[Link].

org/joc Article

Computational Insights into Palladium-Catalyzed Site-Selective

Anilide and Benzamide-Type [3+2] Annulation via Double C−H
Bond Activation
Partha Mondal, Nilangshu Mandal, Arun K. Pal, and Ayan Datta*
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ABSTRACT: The mechanism of palladium-catalyzed annulation reactions of benzamide-

and anilide-type aromatic systems with maleimides is investigated using density functional
theory. Double C−H bond activation is key to forming the desired annulation product. The
first C−H bond activation for anilide- and amide-type ligands can occur at the ortho and
benzylic C−H bonds, while the second C−H activation occurs at the meta carbon of the
aromatic rings. For the anilide-type system, ortho and benzylic C−H bond activations occur
via four- and five-membered palladacycles, respectively. In contrast, for the benzamide-type
system, ortho and benzylic C−H bond activations occur via five- and six-membered
palladacycles, respectively. The energy span model suggests that the initial C−H bond
activation step at the benzylic position determines the turnover frequency for both anilide-
and benzamide-type systems. Energy decomposition analysis and distortion-interaction/
activation-strain analyses are employed to understand the electronic and steric factors
controlling the turnover frequency-determining transition state.

■ INTRODUCTION
In recent years, innovative strategies for constructing C−C
(III)-catalyzed asymmetric [3+2] transannulation of arenes
with 7-azabenzonorbornadienes where activation of ortho and
meta C−H bonds takes place consecutively to form five-
bonds in an environmentally friendly, highly atom-efficient,
membered rings.38 Cao and Yao showed visible-light-induced
and highly selective manner have emerged.1−3 These advances
intermolecular [3+2] annulations of indolizine with internal
leverage transition-metal-catalyzed, chelation-assisted C−H
alkynes to yield pyrrolo[2,1,5-cd]indolizine.41 An example of
bond functionalization with alkenes.4−10 C−H functionaliza-
Pd-catalyzed [3+2] annulation of aliphatic amides with
tion with alkenes covers several reactions such as alkylation,
maleimides involving double C(sp3)−H bond activation was
annulation, and oxidative alkenylations.11−17 Among them,
reported by Yu.42
transition-metal-catalyzed annulation reactions via functional-
Most of the examples of transition-metal-catalyzed chela-
ization of C−H bonds have attracted attention as intriguing
tion-assisted C−H bond functionalization of aromatic
and efficient methods for the production of site-selective cyclic
compounds result in an ortho selectivity.43−48 In these
compounds.18,19
reactions, substrates possessing both an ortho C(sp2)−H
Annulation reactions can occur through various modes, such
bond and an o-methyl C(sp3)−H bond exhibit exclusive
as [2+2], [3+2], [4+2], [5+1], [4+1], [2+2+1], and
functionalization of the ortho C(sp2)−H bond, while the o-
[5+2].20−30 The [4+2] catalytic annulation reactions of
methyl C(sp3)−H bonds remain unreactive. The origin for the
aromatic amides and carboxylic acid with alkenes or alkynes ortho selectivity lies in the formation of five-membered
occur through the functionalization of ortho C−H bond and metallacycles that are both thermodynamically and kinetically
the cleavage of an O−H or N−H bond and have been favored.
extensively investigated in the past several decades.31−33 On the contrary, the formation of six-membered metalla-
Although many annulation reactions focus on single C−H cycles is less preferred and requires harsh reaction conditions
bond activation, double C−H bond activation is emerging as a or designing substrates with specialized frameworks. Most of
promising method for synthesizing complex cyclic structures.
The synthesis of naphthalene derivatives via [2+2+2]
annulation with alkynes is one of the most thoroughly Received: April 30, 2024
investigated C−H annulation reaction.34,35 On the contrary, Revised: July 1, 2024
there have been few examples in which annulations take place Accepted: July 19, 2024
through a [2+2]36,37 or [3+2]38−40 manner through double Published: July 29, 2024
C−H bond activation to form four- or five-membered
annulation products, respectively. Li et al. reported rhodium-

© 2024 American Chemical Society [Link]

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the widely investigated reports of benzylic C−H bond functional theory (DFT). This computational work provides
functionalization occur through a six-membered metallacycle an understanding of the site-selective functionalization of
and take place at secondary and tertiary benzylic positions, benzamide- and anilide-type [3+2] annulation reactions having
where the generation of radical species is facile. Most of the different steric and electronic demands.
widely investigated reports of benzylic C−H bond function-
alization occur through a six-membered metallacycle and take
place at the secondary and tertiary benzylic positions where the
■ COMPUTATIONAL DETAILS
DFT calculations were performed using the Gaussian16 (revision
generation of radical species is facile.23,40 B.01) suite of quantum chemical programs.49 All geometry
In this work, we investigate the detailed reaction mechanism optimizations and normal coordinate analyses at stationary points
of Pd-catalyzed site-selective [3+2] annulation of aromatic were carried out in the gas phase using the M06 density
amides and anilides with maleimides by the N,S-bidentate functional.50,51 For palladium, the relativistic effective core potential
(ECP) SDD was used, and the 6-31G(d,p) basis set was employed for
chelation system shown in Scheme 1 employing density all of the other elements.52−55 Analytical harmonic vibrational
frequencies were computed to classify stationary points as either
Scheme 1. Palladium-Catalyzed Annulation via Double C− transition states (TS) with one imaginary frequency or minima with
H Bond Activation for Anilide- and Benzamide-Type zero imaginary frequencies. Intrinsic reaction coordinate (IRC)
Systems calculations were conducted at the same level of theory to confirm
that the TS connects to the appropriate reactants and products
(Figures S1 and S2).56,57 Implicit solvent effects were considered
using the SMD solvation model in dichloromethane (DCM) (ε =
8.93).58 DFT method optimization was also carried out (Table S1).
The reported Gibbs free energies are based on single-point
calculations of the optimized structures at the SMD(DCM)/M06/6−
311G+(d,p),def2-TZVP(Pd) level of theory at 298.15 K and a
pressure of 1 atm.59 Electron decomposition analysis (EDA) was
performed using Multiwfn version 3.3.8 (MWF), and the structures
were illustrated using CYLView and ChemDraw.60−63

■ RESULTS AND DISCUSSION

The proposed mechanistic pathway for [3+2] annulation of
aromatic anilides and benzamides is shown in Scheme 2. It
starts with the formation of a palladacycle through the
coordination of the ligand to the Pd(II) complex accompanied
by the benzylic C−H bond activation.
Next, maleimide is inserted in a syn manner into the Pd−C
bond of structure A4/P4, and subsequently, protonation of the
Pd−N bond by pivalic acid gives intermediate A9/P9. Again,

Scheme 2. Catalytic Cycle for Anilide- and Benzamide-Type [3+2] Annulation Reaction

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one more C−H activation at the meta position gives

palladacycle A11/P11. Finally, reductive elimination forms
the desired annulation product A12/P12 with regeneration of
the palladium catalyst by the copper pivalate through
oxidation.
For the anilide-type system depicted in Figure 1, the
catalytic cycle starts with the coordination of anilide-type
ligands to catalyst Pd(OPiv)2 to form intermediate A0.
Subsequently, a 6.2 kcal/mol stabilizing interaction between
an N−H bond and a pivalate ligand forms A1. Following this, a
concerted deprotonation of the anilide nitrogen by the pivalate
ligands gives A2 through a transition state (TSA1) with a free
energy barrier of 0.9 kcal/mol.
The release of the coordinated PivOH from A2 gives A3 and
A3′ with exergonicities of −6.4 and −6.7 kcal/mol,
Figure 1. Relative Gibbs free energy profiles for substrate respectively. The C−H activation at the benzylic C(sp3)−H
coordination and cleavage of the N−H bond at 298 K. bond via TSA2 and the ortho C(sp2)−H bond via TSA2′

Figure 2. Computed relative Gibbs free energy profiles (ΔG in kilocalories per mole) for the [3+2] annulation product (blue) and [2+2]
annulation product (red) for anilide-type systems at 298 K.

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Figure 3. Structures of transition states TSA2 and TSA2′. The relevant distances are shown in angstroms.

the detachment of the amide NH and SMe groups from the Pd

center to form A9 or A9′, respectively.
In the next step, the second C−H bond activation takes
place at the meta position by the pivalate to form A10 through
TSA5 (ΔG⧧ = 5.1 kcal/mol) and A10′ through TSA5′ (ΔG⧧
= 11.4 kcal/mol).
We have also explored alternative pathways for the second
meta C−H activation without a second pivalic acid, which
yields a much higher Gibbs free energy for TSA5″ (ΔG⧧ =
16.6 kcal/mol) and TSA5* (ΔG⧧ = 17.8 kcal/mol). This
suggests that the C−H bond activation at the meta position
proceeds favorably in the presence of the second pivalic acid.
The [3+2] annulation product, A12, is formed by reductive
elimination via transition state TSP6 with a ΔG⧧ of 18.1 kcal/
mol. Further reductive elimination occurs via transition state
Figure 4. Relative Gibbs energy profiles for the cleavage of the N−H TSA6′ to yield the final [2+2] annulation product, A12′, with
bond for the formation of intermediate P2 at 298 K. a ΔG⧧ of 31.2 kcal/mol. Both pathways eventually produce the
Pd(0) species eventually. The [2+2] annulation product, A12′,
is thermodynamically unstable with respect to the [3+2]
(Figure 2) generates five-membered palladacycle A4 from A3 annulation product, A12. The Pd(II) species is regenerated by
and four-membered palladacycle A4′ from A3′, respectively. CuO oxidation. All of the steps in the formation of the [2+2]
The free energy barriers for benzylic C(sp3)−H and ortho annulation product require activation free energies higher than
C(sp2)−H activation are 22.6 and 26.8 kcal/mol, respectively. that for the formation of the [3+2] annulation product, clearly
Additionally, five-membered palladacycle intermediate A4 is indicating the kinetic and thermodynamic advantage (see
more stable than A4′ by 13.3 kcal/mol, which implies that the Figure 2) of the latter consistent with the experimental
formation of the five-membered palladacycle is kinetically and findings.23 According to the energetic span model,64 benzylic
thermodynamically favorable. C−H bond activation transition state TSA2 is the turnover
In the next step, insertion of the maleimide into the Pd− frequency-determining transition state (TDTS) for the
C(sp2) bond of five-membered A5 to form seven-membered formation of the [3+2] annulation product.23 Figure 3 depicts
palladacycle A6 via transition state TSP3 requires a ΔG⧧(TSP3) transition states TSA2 [benzylic C(sp3)−H], which has a
of only 12.6 kcal/mol. However, the insertion of the maleimide stable five-membered palladacycle, over TSA2′ [ortho C(sp2)−
group into the Pd−C(sp2) bond of four-membered pallada- H], with a four-membered palladacycle.
cycle A5′ occurs with a ΔG⧧(TSP3′) of 18.5 kcal/mol. Therefore, Similarly, the mechanistic cycle of the benzamide-type
the formation of a five-membered palladacycle and insertion of system is initiated by the coordination of the sulfur (-SMe) of
the maleimide into the five-membered palladacycle are the benzamide-type substrate to Pd(OPiv)2 to form P0, which
energetically favorable. The insertion of pivalic acid (PivOH) is succeeded by the interaction of the N−H bond and the
occurs after the migratory insertion step. The PivOH helps the pivalate ligand to form P1 (Figure 4). Then, abstraction of the
cleavage of Pd−N bonds through transition state TSA4 or N−H proton by the pivalate ligand through transition state
TSA4′ by the protonation of the N atom attached to palladium TSP1 forms complex P2.
to form intermediate A8 or A8′, respectively. Following this, a The overall free energy profiles for both [3+2] and [2+2]
second PivOH molecule interacts with A8 or A8′, resulting in annulation for the benzamide system are shown in Figure 5.
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Figure 5. Computed relative Gibbs free energy profiles (ΔG in kilocalories per mole) for the [3+2] annulation product (blue) and [2+2]
annulation product (red) for the benzamide-type system at 298 K.

The coordinating PivOH is released from P2 to form P3 or migratory insertion of maleimide into the Pd−C(sp2) bond
P3′ with a stabilization energy of 5.0 or 9.7 kcal/mol, of five-membered palladacycle P5′ through TSP3′ has a free
respectively. The formation of six-membered palladacycle P4 energy barrier (ΔG⧧ = 25.3 kcal/mol) that is higher than that
from P3 proceeds through the C−H activation step at the for the insertion of maleimide into the Pd−C(sp3) bond of six-
benzylic position by the CMD mechanism via TSP2 (ΔG⧧ = membered palladacycle P5 through TSP3 (ΔG⧧ = 14.9 kcal/
18.1 kcal/mol). On the contrary, generation of five-membered mol). The migratory insertion generates eight-membered
palladacycle P4′ from P3′ proceeds through the C−H palladacycle P6 through TSP3, whereas seven-membered
activation step at the ortho position by a concerted metalation palladacycle P6′ is generated through TSP3′. P6 is
deprotonation (CMD) mechanism via TSP2′ (ΔG⧧ = 17.1 significantly more stabilized than P6′ [ΔG(P6) − ΔG(P6′)
kcal/mol). As one can see in Figure 5, five-membered = −14.6 kcal/mol]. Therefore, even though the five- and six-
palladacycle (Figure 6) P3′ is kinetically and thermodynami- membered palladacycles can be obtained, the formation of the
cally favored. However, in contrast to the lower energy barrier five-membered palladacycle is the kinetically favorable step,
for the formation of a five-membered palladacycle, the while for the migratory insertion step, the six-membered
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Figure 6. Structures of transition states TSP2 and TSP2′. The relevant distances are shown in angstroms.

Table 1. EDAs for the Second meta C−H Activation pathways for second meta C−H activation without second
Transition States for the Anilide and Benzamide Type pivalic acid yields a much higher Gibbs free energy [TSP5″
Systems (energies in kilocalories per mole) (ΔG⧧ = 11.4 kcal/mol) and TSP5* (ΔG⧧ = 14.0 kcal/mol)].
This suggests that the C−H bond activation at the meta
ΔEtot ΔEorb ΔEsteric
position proceeds favorably in the presence of the second
TSA2′ −58.0 −103.5 45.6
pivalic acid. Further reductive elimination takes place with
TSA2 −63.5 −115.0 51.5
transition states TSP6 and TSP6′ to yield final products P12
TSP2′ −62.2 −118.8 56.6
and P12′, respectively. According to the energy span model,
TSP2 −64.3 −124.5 60.1
meta C−H bond activation transition state TSP2 is the TDTS.
palladacycle is energetically favored. Following the migratory For the [2+2] annulation product, the reductive elimination
insertion step, the insertion of pivalic acid (PivOH) takes step [ΔG⧧(TSP6′) = 32.0 kcal/mol] is the TDTS.
place. The PivOH helps in the protonation of the N atom To qualitatively understand the intrinsic factors responsible
attached to palladium, and then the cleavage of Pd−N bonds for the difference in the activation energies for the initial C−H
occurs through transition states TSP4 and TSP4′ to form activation transition states, namely, TSA2′ and TSA2 for
intermediates P8 and P8′, respectively. The addition of a anilide-type systems and TSP2′ and TSP2 for benzamide-type
second PivOH molecule interacts with P8 or P8′, resulting in systems (Figures 3 and 6), energy decomposition analysis
the detachment of the amide NH and SMe groups from the Pd (EDA) was performed. The total energy of the system (ΔEtot)
center to form P9 or P9′, respectively. In the next step, the is represented as the sum of the orbital energy (ΔEorb) and
pivalate attached to palladium undergoes a second C−H bond steric interactions (ΔEsteric). The steric interactions include
activation at the meta position via TSP5 and TSP5′ and contributions from exchange correlations (ΔEXC), the Pauli
produces P10 and P10′, respectively. Exploration of alternative repulsion (ΔEPauli) between the filled orbitals, and the

Figure 7. Two fragments, namely, pivalic acid moieties (Frag1 in blue) and palladium including the substrate (Frag2 in red).

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Table 2. Distortion-Interaction/Activation-Strain (DI-AS) Analyses for the Second meta C−H Activation Transition States for
Anilide and Benzamide Type Systems (energies in kilocalories per mole)
distortion energy in TS (Edist) (kcal/mol)
BE of reactant Edist = Edist(Frag1) + Edist(eff) = Edist − BE interaction energy in TS [Eint =
ΔE⧧ (P3/A3) Edist(Frag1) Edist(Frag2) Edist(Frag2) (P3/A3) ΔE⧧ − Edist(eff)]
TSA2 24.1 −76.2 4.9 24.4 29.3 105.5 −81.4
TSA2′ 25.8 −65.4 5.9 11.2 17.1 82.5 −56.7
Δ (TSA2 − −1.7 −10.8 −1.0 13.2 12.2 23.0 −24.7
TSA2′)
TSP2 18.5 −68.5 4.7 27.9 32.6 101.1 −82.5
TSP2′ 14.6 −69.3 5.5 23.5 29.0 98.3 −83.7
Δ (TSP2 − 3.9 0.8 −0.8 4.4 3.6 2.8 1.2
TSP2′)

elctrostatic interactions (ΔEelec) between the fragments in the benzamide system features reductive elimination (TSP6′) as
transition state complex.61 the rate-determining step. Transition states TSA3′ and TSP6′
For all of the transition states, we have created two are characterized by higher energies due to the formation of
fragments, namely, pivalic acid moieties (Frag1) and palladium four-membered bridged compounds, leading to significant ring
including the substrate (Frag2). As shown in Table 1, while the strain. This study underscores the critical role of ring strain and
steric interaction energy for TSA2 (51.5 kcal/mol) is greater stabilization energy in governing the selectivity of double C−H
than that for TSA2′ (45.6 kcal/mol), there is a significant bond activation processes.
stabilization of TSA2 over TSA2′ due to the greater orbital
interaction energy [ΔΔEorb(TSA2′‑TSA2) = 11.5 kcal/mol].
Hence, TSA2′ becomes significantly destabilized. In the case
■ ASSOCIATED CONTENT
Data Availability Statement
of the benzamide-type system, the total interaction energy is The data underlying this study are available in the published
similar for TSP2′ (−62.2 kcal/mol) and TSP2 (−64.3 kcal/ article and its Supporting Information.
mol) but there is a significant difference in the steric *sı Supporting Information
interactions energy [ΔΔEsteric(TSA2′‑TSA2) = 3.5 kcal/mol],
The Supporting Information is available free of charge at
which is the primary reason for the preference of TSP2′
[Link]
over TSP2.65
Additionally, the distortion-interaction/activation-strain DI-AS and EDA analyses and optimized Cartesian
(DI-AS) analysis66−68 is employed using two fragments coordinates and harmonic frequencies (PDF)
(Figure 7), pivalic acid moieties (Frag1 in blue) and palladium
including the substrate (Frag2 in red), to gain a simplistic
picture of the stabilization of TSA2 over TSA2′ and TSP2
■ AUTHOR INFORMATION
Corresponding Author
over TSP2′. Table 2 shows that although the strain (distortion,
Ayan Datta − School of Chemical Sciences, Indian Association
Deff) for TSA2 is 23.0 kcal/mol higher than that for TSA2′, the
for the Cultivation of Science, Jadavpur 700032 West Bengal,
overall stabilization of TSA2 results from the interaction
India; [Link]/0000-0001-6723-087X; Email: spad@
between the two fragments in TSA2, which is 24.7 kcal/mol
[Link]
greater than in TSA2′. Similarly, for the benzamide system,
TSP2′ is preferred over TSP2 due to the 2.8 kcal/mol lower Authors
distortion energy and 1.2 kcal/mol higher stabilization energy. Partha Mondal − School of Chemical Sciences, Indian
The EDA and DI-AS calculations for the first C−H Association for the Cultivation of Science, Jadavpur 700032
activation step (ortho C−H vs benzylic C−H) both provide West Bengal, India
crucial insights into the preference of one transition state over Nilangshu Mandal − School of Chemical Sciences, Indian
the other for the anilide and benzamide systems. Therefore, it Association for the Cultivation of Science, Jadavpur 700032
is envisioned that tuning these stabilizing and destabilizing West Bengal, India; [Link]/0000-0002-7133-8346
interactions in the rate-limiting first C−H bond activation Arun K. Pal − School of Chemical Sciences, Indian Association
transition state can control the annulation products. for the Cultivation of Science, Jadavpur 700032 West Bengal,
India; [Link]/0000-0002-9320-420X
■ CONCLUSIONS
This computational study elucidates the mechanisms of
Complete contact information is available at:
[Link]
palladium-catalyzed site-selective annulation reactions in
anilide and benzamide systems. We investigated pathways Notes
leading to [2+2] and [3+2] annulation products and The authors declare no competing financial interest.
determined that only the [3+2] product is both thermody-
namically and kinetically feasible. The rate-limiting step for the
[3+2] product is the first benzylic C−H activation, consistent
■ ACKNOWLEDGMENTS
P.M. thanks DST-INSPIRE India for a fellowship. N.M. thanks
with the experimental findings. In contrast, for the [2+2] IACS for a postdoctoral fellowship. A.K.P. thanks TRC-IACS
product, the rate-limiting step differs between the anilide and for financial support. A.D. thanks TRC-DST and SERB Grants
benzamide systems. The anilide system exhibits a migratory DIA/2018/000013 and CRG/2020/000301 for partial fund-
insertion transition state (TSA3′) as the TDTS, while the ing.
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