{3}$ is used as a weak
base while in Figure~\ref{fig1}B, NaH is used as a strong base to
remove the proton from the N--H group of the indole moiety.
\looseness=-1

\begin{table*}
\caption{\label{tab1}Transition state and activation energies
(kcal${\cdot}$mol$^{-1}$)\vspace*{-3pt}}
\begin{tabular}{ccccccc}
\thead
&React\textbf{1}& TS\textbf{1B} & Product\textbf{1B} 
&  React\textbf{2} & TS\textbf{2B} & Product\textbf{2B} \\
\endthead
${\Delta}{E}$ & 0.00 & 36.23 & 1.55   & 0.00 & 10.03 & ${-}$1.43 \\
${\Delta}E+$Zero-Point Energy (ZPE) & 0.00 & 36.29 & 1.34 & 0.00 & 10.21 & \mn0.37 \\
${\Delta}{H}$ & 0.00 & 35.13 & 1.57    & 0.00 & \09.31 & ${-}$0.60\vspace*{2pt} \\
${\Delta}{G}$ & 0.00 & 43.16 & 3.54    & 0.00 & 13.64 & \mn4.10
\botline
\end{tabular}
\vspace*{-4pt}
\end{table*}

The activation energy, $E_{\mathrm{a}}$, of 3-nitrophthalonitrile and
2-methylindole was studied to understand the factors that control their
reactivity. Deprotonation of the nitrogen atom of the indole moiety
reduces the activation energy, facilitating the coupling of
\mbox{2-methylindole} with 3-nitrophthalonitrile via the C--C bond. 
The structure of the transition state was determined by the Beckes
three parameter hybrid B3 and the nonlocal correlation of the
Lee--Yang--Parr (B3LYP) method, DFT/B3LYP/6-311+G(d,p).
The location of the transition
states was confirmed by the presence of only one imaginary
frequency in the {Hessian} matrix. All calculations were performed with
{Gaussian} 09 programs~\cite{41}. A comparison of the activation energies was
carried out to assess the influence of deprotonation on the indole
moieties. The geometries of the transition states corresponding to 
reaction \textbf{1} using DFT/B3LYP 6-311+G(d,p)~\cite{42} are shown in
Figure~\ref{fig1}. \looseness=-1

The calculation of the transition states and their activation energies
are shown in Table~\ref{tab1} with the maximum barrier. It is worth
mentioning that the lower transition state energy is the stable state
and promotes the coupling reaction.

The geometries of the reagents, products, and transition states have
been optimized. The intrinsic reaction coordinate  computations
were performed in order to verify the geometry of the transition
states. The calculations were carried out without and with the removal of the
proton, that is, with the use of a weak base and with the use of a strong
base. As indicated in Table~\ref{tab1}, we found that the energy barrier
for the formation of product \textbf{1B} is 
36.23~kcal${\cdot}$mol$^{-1}$~while that for the formation of product
\textbf{2B} is 10.03~kcal${\cdot}$mol$^{-1}$.
\looseness=-1

The weak base results in relatively high energy barriers, which prevent
the reaction from taking place, while a strong base leads to 
weak energy barriers, allowing the reaction to proceed more
rapidly.

\subsection{Optimized geometry parameters}\label{sec23}

To determine the configuration of the intermediate that has the minimum
energy, geometry optimizations were performed. The DFT/B3LYP optimized
geometry at the 6-311+G(d,p) level of \textbf{1} is shown in
Figure~\ref{fig2}. The structure of the molecule is nonplanar. In terms
of energy, the global minimum is ${-}$1023.453090 (u.a) and the dipole
moment is 15.282~D. \looseness=-1

\begin{figure}
\includegraphics{fig02}
{\vspace*{-3pt}}
\caption{\label{fig2}The optimized structure of \textbf{1} based on DFT
B3LYP/6-311+G(d,p) basis set.}
\end{figure}

\begin{figure*}
\includegraphics{fig03}
{\vspace*{-3pt}}
\caption{\label{fig3}Rotation of \textbf{1} through the C--C bond axis.}
\end{figure*}

Table~\ref{tab2} shows the bond length and the dihedral angles of
compound \textbf{1}. The bond length of \mbox{C8--C19} was 1.460~\AA{} and the
calculated dihedral angle of C2--C8--C19--C20 was 7.68\textdegree.

\begin{figure*}
\includegraphics{fig04}
{\vspace*{-8pt}}
\caption{\label{fig4}HOMO and LUMO of \textbf{1}.}
{\vspace*{-3pt}}
\end{figure*}

\begin{table}
\caption{\label{tab2}The calculated bond length (\AA{}) and dihedral
angles (\textdegree) by B3LYP/6-311+G(d,p) of \textbf{1}{\vspace*{-3pt}}}
\tabcolsep=4pt
\begin{tabular}{cc}
\thead
{Parameters} & \textbf{1} \\
\endthead
{Bond length (\AA{})} &  \\
{C8--C19} & \01.460 \vspace*{5pt}\\
{Dihedral angles} (\textdegree) &  \\
{C3--C2--C8--C19} & 52.24\0 \\
{C2--C8--C19--C20} & \07.68\0
\botline
\end{tabular}
{\vspace*{-3pt}}
\end{table}

\subsection{Chirality analysis}\label{sec24}

In racemic \textbf{1}, the molecular structure contains a chiral axis,
whose isomers---an (${S}$)-isomer and an \mbox{(${R}$)-isomer---are} generated by
the symmetry {operation} in their space groups. A theoretical study was
conducted to determine the rotational transition state of the
stereochemistry. A scan dihedral angle calculation was performed for
C2--C8--C19--C20. Structural optimization indicated that the most stable
structure has an angle of 52.24\textdegree. The eclipsed form having
$\uptheta = 0$\textdegree~and $\uptheta = 180$\textdegree~should be the
transition state for \textbf{1}. The rotational barrier of \textbf{1} is 
16~kcal${\cdot}$mol$^{-1}$.

According to LaPlante et~al., \textbf{1} is classified as a class 1
atropisomer that possesses a barrier of rotation around the chiral axis
${<}$20~kcal/mol and racemizes in less than 1~min or faster.

\subsection{Frontier molecular orbital analysis}\label{sec25}

The energy gap between the HOMO and the LUMO can be used to calculate
intramolecular charge transfer activity~\cite{40}. Molecular
interactions with other species can be determined by frontier molecular
orbitals (FMOs). The transition from the HOMO to the LUMO corresponds to 
electronic absorption. The HOMO energy represents the ionization 
\mbox{potential} (IP)
while the LUMO energy is related to electron affinity (EA). The energy difference
between the HOMO and LUMO orbitals is called the energy gap.
Figure~\ref{fig4} shows the 3D plots of the HOMO and LUMO frontier
orbitals computed at the B3LYP/6-311+G(d,p) level of \textbf{1}. The
red color represents the positive phase and the green color 
the negative phase. According to theory, the energy gap for
\textbf{1} is 2.53~eV (Table~\ref{tab3}).

\subsection{Density of states}\label{sec26}

\begin{table}
\caption{\label{tab3}Theoretical HOMO, LUMO, and gap
energies (in eV) for \textbf{1}}
\begin{tabular}{ccc}
\thead
${E}_{\text{HOMO}}$ & ${E}_{\text{LUMO}}$ &  $E_{\text{g}}$ \\
\endthead
${-}$6.12 & ${-}$3.59 & 2.53 
\botline
\end{tabular}
{\vspace*{8pt}}
\end{table}

The electronic density of states (DOS) of \textbf{1} comes from the
difference of energy between the HOMO and the LUMO. An FMO
energy level is related to its ionization potential and
electron affinity  according to the Koopmans theorem~\cite{43}. In
order to evaluate the global indices of activities like 
IP, EA, global hardness (${\upeta}$),
and global softness (G) of \textbf{1}, theoretical calculations were
made and are summarized in \mbox{Table~\ref{tab4}}. The IP is the minimum
amount of energy required to remove an electron from the least 
bound level in the gaseous phase. The IP of \textbf{1} is 6.12~eV. In the gaseous
state, the EA is 3.59~eV. The hardness
(${\upeta}$) represents the resistance of an atom to a charge transfer
that was 1.27~eV. Generally, the softest material has the smallest band
gap. The global softness is calculated as 0.79~eV$^{-1}$. The IP,
EA, ${\upeta}$, and G are defined as follows:
{\begin{eqnarray*}
&\displaystyle \mathrm{IP}= - E_{\mathrm{HOMO}} \\ 
&\displaystyle \mathrm{EA}= -E_{\mathrm{LUMO}}  \\
&\displaystyle \eta=  (\mathrm{IP}-\mathrm{EA})/2 \\
&\displaystyle \mathrm{G}=1/\eta .
\end{eqnarray*}}\unskip

\begin{table}[h!]
\caption{\label{tab4}The quantum chemical parameters of~\textbf{1}}
\begin{tabular}{ccccc}
\thead
&  IP (eV) & EA (eV) & $\upeta$ (eV) & G (eV$^{-1}$) \\
\endthead
\textbf{1} &  6.12 &  3.59 &  1.27 &  0.79 
\botline
\end{tabular}
\end{table}

\section{Conclusion}\label{sec3}

In this study, we have demonstrated that 2-methylindole and
3-nitrophthalonitrile can be coupled at RT using NaH as the
base without utilizing a transition metal catalyst. 
The theoretical studies
confirmed the nucleophilic attack of \mbox{2-methylindol-3-ide} on the
mesomeric form IV of 6-nitrophthalonitrile. This leads to the formation of
a C--C bond in DMSO. This is verified by calculating the activation energies of
\textbf{1} and its transition state structure as well as its rotational
barrier to demonstrate the axial chirality of \textbf{1} and its
corresponding atropisomerism characteristic. Calculations were made to
determine the optimized geometry parameter values (bond length, bond
angle, and dihedral angle). FMO and
DOS analysis were also conducted, and the energy gap
for \textbf{1} was determined to be 2.53~eV.

\section{Experimental section}\label{sec4}

\subsection{Synthesis of 3-(2-methyl-1\emph{H}-indol-3-yl)-6-nitrophthalonitrile}
\label{sec41}

A preliminary assay revealed that the reaction of 3-nitrophthalonitrile
with 2-methyl indole using K$_{2}$CO$_{3}$ as the base did not result
in a nucleophilic aromatic substitution---which is not the case for the
second reaction with NaH as the base---but rather results in a C--C
coupling reaction (Table~\ref{tab5} and Scheme~\ref{sch3}).

\begin{table}
\caption{\label{tab5}Reaction conditions between 3-nitrophthalonitrile
and 2-methylindole}
\tabcolsep=3pt
\begin{tabular}{cccccc}
\thead
Base &  Solvent &  $T$ (\textdegree C) &  Time (h) &  Yield (\%)\\
\endthead
K$_{2}$CO$_{3}$ &  DMF & 70 & -- &  NR \\
NaH & DMSO & RT & 4 & 69 
\botline
\end{tabular}
\end{table}

\begin{scheme*}
\includegraphics{sc03}
{\vspace*{6pt}}
\caption{\label{sch3}Synthesis pathway of \textbf{1}.}
{\vspace*{-6pt}}
\end{scheme*}

To a solution of 2-methylindole (302.4~mg, 2.3~mmol, 1~equiv) in
anhydrous DMSO (9~mL), NaH (110.4~mg, 4.58~mmol, 2~equiv) was added
under a nitrogen atmosphere. The solution was stirred for 5~min.
To this solution, 3-nitrophthalonitrile (800~mg, 4.62~mmol, 2~equiv) 
was then added. The reaction mixture was stirred at RT under a nitrogen
atmosphere. After 4 h, the reaction mixture was poured into a
saturated aqueous NaHCO$_{3}$ solution (15~mL). The resulting
mixture was extracted with ethyl acetate ($3\times20$~mL). The
organic layers were combined, dried over anhydrous Na$_{2}$SO$_{4}$,
filtered, and concentrated in vacuum. The crude product was purified by
column chromatography using EtOAc/hexane (20:80) as an eluent. A solid
reddish color compound was obtained. Yield: 69\% (480~mg). $^{1}$H
NMR (500~MHz, DMSO-d$_{6}$) ${\updelta}$: 11.85 (s,~1H), 8.65 (d,
$J= 8.8$~Hz,~1H), 8.17 (d,~$J= 8.8$~Hz,~1H), 7.44 (ddd, $J= 8.2$, 2.8,
1.8 Hz,~2H), 7.18 (ddd, $J= 8.2$, 7.1, 1.2~Hz,~1H), 7.11 (ddd, $J=
8.0$,  7.0, 1.0~Hz,~1H), 2.47 (s,~3H). $^{13}$C NMR (500~MHz,
DMSO-d$_{6}$) ${\updelta}$: 146.3, 146.0, 137.0, 136.3, 135.3, 129.1,
126.1, 121.9, 120.3, 117.7, 116.8, 115.3, 113.6, 112.5, 111.3, 108.1,
12.8. APCI MS ($m/z$) calculated for C$_{17}$H$_{10}$N$_{4}$O$_{2}$:
302.080; found: 302.079.

\subsection{Computational details}\label{sec42}

Theoretical calculations were performed using the density functional
theory method to optimize the considered structure of \textbf{1} with
hybrid B3~\cite{42}, with B3LYP method~\cite{44}, and the 6-311+G(d,p)
basis set. Software package and
GaussView 06, a molecular visualization program package, were
used~\cite{45}. The HOMO--LUMO analyses were conducted to explain
the charge transfer that takes place in \textbf{1}. The chemical
hardness and chemical potential were also calculated using the HOMO and
LUMO. The structure optimization of the transition states was performed
by the DFT B3LYP method using 6-311+G(d,p) as the basis. The
corresponding energies were calculated at the same level with 
B3LYP/6-311+G(d,p). 

{\vspace*{-2pt}}

\section*{Declaration of interests} 
The authors do not work for advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

\back{}

{\vspace*{-2pt}}

\section*{Supplementary data}
Figures 1--3 and Table 1 are given in the Supplementary Information (SI).
Supporting information for this article is available on the journal's
website under \printDOI\ or from the author.

\CDRsupplementaryTwotypes{supplementary-material}{\cdrattach{crchim-340-suppl.pdf}}

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