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The application of aromaticity and antiaromaticity to reaction

mechanisms

Qin Zhu , Shuwen Chen , Dandan Chen , Lu Lin , Kui Xiao ,

Liang Zhao , Miquel Solà , Jun Zhu

PII: S2667-3258(23)00117-6
DOI: https://doi.org/10.1016/j.fmre.2023.04.004
Reference: FMRE 536

To appear in: Fundamental Research

Received date: 14 January 2023

Revised date: 31 March 2023
Accepted date: 24 April 2023

Please cite this article as: Qin Zhu , Shuwen Chen , Dandan Chen , Lu Lin , Kui Xiao , Liang Zhao ,
Miquel Solà , Jun Zhu , The application of aromaticity and antiaromaticity to reaction mechanisms,
Fundamental Research (2023), doi: https://doi.org/10.1016/j.fmre.2023.04.004

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Review

The application of aromaticity and antiaromaticity to reaction mechanisms

Qin Zhua,b, Shuwen Chena, Dandan Chena, Lu Lina, Kui Xiaob, Liang Zhaoc, Miquel Solàd, Jun
Zhua,e,*
a
State Key Laboratory of Physical Chemistry of Solid Surfaces and Collaborative Innovation
Center of Chemistry for Energy Materials (iChEM), College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China
*
Corresponding author: jun.zhu@xmu.edu.cn (J. Zhu).
b
Key Laboratory for Organic Electronics & Information Displays (KLOEID) and Institute of
Advanced Materials (IAM), SICAM, Nanjing University of Posts & Telecommunications,
Nanjing 210023, China
c
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
d
Institute of Computational Chemistry and Catalysis and Department of Chemistry,
University of Girona, C/ M. Aurèlia Capmany, 69, 17003 Girona, Catalonia, Spain.
e
School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen 518172,
China

Abstract:

1
 Aromaticity, in general, can promote a given reaction by stabilizing a transition state or
a product via a mobility of  electrons in a cyclic structure. Similarly, such a promotion could
be also achieved by destabilizing an antiaromatic reactant. However, both aromaticity and
transition states cannot be directly measured in experiment. Thus, computational chemistry
has been becoming a key tool to understand the aromaticity-driven reaction mechanisms. In
this review, we will analyze the relationship between aromaticity and reaction mechanism
to highlight an importance of density functional theory calculations and present it according
to an approach via either aromatizing a transition state/product or destabilizing a reactant
by antiaromaticity. Specifically, we will start with a particularly challenging example of
dinitrogen activation followed by other small-molecule activation, C-F bond activation,
rearrangement, as well as metathesis reactions. In addition, antiaromaticity-promoted
dihydrogen activation, CO2 capture, and oxygen reduction reactions will be also briefly
discussed. Finally, caution must be cast as the magnitude of the aromaticity in the transition
states is not particularly high in most cases. Thus, a proof of an adequate electron
delocalization rather than a complete ring current is recommended to support their
relatively weak aromaticity in the transition states.

Keywords ： aromaticity; antiaromaticity; reaction mechanism; frustrated Lewis pairs;

dinitrogen activation; small molecule activation

1. Introduction

Aromatics exhibit numerous applications to various fields, including biomedicine,

materials science, energy science and environmental science [1]. Aromaticity, as the
footstone of aromatic chemistry as well as one of the most important concepts in chemistry,
can be used to rationalize reaction mechanisms due to electron delocalization caused by
bond length equalization in an intermediate, transition state or a product [2,3]. For
example, a summary of the application of this concept to organic reactions was reported by
Zimmerman as early as 1971 [4]. Very recently, the role of aromaticity in Diels–Alder
reactions was summarized by Houk and co-workers [5]. However, the important role of
aromaticity in the transition state has been overlooked to some extent. As both aromaticity
and transition state cannot be directly measured experimentally, computational chemistry
has been an effective tool to quantify and understand the aromaticity in a transition state.
Early in 1939, Evans pointed out “the greater the mobility of the π electrons in the transition
state, the greater will be the lowering of the activation energy” [6]. However, to the best of
our knowledge, only one review involving aromaticity in the transition state was published
in 2014 by Cossío, Fernández, and co-workers [7], focusing on pericyclic and pseudo-
pericyclic reactions. Therefore, in this review, we mainly focus on the recent development
of aromaticity-driven reactions in the past nine years (2015-2023) with the emphasis on the
stabilization of transition states.

2
 Hückel's rule states that monocyclic π-conjugated systems with 4n + 2 π-electrons are
aromatic in the ground state, which has been fully developed in organic chemistry. In
contrast, Baird’s rule states that species with 4n + 2 π-electrons are antiaromatic in the
lowest triplet state and those with 4n π-electrons are aromatic [8]. Excited-state aromaticity
could become a cornerstone for photochemistry but is less developed [9,10]. Currently,
excited-state (anti)aromaticity can be used to explain some observations of photophysical
and photochemical behaviors [11-13]. For instance, excited-state antiaromaticity has an
important effect on the photoinduced proton-coupled-electron-transfer (PCET) [14] and the
electrocyclization of dithienylbenzene swithes [15]. Singlet fission is a photophysical process
where an organic chromophore absorbs one photon and splits a high-energy singlet exciton
into two relatively low-energy triplet excitons, and excited-state aromaticity plays an
important role in the search of novel singlet fission materials [16]. The experimental
assessment of excited-state aromaticity in the expanded porphyrins was realized and
further verified by time-resolved optical spectroscopic measurements [17].

On the other hand, aromaticity also exhibits important applications in reaction

mechanisms, such as in the mechanisms of small-ecule activations, cycloaddition reactions,
intramolecular rearrangements, isomerization, electrocyclic reactions, [1, X]-shift reactions
as well as aromaticity-driven metallacycle syntheses. Taking small-molecule activation as
an example, the main components in the atmosphere (N2 and O2) can be used to construct
value-added species containing C-N or C-O bonds and the methane in natural gas can be
activated to form valuable chemicals [18]. Moreover, the capture and sequestration of
environmentally unfriendly small molecules such as CO2 and CS2 are important projects to
achieve green chemistry. Great progress in small-molecule activation has been made by
transition metal complexes due to the appropriate energy and symmetry of the d orbitals of
transition metals [19]. Over the last decades, main-group species have also shown great
potential in small-molecule activation, such as frustrated Lewis pairs (FLPs) [20], main-group
pincer compounds [21], low-valent species of group 13 and 14 elements [22] and singlet
carbenes [23]. However, most of these reactions in small-molecule activation involve cyclic
transition states or products and their aromaticity has not received adequate attention.

In this review, we will analyze the relationship between the reaction mechanism and
aromaticity and discuss it according to an approach via either stabilizing a transition
state/product by aromaticity or destabilizing a reactant by antiaromaticity, as illustrated in
Fig. 1. Specifically, enabling an antiaromatic reactant will facilitate a reaction both kinetically
and thermodynamically in most cases, whereas aromaticity gained or enhanced in a
transition state promotes a reaction kinetically and that in a product does
thermodynamically.

3
Fig. 1. Illustration of strategies for (anti)aromaticity-driven reaction via enabling an
antiaromatic reactant or aromatizing a transition state/product.

2. A procedure for the selection of an aromaticity index

Many aromaticity descriptors have been proposed on the basis of multiple

manifestations of aromaticity [24]. However, one must utilize a set instead of a single
one to justify aromaticity in a given system [25-27]. Choosing the “right” aromaticity
descriptors is not a trivial task, whereas under many circumstances, we should
perform all the suitable methods to determine if some aromaticity indices reach the
same conclusion or correlate well with each other. Note that aromaticity indices are
not always consistent with each other. In most cases, the contradictions are mainly
caused by the incorrect use of some indices rather than the multidimensional nature
of aromaticity. In our opinion, as the nature of aromaticity is electron delocalization,
electronic indices should have a top priority. Then other aromaticity indices based on
geometric, energetic, and magnetic properties could be considered in sequence. A
general procedure including a few steps is personally suggested to evaluate
aromaticity in a simple but efficient manner (Fig. 2). Long-range corrected density
functionals (e.g., CAM-B3LYP and ωB97XD) have better performance in the evaluation of
electron delocalization [28]. For geometry optimization of transition metal-containing
complexes, we usually use B3LYP, TPSS, PBE0, M06L, etc., together with the ECPnMDF basis
sets (n is the number of core electrons) with fully relativistic effective core potentials (ECPs)
for heavy transition metal systems.

The electron density of delocalized bonds (EDDB) method [29] can be used for
almost all types of systems. EDDB measures electron delocalization quantitatively,
with the capability of dissection into components based on orbital symmetries (σ, π,
δ, etc.), open-shell α/β subspaces, molecular fragments, designated paths, and
atomic and orbital contributions. To distinguish between nonaromaticity and
antiaromaticity, the electron localization function (ELF) is recommended [ 30 ],
especially for planar systems. As long as we obtain the optimized structure of a
4
system, it is always recommended to check the difference between the longest and
the shortest bonds (BL). BL is the most direct index for bond equalization, but the
investigated bonds must be of the same nature. Although EDDB and BL are listed
only for a few cases in Fig. 2, these two methods can be used for almost every type of
cyclic structures.

For small rings, the multicenter index (MCI) [30] is one of the most popular
aromaticity descriptors based on electron delocalization. The normalized form,
MCI1/n (n is the number of ring atoms), can be used to compare aromaticity between
rings with various sizes. Since each MCI analysis involves (n-1)! calculations, it is not
recommended for large rings (n>12). Magnetic indices, such as nucleus-independent
chemical shift (NICS) [31], iso-chemical-shielding surface (ICSS) [32], anisotropy of the
current-induced density (ACID) [ 33 ], and gauge-including magnetically induced
current (GIMIC) [34] are suitable for planar systems, as it is much easier to align an
external magnetic field perpendicular to the molecular plane. NICS is one of the most
widely used aromaticity descriptor. However, it should be carefully analyzed in
transition metal systems, as the extreme deshielding of the light atoms in the vicinity
of the osmium atoms in osmapentalene derivatives could be caused by paramagnetic
couplings between σOs-C bonding orbitals and the π*Os orbitals rather than
aromaticity [35]. The ICSS can characterize aromatic and antiaromatic rings by
shielding and deshielding cones, respectively. Both the ACID and GIMIC provide
visualization of diatropic ring currents in aromatic systems and paratropic ring
currents in antiaromatics.

Finally, the harmonic oscillator measure of aromaticity (HOMA) [36] could be

used for non-metal systems and the isomerization stabilization energy (ISE) [37] for
all-carbon, heterocyclic, and organometallic systems. It is impossible to use HOMA
for all-metal systems, as it requires the parameterization of metal-containing bonds,
which is not available to date. ISE depends on the definition of a reference system,
for which no designs for all-metal systems have been proposed in the literature.

5
Fig. 2. A proposed procedure for selection of an aromaticity index. Y: Yes; N: No.  means
the aromaticity index is suggested for this system whereas “” is not. EDDB, ICSS and
BL can be used for almost all systems. ELF can distinguish nonaromaticity and
antiaromaticity in planar systems. MCI is recommended for small rings whereas NICS,
ACID, and GIMIC are suitable for planar systems. HOMA can be used for non-metal
system and ISE for all-carbon, heterocyclic, and organometallic systems.

3. Aromaticity-stabilized transition states in triple bond activation

As we mentioned before, the approach for aromaticity-driven reactions could be

divided into aromatizing a transition state/product or destabilizing a reactant by
antiaromaticity. We start with a discussion of aromaticity-stabilized transition states.
In this section, some key achievements in aromaticity-driven triple bond activation
are summarized first. The functionalization of dinitrogen (N2) under mild conditions is
one of the most significant challenges in chemistry due to the remarkably strong and
non-polar NN triple bond. Dinitrogen activation has been achieved by either boron
species or metallic systems via mononuclear or polynuclear metal complexes [38].
However, the development of main-group elements for N2 fixation or activation
remains limited [39,40]. Recently, some of us proposed a new strategy that combines
the concept of aromaticity with FLPs for N2 activation for the first time [41]. It is
found that the combination of a methyleneborane with a N-heterocyclic carbene
could achieve metal-free N2 activation (Fig. 3a). Mechanistic studies reveal that such
metal-free N2 activation is favorable both kinetically and thermodynamically (with an
activation energy as low as 9.1 kcal mol-1 and an exothermicity of 18.9 kcal mol-1). In
general, a distinctly negative NICS value suggests aromaticity, and a distinctly positive
one means antiaromaticity. The calculated NICS(1)zz values and ACID results show
that the number of aromatic rings in this process gradually increased from one in the
reactant to two in the transition state and to three in the product, highlighting a
crucial role of aromaticity in N2 activation in this system. Interestingly, when two
rings in the product (5) become nonaromatic, the reaction becomes endergonic (Fig.
3a) [41].

The cleavage of CN triple bond has attracted great interest for its wide
application in organic synthesis. Xi, Takahashi, and co-workers discovered that in the
presence of two molecules of MeCN, one of the Cp units on titanacyclopentadiene
Cp2Ti(C4Et4) (6) was cleaved into a two-carbon unit and a three-carbon unit (Fig. 3b),
which were converted into a benzene derivative (11) and a pyridine derivative (12),
respectively [42]. This reaction involves the cleavage of two C=C double bonds and
one CN triple bond. Suresh and Koga investigated the reaction mechanism by
density functional theory (DFT) calculations [43]. Results show that the titanium
nitride intermediate was stabilized by the formation of an aromatic titanacycle. The
formation of 6π-electron metallaheterocycles 8 and 10 was an aromaticity-driven
6
step with low reaction barriers. Delocalized electronic structures, energetic
stabilization, and negative NICS(0) values in 7-TS (-4.8 ppm), 8 (-9.2 ppm), 9-TS (-7.1
ppm), and 10 (-9.0 ppm), indicate that aromaticity plays an important role in the
stabilization of the intermediate and transition states in this unique process.

Alkyne, containing a CC triple bond, is also an important synthon in synthetic

chemistry. The aromatic system with a CC triple bond, aryne, is an active
intermediate. Hoye et al. reported post-aromatization of a hexadehydro-Diels-Alder
reaction (HDDA) of triynes or tetraynes (FIG. 3c) [44]. DFT calculations show that
cycloaromatization of the triyne approach to the ortho-benzyne intermediate (16)
was exothermic by -51.4 kcal mol-1, and the trapping step to form 17 by t-butanol of
the strained alkyne was exothermic by -73.0 kcal mol-1. The formation of a benzyne
intermediate from triyne or tetrayne substrates in this reaction could be viewed as an
aromaticity-driven process. Subsequently, they found that the aromaticity-driven
HDDA reaction can be extended to alkane desaturated reaction [45]. As shown in
Fig.3c, the HDDA-generated benzyne intermediate (19) accepts two hydrogen atoms
from a saturated alkane, leading to the formation of the corresponding benzenoid
product (20) and alkene. This study shows that the benzyne intermediate is capable
of concerted deprotonation of a hydrocarbon. Interestingly, DFT calculations indicate
that these reactions have relatively low reaction activation barriers via in-plane
aromatic transition states (22-TS) (Fig. 3d). The negative NICS values ranging from -
10.0 to -20.8 ppm computed at the (3,+1) ring critical point and diatropic ring current
in an ACID plot confirmed the aromaticity of transition states [46].

7
Fig. 3. Aromaticity-stabilized transition states in triple or double bond activation. (a) Gibbs
energy profiles of the N2 fixation by carbon-boron FLPs together with the NICS(1)zz
values (in ppm) in blue [41]. Computational method, ωB97X-D/cc-pVTZ. (b) Activation
of the CN triple bond in MeCN. ethyl and R group were replaced for H and methyl in
DFT calculation [42,43]. NICS(0) values given (in ppm) in blue. Computational method,

8
B3LYP/6-31(G)(LanL2DZ). (c) HDDA of triyne or tetrayne [44,45]. Computational
method, M06-2X/6-31+G(d,p). (d) Electron barrier and reaction energies for the
reaction of benzyne with cyclic hydrocarbon (E‡ and ER, in kcal mol-1,
Synchronicities (Sy), and NICS (in ppm) computed at the [3,+1] ring critical point [46].
Computational method, M06-2X/6-311+G(d,p). (e) Gibbs energy profile and
aromaticity valuate (ACID plots, EDDB isosurfaces and MCI analysis) in the
cycloreversion step [47]. Computational method, SMD(dichloroethane)-(U)ωB97X-
D/def2-TZVP//(U)B3LYP-D3(BJ)/6-31G(d) (LanL2DZ). Isovalues for EDDB and ACID are
0.01 and 0.035, respectively. The NICS(1) zz values of the five membered-rings (5MRs)
in ppm. (f) NICS(1)zz values (ppm) in the 5MR and Gibbs energy barrier (kcal mol-1) for
CO2 capture by hetero-cyclopentadiene [48]. Computational method, M06-2X/6-
31+G(d).

4. Aromaticity-stabilized transition states in double bond activation.

Transition metal-catalyzed olefin metathesis is an important reaction in organic

synthesis and material science. However, the metathesis between C=O and C=C
double bonds has been less developed. Some of us performed a DFT study on an
iron(III)-catalyzed carbonyl-olefin metathesis (COM) reaction by introducing the
concept of hyperconjugative aromaticity in the transition state and product (Fig. 3e)
[47]. The concerted cycloreversion step from 27 to 28 was found to be strongly
related to aromaticity. Lowering activation energy of the cycloreversion step is
closely related to the aromatic character of the transition state (27-TS) caused by
hyperconjugation, which was supported by the larger π-EDDB (0.987 e) of the 5MR
and MCI values (0.462). This study shows that the hyperconjugative aromaticity of
transition states could play an important role in this COM reaction.

Recently, some of us reported an aromaticity-promoted CO2 activation by a

heterocyclopentadiene-bridged P/N-FLPs system [48]. In the open form of P/N-FLPs,
the increase of aromaticity determines the activation energy in the reaction. The
activation energies for aromatic furan- or pyrrole-bridged FLPs 29 and 31 were in the
range of 5.4-7.7 kcal mol-1. The aromaticity of transition states and the products was
evaluated by NICS and ACID analyses (Fig. 3f). The calculated NICS(1)zz values for the
5MR were gradually increased in the reactant (-9.1 and -9.4 ppm for 29 and 31,
respectively) to the transition state (-14.1 and -14.6 ppm for 29-TS and 31-TS,
respectively) and to the product (-23.3 and -26.6 ppm for 30 and 32, respectively),
indicating that the aromaticity plays an important role in the reaction. Interestingly,
the investigation of CS2 activation through a heterocyclopentadiene-bridged P/N-FLPs
system drew the same conclusion. It’s worth noting that the CO2 activation is more
efficient than that of CS2 through a comparative DFT study with CO2 capture [49]. It
could be attributed to the electrostatic attraction between FLP and CO2 rather than the
electrostatic repulsion caused by the reversed polarity of C=S in CS2.
9
5. Aromaticity-stabilized transition states in single bond activation.

Recent studies have reveals that the aromaticity of the transition-state also
plays a dominating role in the single bond activation and isomerization. For instance,
a metal-free C−H allylation was achieved by the iodane-guided “iodonio-Claisen” allyl
transfer of hypervalent (diacetoxy)iodoarenes [50]. In the mechanism of this reaction,
an aromatic transition state for the [3,3] sigmatropic rearrangement was proposed
and confirmed by DFT calculations (Fig. 4a). The synchronicity (Sy) value (0.83),
diatropic induced ring currents in ACID analysis, negative NICS(0)zz and NICS(1)zz
values (-16.3 and -14.3 ppm) support the aromaticity of the iodine-containing six-
membered ring (6MR) transition state.

In comparison with numerous approaches to C−H bond activation, the C−F bond
activation has also attracted considerable attention from scientists [51]. However,
the activation of C−F is challenging, which might be attributed to the high bond
dissociation energy (e.g., 109 kcal mol-1 for CH3−F). Although different strategies have
been developed for the C−F bond activation, the aromaticity-driven C−F bond
activation is less developed. Recently, some of us found aromaticity-promoted C−F
bond activation in the tautomerization of a rhodium complex (Fig. 4b) [52]. The
aromaticity in the transition states and the products was indicated by the calculated
negative NICS(0) values (-22.0 and -25.0 ppm) and small bond length alternations
(BLs, 0.027 and 0.036 Å) values of the Cp* ring in 40-TS and 41, which makes the
tautomerization both thermodynamically favorable and kinetically feasible. This
study highlights an important role of aromaticity in C−F bond activation via the
stabilization of transition states and products.

In addition, some of us found that the aromaticity also played an important role
in the [1,5]-migration of pyrrolium derivatives (Fig. 4c) [53]. Although the N−Au (98.8
kcal mol-1) and N-Sn (81.7 kcal mol-1) bonds have higher bond dissociation energies
than the N−F bond (57.6 kcal mol-1), they have lower activation barriers (4.5 and 4.9
kcal mol-1 for AuPMe3 and SnH3, respectively) than the N−F bond in the [1,5]-
migration of pyrrolium derivatives. This unexpected phenomenon could be attributed
to the aromatic stabilization of the transition states. The [1,5]-migration of pyrrolium
derivatives shows that the synergistic effect of aromaticity, bond strength, and
frontier molecular orbital determines the activation energies and reaction energies. It
should be noted that aromatic-promoted [1,5]-migrations were also observed
previously [54,55]. For instance, Alabugin and co-workers found that the NICS(1)
value for the transition state in [1,5]-migration was negative, which was consistent
with the facile thermodynamics and kinetics process [54]. Electropositive migratory
groups were found to reduce the [1,5]-migration activation energies due to the
aromatic character of the transition states [55]. In addition, some of us also found
that aromaticity can be used to explain the thermodynamic stability between C-
10
binding and N-binding complexes in the reaction of [1,2] carbon migration in N-
heterocyclic carbene-coordinated transition metal complexes [56].

Very recently, some of us demonstrated a novel strategy to achieve

thermodynamically and kinetically favorable activation of the C−F bond over the C−H
bond dually driven by coordination and aromaticity (Fig. 4d). MCI values increase
gradually along reaction coordinates, suggesting that aromaticity plays an important
role in stabilizing the transition states and products during the reactions [57].

Aromaticity also plays a critical role in a bond shifting in [4n]annulene chemistry.

Castro and co-workers found that the thermal cis-trans isomerization of [12]annulene
involves a Möbius aromatic transition state (Fig. 4e) [58]. The reaction barrier for the
isomerization of 57 to 60 was only 18.0 kcal mol-1. The Möbius-twist transition state
(57-TS) for this process is highly aromatic, which was supported by a small BL value
(the variation between the longest and shortest C−C bonds in the annulene ring,
0.031 Å), a negative NICS(0) value (-13.9 ppm) and magnetic susceptibility exaltation
(Λ, -43.8 cgs-ppm). This work represents a rare example of the Möbius aromatic
transition state in the bond isomerization of [4n]annulenes.

The Möbius aromatic transition state was also proposed computationally in the
[1,7]-hydrogen shift of 1,3,5-heptatriene by Jiao and Schleyer in 1993 [59]. In addition,
Rzepa reported double-twist Möbius aromaticity in the transition state of a 10
electron electrocyclic reaction of a (Z,E,Z)-decapentaene [60]. In 2009, Mauksch and
Tsogoeva proposed a Möbius aromatic transition state in an electrocyclic reaction
with Möbius twisted topology [61]. As shown in Fig. 4f, the 12-electron transition
states 61-TS and 10-electron 62-TS were aromatic according to the calculated
negative NICS(0) values (-12.8 and -12.1 ppm, respectively). In addition, they
extended this study to a system with a shorter carbon chain, that is, an 8-electron
acyclic decapentaene dication 64 undergoes ring closure via a Möbius aromatic
transition state 64-TS (NICS (0) = -13.8 ppm) with a reaction barrier of 23.9 kcal mol-1.
In addition, a Craig–Möbius-like σ-aromatic transition state (NICS(0) = -19.4 ppm) was
proposed in the Pd-catalyzed *π2s + π2s + σ2s + σ2s+ pericyclic reaction, which was
symmetry-allowed in the ground state due to the phase inversion introduced by d
orbitals of the Pd atom (Fig. 4g) [62].

11
Fig. 4. Aromaticity-stabilized transition states in single bond activation. (a) DFT
calculation of the “iodo-Claisen” rearrangement step. ACID plot (isovalue: 0.020 a.u.)
12
along with the key distances (Å) and NICS (ppm) values [50]. Computational method,
M06-2X/aug-cc-pVTZ(-PP)//M06-2X/def2-SVP. (b) Energy profiles for C-F bond
activation by the RhI complex at the level of GD3-SMD (acetonitrile)-M06/6-
311++G(d,p)(LanL2TZ(f))//B3LYP/6-31G(d,p)(LanL2DZ) [52]. The BLs (Å), dihedral
angles of the Cp* ring (DA) and NICS(0) values (ppm) were calculated at the level of
B3LYP/6-311++G(d,p)(LanL2TZ(f)). (c) Gibbs energy profiles for the [1,5] shift of
substituted pyrroliums [53]. Computational method, GD3-M06L/6-
311++G(d,p)(ECPnMDF)//TPSS/6-311++G(d,p)(ECPnMDF). NICS(1)zz value (in ppm)
calculated at the level of TPSS/6-311++G(d,p)(ECPnMDF). (d) Gibbs energy profiles
calculated of C-F and C-H bonds activation in different metal complexes; MCI values
along the intrinsic reaction coordinate of C-F [57]. Computational method, at the
level of SMD (acetonitrile) (U)B3LYP-D3/6-311++G(d,p)(LanL2TZ(f))//(U)B3LYP-D3/6-
31G(d,p)(LanL2DZ). The BLs (Å), dihedral angles of the Cp* ring (DA) and NICS(0)
values (ppm) were calculated at the level of B3LYP/6-311++G(d,p)(LanL2TZ(f)). (e)
Gibbs energy profile for the isomerization of [12]annulene. C and T represent cis and
trans configurations, respectively [58]. Computational method, CCSD(T)/cc-
pVDZ//BH&HLYP/6-311+G(d,p). NICS(0) (ppm) and Λ (cgs-ppm) computed at the
B3LYP/6-311+G(d,p)//BH&HLYP/6-311+G(d,p). (f) Gibbs energy profile for the thermal
electrocyclic reaction [61]. Computational method for C12H14 and C10H12 species at
the level of CCSD(T)/6-31G//B3LYP/6-31G(d) and CCSD(T)/6-31G(d)//B3LYP/6-31G(d),
respectively. NICS values calculated for the center of mass (in ppm) at the B3LYP/6-
31G(d) level. Multiplicity (Singlet = S, Triplet = T] and charge are given in black
parentheses. (g) Pd-catalyzed *π2s + π2s + σ2s + σ2s+ pericyclic reaction [62].
Computational method, PBE0-D3(BJ)/NEVPT2. (h) Transition state structures and NICS
(ppm) for the transition states of rearrangement of 1,2-dichloroethane and syn-
sesquinorbornene, as well as the S3 transfer reaction [63].

Aromatic transition state was also involved in the pericyclic reactions. For
instance, the two triangles in the transition state (68-TS) for the rearrangement
reaction of 1,2-dichloroethane are aromatic, as suggested by the larger negative
NICS(0) values of -22.2 ppm (Fig. 4h) [63]. In addition, the 6MR transition state in the
double-group transfer reaction (rearrangement of syn-sesquinorbornene) has also
been demonstrated to be aromatic via the negative NICS value of -27.7 ppm (at the
(3,+1) ring critical point of electron density) [64]. It should be noted that the products
and reactants in this rearrangement process are non-aromatic. Interestingly, Algarra
reported an unusual pericyclic reaction that involves an intermolecular S3 transfer
(Fig. 4h), which occurs via a concerted transition state featuring two five-membered
C2S3 fused rings [65]. The calculated NICS at the (3,+1) ring critical points of electron
density and ACID suggest that the two five-membered C2S3 rings are aromatic.

6. Antiaromaticity-destabilized reactants in reaction mechanisms

13
 As antiaromaticity is a destabilized effect, antiaromatic reactants should exhibit
higher reactivity than nonaromatic or aromatic reactants. With this idea in mind,
some of us recently developed an antiaromaticity-promoted H2 splitting by the
combination of antiaromatic borole and aromatic pyridine into the cyclooctetraene
skeleton [66]. This system can be viewed as FLPs due to the geometric constraints. In
the process of H2 activation, breaking an antiaromatic boron-containing heterocycle
will reduce the reaction barrier whereas reacting with aromatic boron-containing
heterocycle will increase the reaction barrier (Fig. 5a). In contrast, for nonaromatic
and aromatic B/N-substituted cyclooctatetraenes, the activation energies for H 2
splitting were moderately higher. Especially for aromatic reactant, both kinetically
and thermodynamically are unfavourable and the reaction barrier was as high as 36.1
kcal mol-1. This study provides a novel strategy to design FLP systems for the
activation of H2 or other small molecules via antiaromaticity.

Fernández and Cabrera-Trujillo demonstrated that antiaromaticity can enhance

the reactivity of FLPs for CO2 and CS2 activation [67]. For CO2 and CS2 activation (Fig.
5b), the activation barriers increased in the order of antiaromatic 78b (5.8 and 8.3
kcal mol-1 for CO2 and CS2, respectively) < non-aromatic 78a (7.5 and 13.6 kcal mol-1).
The calculated NICS(0) values for 78b, 79b-TS and 80b decrease in the order of 14.0,
7.9 and 4.2 ppm for CO2 activation with 78b. In other words, along with the reaction
coordinate, the transition state and product become less antiaromatic. A similar
conclusion can be drawn for CS2 activation. Obviously, the antiaromaticity of reactant
plays a crucial role in the activation of CO2 and CS2, and along the reaction coordinate,
the antiaromatic character was mitigated, thus reducing the energy barrier.
Moreover, this antiaromatic reactant-promoted activation strategy can be extended to
other small molecule activations, including H2, CH4, SiH4 and acetylene [67]. In contrast,
the author recently reported aromaticity-enhance reactivity of geminal FLP [68].

Subsequently, Houk, Raines and co-workers investigated the Diels−Alder

reaction between 4,4-difluoro-3,5-diphenyl-4H-pyrazole and endo-bicyclo[6.1.0]non-
4-yne both experimentally and theoretically (Fig. 5c) [69]. They found that the 4,4-
dimethyl-3,5-diphenyl-4H-pyrazole was inactive in this reaction and thus the
hyperconjugative antiaromaticity induced by fluorination of the cyclopentadiene
enhanced the reactivity. Further studies show that the NICS(0) values for the
unsubstituted 4H-pyrazole and the fluorinated one were 0.5 ppm and 6.2 ppm,
respectively, whereas that of silylated 4H-pyrazole was -3.3 ppm, suggesting the
hyperconjugative antiaromaticity induced by fluorination of 4H-pyrazole. In addition,
Harper and co-workers found that the antiaromaticity dramatically affects the rate of
the acid catalyzed methanolysis of a series of substituted benzhydrols and fluorenols
even though they undergo the same reaction mechanism [70].

14
Fig. 5. Antiaromaticity-destabilized or aromaticity-reduced reactants in reaction
mechanisms. (a) Gibbs energy profile for H2 activation by a boron-containing
heterocycle [66]. Computational method, ωB97x-D27/cc-pVTZ. NICS(1)zz values (in
ppm) computed at the B3LYP/6-311G(d) level. (b) FLP-mediated CO2 and CS2 (in
parentheses) activations [67]. Relative energies (in kcal mol-1) obtained at the
PCM(toluene)-M06-2X/def2-TZVPP//M06-2X/def2-SVP level of theory. (c) Diels−Alder
reaction between pyrazole and cyclic alkyne. Hyper-conjugative antiaromaticity
induced by fluorination accelerates the reactivity [69]. (d) Diels−Alder reactions
between cyclopentadiene and substituted cyclopropenes [71]. Correlation of the
15
endo (green) and exo (red) Diels–Alder reactions activation enthalpy (ΔH‡) with
hyperconjugative aromatic stabilization enthalpy (ΔHASE) of butadiene with
cyclopropenes. The hyperconjugative aromaticity or antiaromaticity of the
cyclopropenes has a great effect on the stereoselectivity. (e) Syn and Anti Diels–Alder
cycloaddition between cyclopentadiene and ethylene [72]. The stereoselectivities for
this reaction were also controlled by hyperconjugative (anti)aromaticity. (f) Excited-
state antiaromaticity triggers nucleophilic addition of MeOH to benzene [74]. (g)
Aromatic Diels–Alder reactions of benzene tuned by geometric distortion and/or
heteroatom substitution [76]. (h) Predictive Aromaticity-based criteria (PAC) for the
Bingel-Hirsch addition to isolated pentagon rule endohedral metallofullerenes [78,79].

Houk and Lewandowski also examined the stereoselectivities for the Diels−Alder
cycloaddition reactions between the substituted cyclopropenes and cyclopentadiene
(Fig. 5d) [71]. They found that the hyperconjugative aromaticity or antiaromaticity of
the cyclopropenes has a great effect on the reactivity. For example, the endo
stereoselectivity and reactivity were increased by introducing a σ-donor substituent
at the C3 position due to antiaromatic character of cyclopropene ring caused by
pseudo four electrons, whereas the acceptor substituents had the opposite effect.
The antiaromatic character was confirmed by the negative aromatic stabilization
enthalpy (e.g., -2.8 kcal mol-1 for 3-silylcyclopropene). Therefore, σ-donors destabilize
the antiaromatic cyclopropene ring and the reactivity is enhanced.

In addition, they also investigated the stereoselectivities for the Diels−Alder

cycloadditions of 5‑substituted cyclopentadienes [ 72 ]. Result shows that the
substituent X at the C5 atom influences the stereoselectivities of the reaction (Fig.
5e). When X is a σ-acceptor, cyclopentadiene prefers to predistort in the opposite
direction to minimize the destabilizing effect of hyperconjugative antiaromaticity,
which was also confirmed by the negative aromatic stabilization enthalpy (e.g., -3.4
kcal mol-1 for F-substituted cyclopentadiene). In contrast, cyclopentadiene with a σ-
donor prefers to transform into an envelope conformation to maximize the
hyperconjugative effect. For example, the Diels−Alder cycloaddition reaction of 5-
acetoxycyclopentadiene with ethylene exclusively forms the Syn adduct [73].

Benzene is the most typical aromatic molecule in the electronic ground state,
however, it is antiaromatic in the lowest S1 excited state according to Baird’s rule.
Therefore, the antiaromatic benzene in the excited state could be activated.
Recently, Ottosson and co-workers reported that an excited-state antiaromaticity
triggers nucleophilic addition of benzene to synthesize a series of substituted
bicyclo[3.1.0]hex-2-enes (Fig. 5f) [74]. In addition, the excited-state antiaromaticity
triggered reaction could be also extended to other 6π-electron heterocycles, such as
silabenzene and pyridinium, leading to the formation of three-dimensional molecular

16
scaffolds. The excited-state aromaticity also affects the ring inversion of a pair of
molecules with thiophene-fused chiral [4n]annulenes [75].

In addition to antiaromaticity-destabilized the reactants, if the aromaticity in the

reactant was reduced or destroyed, the reaction could also be accelerated. For
instance, Bickelhaupt and co-workers found that the distorted aromatic core or
heteroatom-substituted aromatic ring have lower activation barriers in aromatic
Diels–Alder reactions than their planar aromatic analogues, which is probably due to
the aromaticity of the reactants being partially broken due to the structural distortion
(Fig. 5g) [76]. In addition, Ullmann and co-workers reported that the Tungsten-
Containing Benzoyl-CoA Reductase could degrade the aromatic compounds as the
W(IV) center lowers the barrier for breaking the aromaticity of the substrates [77].

Some of us found that the different aromaticities of the 5MRs and 6MRs of
fullerene C60 have a significant impact on the energy barriers and regioselectivity of
Diels-Alder, 1,3-dipolar, and carbene cycloadditions, which can take place over the
[6,6] and [5,6]-bonds of C60 [78,79]. For example, the aromaticity of the 6-MRs in C60
decreases when the negative charge [78] or the spin [79] of C60 increases, whereas
the 5MRs become more aromatic. Therefore, for the Diels–Alder reaction between
negatively charged or high-spin C60 and cyclopentadiene, addition to a [5,6] bond,
which breaks the aromaticity of three 6MRs and only one 5MR, becomes more
favorable than an addition to a [6,6] bond, which breaks the aromaticity of two 6-
MRs and two 5-MRs (Fig. 5h). Moreover, predictive aromaticity criteria was
developed for the regioselectivity Bingel-Hirsch (BH) addition to isolated pentagon
rule (IPR) endohedral metallofullerenes (EMFs) [ 80 ]. The BH addition is a
cyclopropanation reaction where a fullerene and diethyl bromomalonate in the
presence of a strong base such as 1,8-diazabicycloundec-7-ene (DBU) react to
produce a methanofullerene or a fulleroid. In the first step of the reaction
mechanism, the base abstracts the acidic proton of the malonate derivative to
generate a carbanion or enolate. Then this carbanion nucleophilically attacks the
fullerene, thus generating a new carbanion with charge localized at the cage. In the
final step, bromide is displaced in a nucleophilic substitution S N2 reaction causing an
intramolecular three-membered ring (3MR) closure. The regioselectivity patterns for
the BH addition on IPR EMFs can be predicted using a set of aromaticity-based
criteria, the so-called Predictive Aromaticity Criteria (PAC) (Fig. 5h). The PAC criteria
identify the lowest energy intermediates and transition states for a given IPR EMF
from the initial fullerene structure. The most aromatic (and therefore lowest in
energy) intermediates lead to the lowest activation barriers for the BH addition.
Finally, Chen and co-workers found that the aromaticity or antiaromaticity of the
transition metal macrocyclic complexes could have a remarkable effect on their

17
oxygen reduction reaction activity [81]. Macrocycles with antiaromaticity could
enhance the activity of metal centers.

7. Aromaticity-stabilized products in reaction mechanisms

Aromaticity has also a significant effect on polymetalated species. By a

combination of experiments and DFT calculations, some of us found that the indolyl
5MR in complex 93, containing two gem-diaurated tetrahedral carbon atoms,
exhibits extended hyperconjugative aromaticity with two sp3 hybridized carbon
atoms (Fig. 6a) [82]. Based on the calculated BLs and negative NICS(1)zz values,
complex 93 exhibits higher delocalization and more remarkable aromaticity than 92.
Due to the stronger electron delocalization in indolyl 5MR of 93, the lone pair
electrons of the N atom are more involved in the delocalization, which reduces the
electron density of the N-Au bond and thus weakens it. The aromaticity in penta-
aurated indolium 93 shows an extended electron conjugation due to dual
hyperconjugation. Such a difference on aromaticity accounts for a facile
protodeauration for 93.

Fig. 6. Aromaticity-stabilized products in reaction mechanisms. (a) Synthetic and

protodeauration of polyaurated indolium complexes [82]. Computational method,
TPSS/6-31G(d)(ECP60MDF). (b) Gibbs energy profiles for borepin formation by the

18
reaction of borafluorenereacted with alkynes [83]. Computational method,
PCM(dichloromethane)-D3-M05-2X/6-311++G(d,p)//M05-2X/6-31G(d) for C, H, B,
and F, 6-311++G(d,p) for Cl, and LanL2DZ for Si. (c) Aromatic intermediate 101a in CO2
reduction [84]. (d) Gibbs energy profile for the N2 activation by NHC-borole-based FLP
[85]. Computational method, ωB97X-D/cc-pVTZ//ωB97X-D/cc-pVDZ. (e) Gibbs energy
profile for the N2 activation by FLPs [86].

Braunschweig, Lin and co-workers reported the reaction of boroles with alkynes
to generate boranorbornadiene, borepin and/or boracyclohexadiene, respectively, by
DFT studies (Fig.6b) [83]. Among them, they found that the formation of borepin by
the reaction of borafluorene with alkynes was due to the propensity to maintain its
aromaticity, with a reaction barrier and reaction energy of 22.2 and -21.5 kcal mol-1,
respectively. Boranorbornadiene 97 was not observed in this reaction due to the
unfavourable dearomatization.

Wegner and co-workers reported the selective functionalization of CO2 by a

bidentate borohydride Li2[1,2-C6H4(BH3)2] catalyst, in which CO2 was transformed to
either methane or methanol under Et3SiH/B(C6F5)3 or pinacolborane as reducing
agents [84]. They found that the aromaticity in the seven-membered ring plays an
important role in the stabilization of the intermediate (1,3-dioxa-4,7-diborepine
heterocycle) in this bidentate interaction, which was confirmed by the good planarity
of the entire ring of 101a in the X-ray structure (Fig. 6c). This study again
demonstrates that aromaticity could play an important role in the transition-metal-
free activation of small molecules.

Some of us predicted via DFT calculations that replacing the highly active
methyleneborane by tri-coordinated boron species can be also used for N2 fixation
(Fig. 6d) [85]. The Gibbs activation energy (G0ǂ) and overall Gibbs reaction energy for
N2 activation via NHC-borole-based FLPs were 21.2 and -61.7 kcal mol-1, respectively,
indicating that the N2 activation could become thermodynamically favorable and
kinetically feasible. Further study shows that aromaticity plays a crucial role in this
process. The newly formed 5MR (A) and 6MR (B) in product 104 possess significantly
negative NICS(1)zz values of -19.2 and -17.4 ppm, respectively, suggesting aromaticity
in both rings.

Very recently, some of us systematically investigated an experimentally viable

FLP containing two moieties (methyleneborane and carbene) could be effective for
the N2 activation in a thermodynamically and kinetically favorable manner (Fig. 6e)
[86]. Aromaticity is found to play a crucial role in stabilization of the product.
NICS(1)zz values and ACID plots for ring A show comparable hyperconjugative
aromaticity due to pseudo six π-electrons in the 5MR. The NICS(1)zz values in the
rings A, B, and C in product 107 are -23.5, -19.5 and -26.0 ppm, respectively,

19
indicating that aromaticity plays a crucial role in stabilization of the product. This
study further highlights great potential of metal-free FLPs for N2 activation.

Metalla-aromatics exhibit unique properties due to the metal d orbital being

involved in the conjugated structures [87-91]. The aromaticity in the final product
plays an important role in their successful syntheses and characterization. For
instance, in 2013, Xia, Zhu and co-workers reported an unusual complex
(metallapentalyne) with a metal-carbon triple bond in a 5MR, which was synthesized
by the reaction of complex 108 with alkyne (Fig. 7a) [92]. Metallapentalyne 109
exhibits excellent stability although it contains a particularly small carbyne bond
angle (129.5°). The aromaticity in the product was confirmed by the negative
NICS(0)zz values for the two fused 5MRs (-11.1 and -10.8 ppm, respectively) and the
negative ISE values (around -23 kcal mol-1). In addition, by the reaction of complex
108 with allenylboronic acid pinacol ester, metallapentalene complex 110 with a
metallacyclopropene unit was formed (Fig. 7a) [93]. DFT studies show that the NICS(0)
value for the 3MR was -40.6 ppm, which was mainly attributed to the  orbitals (-
34.8 ppm). Therefore, the -aromaticity was first suggested to be dominant in an
unsaturated 3MR. The -aromaticity in the 3MR and the -aromaticity in the two
5MRs were further confirmed by ACID analysis.

Subsequently, Xia and co-workers reported the formation of a metal-bridged

tricyclic aromatic system by the nucleophilic addition of an aryl nucleophile with
osmapentalyne followed by intramolecular C−H activation (Fig. 7b) [ 94 ]. DFT
calculations show that the NICS(1)zz values for the three 5MRs around the osmium
center are distinctly negative. The aromaticity-driven products were further
confirmed by the planarity, high stability, down-field proton chemical shifts, and
calculated ISE values in the three 5MRs of complexes 112 and 113. In addition, Xia
group also reported electrophilic aromatic substitution (EAS) reactions of Craig-
Möbius aromatics (osmapentalenes, fused osmapentalenes), in which the highly
reactive nature of osmapentalene makes it susceptible to electrophilic attack by
halogens [95].

Aromaticity-driven reactions were also observed in the reaction of complex 111

with nitriles. Xia and co-workers found that the CN triple in two molecules of nitriles
could react with the metal–carbon triple bond in 111 via a [2+2+2] cycloaddition (Fig.
7c) [96]. The [2+2+2] cycloaddition reaction [97] gives a metallapyrazine unit first,
followed by oxidative aromatization in the presence of hypervalent iodine and acid,
leading to the formation of a metallapentalenopyrazine derivative. Product 115 has
the character of equalized bond lengths and downshifted proton. The clockwise ring
currents of the ACID plot, negative ISE values of rings A and B measured with two
different reactions (-23.9 and -26.3 kcal mol-1) and negative NICS(1)zz values (for ring

20
A: -26.9 ppm, B: -15.3 ppm, and C: -15.6 ppm) further verify the aromaticity in
metallapentalenopyrazine [96].

Recently, Xia groups reported a metalla-click reaction between metal-carbyne

and azides, in which a metal center shared by four aromatic rings was formed with
remarkable regioselectivity [98]. Mechanistic studies showed that the formation of
1,4 metallatriazole regioisomer 117 was both kinetically and thermodynamically
favorable (Fig. 7d). The NICS(1)zz values of metallatriazole unit in the 117' (-16.2 ppm)
were more negative than those in 118' (-4.8 ppm), indicating that the aromaticity
plays a dominant role in stabilizing 1,4 metallatriazole rather than 1,5 metallatriazole
regioisomers.

Chen and co-workers reported the first example of

cyclopropametallanaphthalenes [ 99 ], in which the -aromaticity in the
osmacyclopropene ring could be used to explain the stability of the product (Fig. 7e).
The aromaticity in complex 121 was documented by the negative NICS value at the
centre of the osmacyclopropene ring from all the -MOs (NICS(1)zz = -31.3 ppm) by
canonical molecular orbital NICS calculations. Moreover, the calculated ISE value and
ACID are in line with the NICS value, further confirming the -aromaticity in the 3MR.

Actually, metallapentalyne can be also synthesized by a one-pot reaction of

multiynes with OsCl2(PPh3)3, which is also an aromaticity-driven process [100]. The
reaction barrier for the rate-determining step is 23.1 kcal mol-1 (Fig. 7f). The negative
NICS(1)zz values (-17.3 and -14.3 ppm in A and B rings, respectively) and positive
aromatic stabilization energy (29.5 kcal mol-1) in complex 128 further confirmed that
the pericyclic reaction was an aromaticity-driven process. In addition, an 11-center-
12-electron d-p conjugated -metallapentalenofurans was also proven to be a
Möbius aromaticity promoted product, which was constructed by the reactions of
osmapentalyne with terminal aryl alkynes in the presence of H2O [101].

Xia groups reported an unusual acid-induced ring contraction of metallacyclobutadiene

to metallacyclopropene via a ring-opening-reclosing process very recently [102]. The results
of theoretical calculations indicate that aromaticity plays a major role in this reaction (Fig.
7g). The ring-opening of A ring (NICS(1)zz, 25.8 ppm) in 130 to form 131 (NICS(1)zz, -15.1 and
-22.6 ppm in B and C rings, respectively) involves the release of antiaromaticity
accompanied by the strengthening of the π-aromaticity in osmapentalene and can be
considered as a π-aromaticity-driven process. Then, the ring-reclosing process from 131 to
132 (NICS(1)zz for ring A: -30.4 ppm, B: -17.0 ppm, and C: -17.6 ppm) further expands the
aromaticity system of the metallacycles with newly formed σ-aromaticity, which are
supported by the results of canonical molecular orbital (CMO) NICS analysis for the 3MR in
complex 132. The total diamagnetic contribution of the NICS(0) value for the 3MR from the
six occupied π molecular orbitals (HOMO, HOMO-1, HOMO-3, HOMO-19, HOMO-25, and
21
HOMO-28) was -9.2 ppm, whereas the NICS(0) value contributed by all the σ-orbitals (-28.4
ppm) was much more negative, indicating that σ-aromaticity is dominant in the 3MR and is
the major contribution to aromaticity in the 3MR of 132.

22
23
Fig. 7. Metalla-aromaticity-stabilized products in reaction mechanisms. (a) Syntheses and
aromaticity evaluation of aromatic metallapentalyne and metallapentalene
derivatives [92,93]. (b) Syntheses and aromaticity evaluation of polycyclic metalla-
aromatics [94]. Computational method, B3LYP/6-311++G(d,p). NICS values given in
ppm. (c) Aromaticity-promoted [2+2+2] cycloaddition reaction of a metal−carbyne
complex with nitriles [96]. Computational method, B3LYP/6-311++G(d,p)(LanL2DZ). (d)
Gibbs energy profiles for cycloaddition reactions of 4-anisyl azide and osmapentalyne
[98]. Computational method, PCM(dichloromethane)-B3LYP-D3BJ/6-
311++G(d,p)(LANL2TZ). Selected bond lengths given in Å. The NICS(1)zz values of
metal-bridgehead tetracyclic complexes. Computational method, B3LYP/6-
311++G(d,p)(LANL2TZ). [Os]' = Os(PH 3)2. (e) -aromaticity promoted the CC triple
bond activation [99]. Computational method, B3LYP/6-311++G(d,p) (LanL2DZ). (f)
Gibbs energy profiles of the aromaticity-driven cyclization reaction of the multiyne
chain with OsCl2(PPh3)3 [100]. Computational method, PCM(dichloromethane)-
TPSS/6-31G(d)(SDD)//B3LYP/6-31G(d)(SDD). (g) Ring contraction of
metallacyclobutadiene to metallacyclopropene driven by π- and σ-Aromaticity Relay
[102]. Computational method, PCM(dichloromethane)-TPSS/6-
31G(d)(SDD)//B3LYP/6-31G(d)(SDD).

8. Limitation

However, there are still some limitations for the application of aromaticity in the
small-molecule activation. First, cyclic structures are required for a reactant,
intermediate, transition state or product in a given reaction as aromaticity is used to
describe the mobility of  electrons in a cyclic species, limiting the types of reactants
or products to some extent. Secondly, although antiaromaticity in a reactant might
promote a reaction, preparation of highly reactive reactants demands harsh synthetic
and storage conditions. Thirdly, some aromaticity indices such as HOMA or FLU
cannot be applied along a reaction coordinate of a given cycloaddition and others,
like NICS, are not reliable in points of space close to transition metals [103]. Fourthly,
the utilization of the strategy by improving the aromaticity of the transition state to
reduce a reaction barrier still remains a major challenge as both aromaticity and
transition state cannot be probed experimentally. It should be also noted that the
interaction involving bond cleavage and formation in most transition states is
particularly weak. It is no wonder that these transition states in some classical
pseudocyclic reactions were considered to be nonaromatic due to lack of adequate
electron delocalization when benzene is used as a reference [104].

9. Conclusion and Outlook

Small molecule activation and functionalization have been widely applied to

construct value-added products, attracting great attention in the field of synthetic

24
chemistry. On the other hand, aromaticity is one of the most important and
fundamental concepts that has been frequently discussed. Here, we devote ourselves
to a summary of aromaticity as a key factor in the reaction mechanisms. The strategy
can be mainly classified into two modes: the first one is to reduce the antiaromaticity
of the reactant whereas the second one is to enable the aromaticity in a transition
state or an intermediate or a product. Hyperconjugative antiaromaticity is usually
employed in the first mode by tuning the substituents. In addition, aromaticity gained
or antiaromaticity reduced along the reaction coordinate is the most common
strategy, which is widely used by experimental and theoretical chemists. Note that
releasing antiaromaticity in an excited arene is another less developed strategy [105]
to promote a reaction. Developing metalla-aromatics as a catalyst in organic
synthesis could be another direction and some examples have been demonstrated to
display robust catalytic activity for metathesis [106] and selective difunctionalization
of unactivated aliphatic alkenes [107]. With the rapid development of computational
resource, quantum chemical calculations will make significant contributions to
aromaticity-driven reactions by rationalizing the proposed reaction mechanisms and
predicting new and novel reactions or catalysts via theoretical design and
computational screening for experimental validation.

Declaration of Competing interest

The authors declare that they have no conflicts of interest in this work.

Acknowledgements
Financial support by the National Science Foundation of China (22073079, 22025105
and 21873079), the Ministry of Education of China (H20200504) and the Top-Notch
Young Talents Program of China is gratefully acknowledged. M.S. thanks the
Ministerio de Ciencia e Innovación of Spain (project PID2020-113711GB-I00) and the
Generalitat de Catalunya (project 2017SGR39).

Author contributions
Q.Z. D.C. and S.C. drafted the paper. J.Z., M.S., and L.Z. refined the text. All authors
discussed the results and contributed to the preparation of the final manuscript

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Qin Zhu received her B.S. degree from Zhengzhou University in 2012 and earned her M.S. degree
(Supervisor: Prof. Haiping Xia) and Ph.D. degree (Supervisor: Prof. Jun Zhu) from Xiamen
University in 2015 and 2020, respectively. From 2020 to 2022, she worked as a postdoctor at Nanjing
University (Supervisor: Prof. Jing Ma). Currently, she works at Nanjing University of Posts and
Telecommunications. Her research interests focus on the inert bond activation and machine learning
models for data-driven material designs.

Jun Zhu is currently a professor at Xiamen University. He obtained the B.S and Ph.D. degrees from
Xiamen University and the Hong Kong University of Science and Technology in 2000 and 2007,
respectively. Then he moved to Hong Kong University and Uppsala University for the postdoctoral
study. In 2010, he joined the Department of Chemistry at Xiamen University. His research group
(http://junzhu.chem8.org) focuses mainly on aromaticity and small molecule activation including
dinitrogen. His motto is “Enjoy chemistry & life to explore the unknown world”.

Declaration of interests

☒ 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.

☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:

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