# Water-Mediated 1,7-Palladium Aryl-to-Aryl Migration in an Unusual Aryne Trimerization Enables the Synthesis of Multihelicenes with Profoundly Hindered Stereogenic Axes

Albert Artigas, Manuel A Ortuño, Jesús Castro-Esteban, Michel Giorgi, Diego Peña, Dolores Pérez, Yoann Coquerel

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Albert Artigas, Manuel A Ortuño, Jesús Castro-Esteban, Michel Giorgi, Diego Peña, et al. Water-Mediated 1,7-Palladium Aryl-to-Aryl Migration in an Unusual Aryne Trimerization Enables the Synthesis of Multihelicenes with Profoundly Hindered Stereogenic Axes. Advanced Synthesis and Catalysis, 2025, 10.1002/adsc.202500338. hal-05207623

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<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Water-mediated 1,7-Palladium Aryl-to-Aryl Migration in an Unusual Aryne
Trimerization Enables the Synthesis of Multihelicenes with Profoundly Hindered
Stereogenic Axes

Albert Artigas, Manuel A. Ortuño, Jesús Castro-Esteban, Michel Giorgi, Diego Peña*,
Dolores Pérez*, and Yoann Coquerel*

Dr. Albert Artigas, Dr. Yoann Coquerel

Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France.

E-mail: yoann.coquerel@univ-amu.fr

Dr. Manuel A. Ortuño, Dr. Jesús Castro-Esteban, Prof. Dr. Diego Peña, Prof. Dr. Dolores Pérez

Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS) and
Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782
Santiago de Compostela, Spain.

E-mail: diego.pena@usc.es, dolores.perez@usc.es

Dr. Michel Giorgi

Aix Marseille Univ, CNRS, Centrale Med, FSCM, 13397 Marseille, France.

Prof. Dr. Diego Peña

Oportunius, Galician Innovation Agency (GAIN), 15702 Santiago de Compostela, Spain

Keywords: C-H activation, 1,7-palladium migration, arynes, trimerization, polycyclic aromatic hydrocarbons

**Abstract**

The nickel(0)-catalyzed [2+2+2] cyclotrimerization of 13,14-picyne, a π-extended aryne intermediate having bay regions at both sides of the aryne triple bond, has recently enabled the synthesis of an overcrowded triple [7]helicene. In contrast, it has now been found that under palladium(0) catalysis, the same π-extended aryne intermediate trimerizes in a very different manner, notably featuring a formal 1,7-hydrogen shift coupled with a rare 1,7-
palladium aryl-to-aryl migration. Remarkably, this new aryne trimerization reaction seems
general, and revealed possible using a further π-extended analog of 13,14-picyne. The two
chiral multi[5]helicenes thus obtained have, in addition to helical stereogenic elements, a
profoundly hindered stereogenic biaryl axis located in the fjord region of a carbo[5]helicene
fragment. Both compounds were characterized by x crystal X-ray diffraction analysis, which
revealed their remarkably compact and severely distorted structures. A thorough mechanistic
study, combining experiments and DFT simulations, showed that the observed 1,7-Pd aryl-to-
aryl migration is a two-step 1,4-to-1,4'-Pd isomerization process enabled by the presence of
trace amounts of water, a proton shuttle, in the reaction mixture.

**1. Introduction**

Controlled 1,n-metal migration in organometallic catalytic processes is establishing as a
powerful approach in organic synthesis, ideally suited for the chemical activation of otherwise
hardly activable positions, typically C(sp³)-H and C(sp²)-H bonds. Especially, a number of
synthetically useful transformations involving a 1,4-Pd migration step are now available.[1]
However, for greater values of n (n ≥ 5), reactions involving a 1,n-metal migration process are
much less common. Concerning 1,7-Pd migration, there is a single occurrence of the
description of such a process in the scientific literature, applied to the regiocontrolled
synthesis of benzotriazoles,[2] with poor mechanistic understanding. We report herein a
second example of a controlled 1,7-Pd aryl-to-aryl migration, which occurs in the course of an
unusual aryne trimerization reaction amenable to the synthesis of two complex π-extended
chiral benzenoid molecules. A thorough mechanistic study unveiled the critical role of water
traces as proton shuttles in the reaction medium to allow for the observed reactivity.

Configurationally stable chiral polycyclic aromatic hydrocarbons (PAH) molecules
made of six-membered ring only, herein referred to as chiral benzenoids, can embed
stereogenic elements of two types: helical and axial. Methods for the controlled synthesis of
chiral benzenoids are highly sought after because these molecules can exhibit strong
chiroptical properties, which are of paramount importance in the fields of organic electronics
and materials science.[3] The size (greatest dimension) of chiral benzenoids can range from a
few Å in small substituted 1,1'-binaphthyl derivatives or [6]helicene, to several nm in large
chiral nanographenes.[4] A productive approach to synthesize chiral benzenoids of various
sizes has been the introduction of multiple helical fragments in the so-called
multihelicenes.[5,6] In contrast, examples of chiral benzenoids with multiple axial, or a mix of both helical and axial, stereogenic elements are very rare.[7]

Among the different synthetic methodologies to introduce helicity in PAHs, transition-metal promoted cyclotrimerization reactions of small pre-functionalized building blocks have emerged as a powerful approach.[8] In these reactions, three units of a given benzenoid are fused in a triphenylene core. The first example of this synthetic approach was introduced in 1991 by Yamamoto to prepare triphenylene from 1,2-dibromobenzene through a Ni⁰-promoted reaction.[9] Then, some of us introduced an alternative, possibly more general, approach now using a Pd⁰-catalyzed [2+2+2] cycloaddition of benzyne to synthesize triphenylene.[10] This strategy has been employed later on to construct π-extended multihelicenes of increasing sizes and degrees of molecular contortion.[11] Although Pd⁰ complexes appear as the catalysts of choice in aryne cyclotrimerization reactions, some of us recently reported the superior capability of a Ni⁰ catalyst to synthesize C₂-T7H (Scheme 1).[12] C₂-T7H resulted from the [2+2+2] cycloaddition of the sterically crowded aryne intermediate 13,14-picyne (I, generated in situ from o-(trimethylsilyl)aryl triflate 1 by a fluoride-induced 1,2-elimination reaction[13]), and its central ring was found exceptionally contorted.
<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Transition metal-catalyzed trimerization of picene-based arynes.</figcaption></figure>

Intriguingly, C₂-T7H could not be obtained when employing conventional aryne cyclotrimerization conditions, that is, using Pd₂(dba)₃·CHCl₃ as the catalyst, albeit mass spectroscopy experiments indicated the formation of a product (or several products) with *m/z* identical to the one of C₂-T7H. We report herein our efforts in understanding the outcome of this palladium-catalyzed reaction, which revealed that aryne intermediate I indeed trimerized in the presence of Pd₂(dba)₃·CHCl₃, albeit in an unusual manner. The product obtained is picene trimer 3, a constitutional isomer of C₂-T7H with an unusual connectivity that displays a very contorted double carbo[5]helicene fragment and a profoundly hindered biaryl single bond that results in a stereogenic axis. Remarkably, the *π*-extended, more complex, and more contorted hexa-benzo analogue 4, exhibiting five carbo[5]helicene moieties in addition to a stereogenic axis, could be synthesized from triyne 2, a precursor of the aryne intermediate II, under comparable palladium-based catalytic conditions.

**2. Results and discussion**

**2.1. Synthesis of Trimeric Chiral Benzenoids 3 and 4**
In the previous study on the synthesis of C₂-T7H,[12a] the [2+2+2] cycloaddition of intermediate I was attempted under the commonly used aryne cyclotrimerization reaction conditions.[11] Accordingly, o-silylaryl triflate 1 was stirred in CH₃CN for 24 h at 70 °C in the presence of 5 mol% Pd₂(dba)₃·CHCl₃ and excess CsF (Scheme 2a, see Supporting Information for further details). Despite our efforts, no evidence of the formation of C₂-T7H could be discerned. Instead, the ¹H NMR analysis of the orangish powder isolated by column chromatography (yield: 49%) revealed a complex mixture comprising at least two polycyclic aromatic reaction products. Subsequent mass spectroscopy (MS) analyses disclosed a sole peak at *m/z* = 828.2, indicative of those reaction products sharing the same molecular formula with the target compound C₂-T7H. Further analyses using HPLC confirmed the presence of two main compounds in an 81:19 ratio. To end, recrystallization from diluted hexanes/EtOAc solutions at -20 °C yielded single crystals suitable for X-ray diffraction (XRD), allowing us to ascertain the peculiar connectivity of the predominant reaction product compound 3a (Scheme 2a). The minor reaction product could not be independently recrystallized from the mixture, but its molecular structure was confidently deduced as 3b, a diastereomer of 3a with the opposite relative configuration of the stereogenic axis (see below). Curiously, together with picene trimers 3a-b, a 9-membered palladacyclic complex 5 (Figure 1 and section S1.4 in the Supporting Information) embedding four picene fragments and an aqua ligand was also isolated from the reaction mixture.
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

**Scheme 2.** Pd-catalyzed synthesis of (a) picene trimers **3a-b**, and (b) dibenzopicene trimer **4**. The torsion angles highlighted in green are unusually large; the length of the C–C bond in red is surprisingly shortened compared to **3a** despite the high steric hindrance; the C atoms noted with a blue star show clear pyramidalization.

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

**Figure 1.** (a) Simplified representation of the central palladacyclononatetraene core of complex **5**. (b) Solid-state structure of palladium complex **5**; H atoms are omitted for clarity.
Remarkably, the unusual Pd-catalyzed aryne trimerization reaction leading to trimer **3a** from the aryne precursor **1** seems generalizable. Indeed, it was found that 17,18-dibenzo[f,j]picyne (**II**), a dibenzo analogue of aryne **I**, now thermally generated in situ from the twisted triyne **2** by a hexahydro-Diels-Alder (HDDA) reaction,[14] is also amenable to the same Pd-catalyzed unusual aryne trimerization reaction, now leading to compound **4** (Scheme 2b). Compound **4** contains five stereogenic carbo[5]helicene units and one stereogenic axis, allowing, in principle, for the existence of 32 diastereomers. Thus, the complex crude product mixture of the Pd-catalyzed trimerization reaction of triyne **2** (ca. 30% yield) was heated at 270 °C in diphenylether for 24 h to induce the formation of substantial amounts of the thermodynamic diastereomer. After removal of diphenylether, the resulting solid material was dissolved in chloroform. Slow evaporation of this solution at room temperature afforded small single crystals of compound **4**, suitable for single crystal X-ray diffraction analysis.

## 2.2. Structural Analyses of Chiral Benzenoids **3** and **4**

Compound **3a** manifests as a trimeric molecule comprising three picene fragments. Two of them are connected forming a 6-membered ring that bridges a bay region of one picene fragment and the central K-region of another. The result is a $\pi$-extended double carbo[5]helicene moiety with two helicene fragments of identical handedness. The third picene fragment is found linked to the double helicene system through a $C(sp^2)$–$C(sp^2)$ biaryl single bond, establishing a stereogenic axis in the fjord region of a carbo[5]helicene unit, an unprecedented situation. From the structural data, **3a** is the $(M,M,R_a)$ [or $(P,P,S_a)$] diastereomer out of four possible. In the racemate crystalline solid state, **3a** exists as two slightly different conformers. Their most notable structural features are: i) an elongated $C(sp^2)$–$C(sp^2)$ single bond with $d = 1.499(7)$ and $1.508(7)$ Å, to be compared with $d = 1.487(7)$ Å in biphenyl,[15] ii) a visible pyramidalization of the $C(sp^2)$ atoms connected by this single bond (meaning, strictly speaking, that they are no longer $sp^2$ hybridized), iii) the torsion angle at the stereogenic axis that deviates largely from the ideal 90° geometry ($\Phi \approx 56°$ for one conformer and 53° for the other conformer), and iv) the unusually large torsion angle at the inner rim of the carbo[5]helicene fragment where the stereogenic axis is anchored ($\Phi = 42.7$ and $42.2°$, green bonds in Scheme 2a, see details in the Supporting Information). Thus, the sum of the three dihedral angles at the inner rim of the [5]helicene fragment to which the stereogenic axis is attached is $83.4°$, a value approaching the symbolic bar of perpendicularity, and comparable with the largest reported value for a carbo[5]helicene,
83.9 °.[16] All these geometrical features are certainly consequences of the compactness of the molecule. Diastereomer **3a** was computed the thermodynamic diastereomer and diastereomer **3b** was found 6.1 kcal·mol⁻¹ higher in energy as the second most stable one. The interconversion pathway between **3a** and **3b** takes place through three additional conformers and has a high barrier of 51.3 kcal·mol⁻¹, making both of them (very!) configurationally stable (see full details in Figure S2 in the Supporting Information).

With regards to the chiral benzenoid **4**, all its 32 diastereomers were identified through DFT simulations (see section S2.3 in the Supporting Information), which revealed that diastereomer **4**, with the (*M*,*M*,*M*,*M*,*R*<sub>*a*</sub>) [or (*P*,*P*,*P*,*P*,*S*<sub>*a*</sub>)] configuration, is the most stable diastereomer. The other diastereomers are 4.6–28.2 kcal·mol⁻¹ higher in energy. The most notable structural features of **4** are: i) The surprisingly normal length of the C(sp²)–C(sp²) single bond with *d* = 1.488(11) Å: albeit steric factors have increased compared to **3a**, the bond is measurably shortened. In a comparable case of profoundly hindered unexpectedly short C(sp²)–C(sp²) single bond, it has previously been suggested that elongation of the bond only slowly releases the steric strain.[17] For **4**, we attribute the shortening of its single bond compared to **3a** to a greater development of attractive London dispersion effects[18] in **4**. ii) The measurable pyramidalization of the C(sp²) atoms connected by the stereogenic aryl–aryl single bond, albeit it is of reduced amplitude in **4** compared to **3a**. iii) The torsion angle at the stereogenic axis that deviates significantly from the ideal 90 ° geometry (Φ ≈ 53 °, comparable to **3a**). And iv) the extreme torsion angle at the inner rim of the carbo[5]helicene fragment where the stereogenic axis is anchored (Φ = 45.3 °, green bonds in Scheme 2b). Thus, the sum of the three dihedral angles at the inner rim of the carbo[5]helicene fragment to which the stereogenic axis is attached in **4** is 94.3 °, an unprecedented overall torsion at a carbo[5]helicene inner rim. Remarkably, this chiral benzenoid shows a >90 ° torsion of its conjugated π-system, so to speak, at only a four-bond distance. All these geometrical features are consequences of the compactness of the molecule.

**2.3. Mechanistic Studies**

From the mechanistic point of view, the most captivating aspect of picene trimers **3a**-**b** and dibenzopicene trimer **4** is the formal H atom transfer occurring from C1 in precursors **1** and **2** to C14 in the picenyl fragment of the final reaction product (see H atoms highlighted in red in Scheme 3). To delve into this phenomenon and, eventually, elucidate how these reaction products are exclusively formed instead of the expected cyclotrimers, we decided to investigate the reaction mechanism in depth.
<figure><img src="image_7.png" /><figcaption>**Scheme 3.** Initially proposed mechanistic explanation. Values shown are Gibbs energies in kcal·mol⁻¹ relative to **INT1**.</figcaption></figure>

At the onset of our mechanistic study, it was verified that C₂-T7H cannot serve as a reaction intermediate, potentially transforming into **3a-b** under the action of the Pd catalyst. As expected, C₂-T7H remained unchanged after being stirred in the presence of Pd₂(dba)₃·CHCl₃ for 24 h at 70 °C. The hypothesis for compound 1 evolving directly into **3a-b**, thus skipping the formation of aryne intermediate I, was also ruled out as no reaction was observed in the absence of a fluoride source. Further evidence supporting the involvement of an aryne is deduced from the synthesis of compound 4 directly from 2 in the presence of the same catalyst (Scheme 2b). The fact that the exact same reactivity is observed from different aryne generation methods ultimately supports the participation of arynes I and II as the precursors of compounds **3a-b** and 4, respectively.

Thus, we hypothesized that the aryne trimers **3a-b** and 4 result from a kinetically allowed 1,7-Pd aryl-to-aryl migration occurring after the first oxidative coupling step (Scheme 3, right). Accordingly, the associated thermodynamic and kinetic parameters were evaluated using DFT methods. We initially considered a Pd⁰ atom as the effective catalytic species and I as the model aryne substrate (Scheme 3 and Figure S5, see Supporting Information for full details). Calculations revealed that three units of I can coordinate to the Pd⁰ center forming a 16-electron species **INT1** with a D₃-symmetric quasi-trigonal planar
geometry in its most stable conformation. Oxidative coupling via TS1 (5.2 kcal·mol⁻¹) then connects two of the arynes through a newly formed C–C bond (highlighted in blue in Scheme 3), resulting in a T-shaped PdII palladacyclopentadiene complex INT2.[¹⁹] To fulfill the vacant coordination site, INT2 features an agostic interaction at the bay region of one of the picene fragments, potentially anticipating a C–H activation step responsible for the observed 1,7-Pd isomerization. Accordingly, two divergent pathways were considered from INT2, namely, insertion and 1,7-Pd isomerization. The first route involves the insertion of a third aryne moiety through TS2ins (ΔG‡ = 29.4 kcal·mol⁻¹), leading to palladacycloheptatriene intermediate INT3ins, which may eventually evolve into cyclotrimer C₂–T7H, as previously described using a Ni⁰ catalyst.[¹²a] In the second route, a 1,7-Pd aryl-to-aryl migration is enabled by a through-space C–H activation via TS2isom (ΔG‡ = 41.5 kcal·mol⁻¹). This results into the palladacyclopentadiene INT3isom, where Pd is now located at the bay region of one of the picenyl fragments. Subsequent insertion of the third aryne and reductive elimination would lead to the observed reaction product 3a. But despite the thermodynamic driving force, where INT3isom is 15.1 kcal·mol⁻¹ more stable than its isomer INT2, the energy barrier of this process is ΔG‡ = 41.5 kcal·mol⁻¹, which is too high to explain the formation of 3a under the experimental conditions employed. This high barrier reflects the severely constrained structure of the palladacycle transition state TS2isom (see Figure S6 in the Supporting Information). In light of these results, we considered alternative pathways that might be operative in the reaction. Wondering if the solvent could play a role, we replaced the coordinated aryne in INT2 by a CH₃CN molecule[²⁰] but the energy barrier did not decrease. We also tested if a CH₃CN ligand could act as a base abstracting the H atom,[²¹] but the resulting charged intermediates were not energetically favored. The participation of the dibenzylideneacetone (dba) ligand was also evaluated[²²] but again no fruitful reaction pathways were found. As a whole, these results indicate that palladacycles like INT2 cannot evolve directly via a 1,7-Pd aryl-to-aryl migration.

Alternatively, we envisioned an isomerization mechanism where the Pd–C bond (highlighted in green in Scheme 3) would be protonated prior to the rupture of the C–H bond. In this sense, the possibility of CH₃CN acting as a proton shuttle (first delivering a proton then abstracting it) was discarded, as no incorporation of deuterium atoms was observed in 3a–b when performing the reaction in CD₃CN. However, inspired by the presence of an aqua ligand in the solid-state structure of complex 5, we eventually considered the potential role of water traces in the reaction. Accordingly, the reaction was conducted in the presence of 20 mol% D₂O (Figure 2a). Under these reaction conditions, about 68% incorporation of deuterium
atoms could be observed at the expected position by MS[23] and NMR experiments (Figures 2b and 2c), supporting the fact that water acts as a proton shuttle during the formation of **3a-b**.

Also, when the reaction was performed with extra dry CH3CN (i.e. pre-treated for 72 h with 3 Å molecular sieves stored for several weeks at 300 °C[24]), C2-T7H was detected in the crude mixture together with **3a-b** (Figure 2d). Furthermore, we observed that when the reaction is performed in the presence of a highly coordinating ligand such as triphenylphosphine, water coordination is prevented and C2-T7H forms exclusively, albeit in a low yield of about 10%.[12a] Overall, these data demonstrate that Pd atoms can indeed promote the usual [2+2+2] cyclotrimerization reaction toward C2-T7H, but water molecules present in the reaction medium switch this reactivity, favoring the formation of trimers **3a-b** and **4**. Taking all these experimental observations into account, we revisited the DFT simulation, now including explicit water molecules in the model.[25] Previous computational studies on transition-metal catalyzed processes have shown that three water molecules are suitable to properly model microsolvated transition states.[26] Furthermore, the role of water assisting transition metal-catalyzed proton transfer processes has also been documented.[27] Hence, the isomerization process was simulated including either one, two, or three water molecules. The lowest in energy path involving three water molecules is discussed in the following paragraphs and summarized in Figures 3 and 4. After a thorough investigation, we concluded that, following a fast oxidative coupling step from **INT1**, one water molecule can coordinate to the PdII center in **INT2**, giving rise to distorted square planar complex **INT2-aq** (Figure 3). The two remaining water molecules are positioned at longer distances from the PdII center, creating a linear H-bond network. From this intermediate, we propose a water-mediated 1,4-to-1,4' isomerization between palladacycles. First, a proton from a non-coordinated water molecule (red H atom) is transferred to one of the C atoms engaged in the palladacycle resulting in the hydroxo PdII complex **INT3-aq**. This step has a reasonable cost of 19.6 kcal·mol⁻¹ through **TS2isom-aq**. The process from **INT2-aq** to **INT3-aq** is considerably exergonic by 25.2 kcal·mol⁻¹, likely due to the strain-release associated to the rupture of the palladacycle. Then, a proton is abstracted by the hydroxo ligand from a C atom at the opposite bay region (blue H atom), regenerating the aqua ligand and forming a new 5-membered palladacyclic complex **INT4-aq**. This second proton transfer surmounts a barrier of 16.6 kcal·mol⁻¹ via **TS3-aq** and releases 2.2 kcal·mol⁻¹. In summary, the title 1,7-Pd aryl-to-aryl migration corresponds to a water-mediated two-step isomerization of palladacycle **INT2-aq** into the isomeric palladacycle **INT4-aq**. Once **INT4-aq** is formed, the third arylene substrate inserts into the Pd-C bond via **TS4-aq**, involving 17.5 kcal·mol⁻¹ and generates palladacycloheptatriene **INT5-**
aq, which is 27.7 kcal·mol⁻¹ below **INT4-aq**. Finally, reductive elimination through **TS5-aq** demands 21.1 kcal·mol⁻¹ and forms **INT6-aq**. The entrance of three equivalents of **I** eventually delivers picene trimer **3a** and regenerates the catalyst back to **INT1**.

<figure><img src="image_8.png" /><figcaption>**Figure 2.** (a) Synthesis of picene trimers **3a**'-**b**' obtained when adding 20 mol% D₂O to the reaction mixture. (b) MALDI-MS spectrum of **3** isolated under standard conditions (black dashed line) and of **3**' isolated in the presence of D₂O (red solid line). (c) ²H NMR spectrum (CHCl₃, 61 MHz, 298 K) of **3**' obtained in the presence of D₂O. The peak at 7.26 ppm corresponds to residual CDCl₃. (d) ¹H NMR spectra (CDCl₃, 400 MHz, 298 K) of C₂-T7H (black), and of the mixture of **3a**-**b** and C₂-T7H (blue) obtained using extra-dry acetonitrile as a solvent; in the latter spectrum, the clear resonances attributed to C₂-T7H are noted with a red star.</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>**Figure 3.** Proposed reaction mechanism for the formation of **3a** from aryne precursor **I**. Calculations were performed at the B3LYP-D3/cc-pVTZ-PP(SMD=acetonitrile)//B3LYP-D3/cc-pVDZ-PP level of theory at 298 K. Values shown are Gibbs energies in kcal·mol⁻¹ relative to **INT1**.</figcaption></figure>

The Gibbs energy profile of the whole process leading to **3a** is shown in Figure 4. It presents an energetic span ($\partial G$)[28] between the turnover frequency (TOF) determining intermediate (TDI, **INT5-aq**) and the TOF determining transition state (TDTS, **TS5-aq**) of 21.1 kcal·mol⁻¹ and is exergonic by 190.0 kcal·mol⁻¹. A very comparable process, with **TS2isom-aq** or **TS3-aq** or **TS4-aq** higher by ca. 1 kcal·mol⁻¹ would account for the formation of the minor diastereomer **3b** (kinetic control of the 3a:3b diastereoselectivity). Thus, the proposed water-assisted mechanism fully accounts for the formation of species **3a-b** and **4** under the experimental conditions. Notably, the model also reproduces the experimental chemoselectivity, with the standard [2+2+2] aryne cyclotrimerization pathway largely kinetically disfavoured over the new aryne trimerization involving the 1,7-Pd migration, by 9.2 kcal·mol⁻¹.
<figure><img src="image_10.png" /><figcaption>**Figure 4.** Gibbs energy profile for the water-mediated formation of **3a**.</figcaption></figure>

**3. Conclusions**

A new Pd-catalyzed trimerization reaction of large π-extended arynes having bay regions at both sides of the aryne triple bond was discovered. An example of serendipity at work in science. This unusual Pd-catalyzed aryne trimerization reaction seems general, and is not dependent on the aryne intermediate generation method. It involves a very rare example of a 1,7-Pd aryl-to-aryl migration, which in the present case kinetically surpasses the robust standard Pd-catalyzed aryne [2+2+2] cyclotrimerization reaction. This new aryne trimerization reaction has led to two extremely compact chiral benzenoid molecules, **3a** and **4**, with unprecedented, and otherwise difficult to access, connectivity: the reaction forges multi[5]helicenes with a stereogenic biaryl axis anchored in the fjord region of a [5]helicene fragment. A consequence of the profound hinderance around these stereogenic aryl-aryl single bonds is the development of extreme torsion in the surrounding honeycomb networks of C(sp²) atoms, notably with torsions of the ‘conjugated π-system’ approaching or exceeding 90 ° at only a four-bond distance. Another consequence of the profound hinderance around the stereogenic aryl-aryl single bonds in compounds **3a** and **4** is that the most hindered one, *i.e.* **4**, exhibits a surprisingly normal length of its aryl-aryl single bond, shorter than in the less hindered analogue **3a**. This can be rationalized by a greater development of intramolecular attractive London dispersion forces in **4**.

The mechanistic investigations detailed in this report indicate, with a high degree of confidence, that the 1,7-Pd aryl-to-aryl migration process involved in the formation of the chiral benzenoids **3a** and **4** is enabled by the presence of an external proton shuttle, residual water molecules in the present case, and that it occurs through an acyclic organopalladium intermediate (*e.g.* **INT3-aq**). We think these conclusions are general for 1,7-Pd migration processes: direct 1,7-Pd migration (with concomitant 7,1-H migration) does not occur through an eight-membered cyclic intermediate or transition state; instead, 1,7-Pd migration occurs
sequentially through a proton shuttle-mediated ring opening / ring closing process of five-
membered palladacycles. After all, it appears possible that 1,7-Pd migration processes don't
exist, because, in reality, they are proton shuttle-mediated 1,4-Pd to 1,4'-Pd isomerizations.
Of course, this is a question of terminology, not science, as to how one prefers to name the
process in order to best understand it.

**4. Experimental section**

**4.1. General information**

For synthesis: Unless otherwise noted, reactions were carried out under an argon atmosphere using syringes, cannula, oven-dried glassware and dry solvents. Anhydrous THF, CH3CN, and CH2Cl2 were obtained from a commercially available solvent purification system. All reagents and commercial anhydrous solvents were purchased from Sigma-Aldrich and used as received without further purification. Reactions were monitored by thin layer chromatography on Merck Kieselgel 60 F254 0.2 mm plates. Visualization was accomplished using ultraviolet light (254 and/or 365 nm). Solvents were removed under reduced pressure with a rotary evaporator. Purifications were routinely performed by column chromatography in silica gel (40-63 µm) eluted with increasingly eluting mixtures of hexanes/EtOAc or hexanes/CH2Cl2. Aryne precursors **1**[12a] and **2**[14b] were synthesized as described previously.

For characterization: Melting points were recorded using a Büchi Melting Point B-540
apparatus and were reported without any corrections. NMR data were recorded at 298 ± 3 K
on a BRUKER Avance III nanobay 400 MHz spectrometer, a BRUKER 500 MHz HD or a
BRUKER Avance III 600 MHz, both equipped with a BBFO+ probe. CDCl3 was used as a
deuterated solvent. Chemical shifts for ¹H and ¹³C NMR are reported in ppm (δ) relative to
residual solvent signals. Coupling constants are given in Hertz (Hz). High resolution mass
spectra (HRMS) were recorded in triplicate on a Waters Synapt G2 HRMS apparatus using
either electrospray (ESI) or matrix-assisted laser desorption (MALDI) ionization sources. The
instruments were operated in the positive ion mode and spectra were obtained with a time-of-
flight (TOF) detector. DCTB was used as a matrix in MALDI analyses.

For computation: Geometries of all stationary points were optimized without symmetry constraints with the Gaussian 16 program[29] using the DFT B3LYP hybrid exchange-correlation functional.[30] The all-electron cc-pVDZ basis set was employed for non-metal atoms[31] and the cc-pVDZ-PP basis set containing an effective core relativistic pseudopotential was used for Pd.[32] The electronic energy was improved by performing single-point energy calculations with the cc-pVTZ[33] and the cc-pVTZ-PP basis set and the
same density functional. Single-point energy calculations of all stationary points were computed including solvent effects (CH3CN) with the solvent model based on density (SMD) continuum solvation.[34] The D3 Grimme energy corrections for dispersion[35] with the original damping function were added in all calculations. Analytical Hessians were computed to determine the nature of stationary points (one and zero imaginary frequencies for transition states and minima, respectively) and to calculate unscaled zero-point energies (ZPE) as well as thermal corrections and entropy effects using the standard statistical-mechanics relationships for an ideal gas.[36] These two latter terms were computed at 298.15 K and 1 atm to provide the reported relative Gibbs energies. As a summary, the reported Gibbs energies contain electronic energies including solvent effects calculated at the B3LYP-D3/cc-pVTZ-PP/SMD(CH3CN)//B3LYP-D3/cc-pVDZ-PP level together with gas phase thermal and entropic contributions computed at 298.15 K and 1 atm with the B3LYP-D3/cc-pVDZ-PP method. Conformational analyses were performed entirely in the gas phase. Input geometries for transition state calculations in conformational analyses were obtained using the CHN algorithm[37] as implemented in the AMPAC package (http://wwwsemichem.com/ampac/). Molecular graphics and structural analyses were performed with UCSF Chimera.[38] All computational data concerning reaction mechanisms and conformational analyses were uploaded to the ioChem-BD repository[39] and are available through the following DOI: 10.19061/iochem-bd-4-82.

**4.2.1. Representative synthesis of picene trimer 3:**

An oven-dried 25 mL Schlenk flask equipped with a magnetic stirring bar was introduced into a glove box and charged with arylene precursor **1** (50 mg, 0.10 mmol), Pd₂(dba)₃·CHCl₃ (5.2 mg, 0.005 mmol) and CsF (91 mg, 0.60 mmol). The reaction flask was then removed from the glove box before the addition of CH₃CN (11 mL), which was introduced into the reaction flask under a stream of inert gas (anhydrous argon). The resulting suspension was vigorously stirred at 70 °C for 24 h, diluted with CH₂Cl₂ (10 mL) and filtered into a separatory funnel containing water. The organic phase was separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered, and the solvent was removed under reduced pressure to provide an orangish solid. Purification by column chromatography in SiO₂ (40-63 µm) using hexanes/EtOAc (100:0 → 98:2) as an eluant provided **3** (13.6 mg, 49% yield) as an 81:19 mixture of conformationally stable diastereomers (**3a:3b**) as estimated by ¹H NMR spectroscopy and HPLC (see Supporting Information). Further elution of the column with EtOAc furnished **5** (ca. 3 mg) as a yellow solution, from which a single crystal analytical
sample could be obtained by slow evaporation at room temperature. Analytical samples
enriched in **3a** were obtained by recrystallization from diluted hexanes/EtOAc solutions (4:1)
at -20 °C. Single crystals suitable for X-ray diffraction were selected from these samples to
unambiguously determine its molecular structure.

For **3a**: MW (C<sub>66</sub>H<sub>36</sub>): 829.0 g/mol; R<sub>f</sub>: 0.25 (pentane/EtOAc 98:2); m.p. (°C): >300 °C (crystals, pentane/EtOAc (99:1), dec.); <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) ∂ (ppm) = 5.90 (ddd, J = 7.8, 6.7, 1.1 Hz, 1H), 6.05 (ddd, J = 7.8, 6.7, 1.1 Hz, 1H), 6.22 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 6.35 (d, J = 7.3 Hz, 1H), 6.43 (d, J = 7.0 Hz, 1H), 6.48 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 6.60 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.02 – 7.17 (m, 3H), 7.24 – 7.28 (m, 1H, overlapped with chloroform signal), 7.30 – 7.34 (m, 1H), 7.45 – 7.49 (m, 1H), 7.62 (t, J = 7.7 Hz, 2H), 7.83 (s, 1H), 7.82 – 7.93 (m, 4H), 7.95 – 8.02 (m, 3H), 8.07 – 8.17 (m, 4H), 8.28 (d, J = 9.5 Hz, 1H), 8.31 (d, J = 9.5 Hz, 1H), 8.39 – 8.44 (m, 3H), 9.19 (d, J = 9.2 Hz, 1H), 9.24 (d, J = 9.3 Hz, 1H); <sup>13</sup>C-<sup>{1</sup>H} NMR (100 MHz, CDCl<sub>3</sub>) ∂ (ppm): 120.4, 121.2, 121.3, 121.8, 122.3, 122.4, 123.0, 123.3, 124.0, 124.2, 124.4, 124.5, 124.5, 124.5, 125.3, 125.5, 125.6, 125.6, 125.7, 125.8, 125.9, 126.0, 126.0, 126.1, 126.4, 126.4, 126.5, 126.9, 127.2, 127.6, 127.7, 127.7, 127.8, 127.9, 128.1, 128.3, 128.4, 128.4, 128.6, 128.7, 129.0, 129.1, 129.2 (x2), 130.3, 130.6, 131.0 (x2), 131.2, 131.3 (x2), 131.4, 131.5, 132.0, 132.5, 132.7, 134.1, 136.9, 137.3 (6 overlapped signals); ESI-HRMS (m/z): calculated for [M+Na]<sup>+</sup> = 867.2448; found 867.2449.

**4.2.2. Single crystal X-ray diffraction of 3a**

Single crystals of racemic **3a** were obtained by slow evaporation of a diluted pentane/EtOAc solutions (99:1) at room temperature. Suitable crystals were selected and mounted on a SuperNova, Dual, Cu at home/near, AtlasS2 diffractometer. Crystals were kept at 295 K during data collection. Using Olex2,[⁴⁰] the structure was solved with the SHELXT[⁴¹a] structure solution program using Intrinsic Phasing and refined with the SHELXL[⁴¹b] refinement package using Least Squares minimization. All H-atoms were found experimentally and refined as riding atoms with their Uiso parameters constrained to 1.2 Ueq (parent atoms). CCDC 2403133 contains the supplementary crystallographic data for **3a**.

**4.2.3. Single crystal X-ray diffraction of palladium complex 5**

Following picene trimers **3a-b**, a 9-membered palladacyclic complex **5** eluted from the chromatographic column using 100% EtOAc. The remarkable structure of palladacycle **5** could be unambiguously confirmed by single crystal X-ray analysis (see Supporting Information). This compound embeds four interconnected picene fragments, cyclized through coordination to a square planar Pd<sup>II</sup> atom with two covalent Pd-C bonds and an additional agostic interaction. Intriguingly, the fourth coordination site of the Pd<sup>II</sup> center is occupied by
an aqua ligand. Complex **5** may be conceptualized as a reaction intermediate of a hypothetical
π-extended tetraphenylene derivative,[¹¹h] the cyclotetramer of 13,14-picyne. However, this
hypothetical reaction byproduct could neither be isolated nor detected in the crude reaction
mixture from **1**. Several attempts to thermally obtain it from palladacycle **5** in separate
reactions were also unsuccessful, most likely due to a kinetically disfavored reductive
elimination step.

Single crystals of racemic **5** were obtained by slow evaporation of a EtOAc solution at room temperature. Suitable crystals were selected and mounted on a SuperNova, Dual, Cu at home/near, AtlasS2 diffractometer. Crystals were kept at 295 K during data collection. Using Olex2,[⁴⁰] the structure was solved with the SHELXT[⁴¹a] structure solution program using Intrinsic Phasing and refined with the SHELXL[⁴¹b] refinement package using Least Squares minimization. All H-atoms were found experimentally and refined as riding atoms with their Uiso parameters constrained to 1.2 Ueq (parent atoms). CCDC 2403132 contains the supplementary crystallographic data for **5**.

**4.3.1. Representative synthesis of dibenzopicene trimer 4**

An oven-dried 10 mL pressure vessel with a magnetic stirring bar was charged with triyne **2** (60 mg, 0.159 mmol) and Pd₂(dba)₃·CHCl₃ (16.5 mg, 0.016 mmol). Then, anhydrous CH₃CN (1 mL) was added to the pressure vessel, and the resulting suspension was vigorously stirred at 75 °C, under argon, for 16 h. Then, the solvent was removed under reduced pressure and the resulting solid was purified by column chromatography in SiO₂ using hexanes/CH₂Cl₂ (70:30) as an eluant. After the purification, dibenzo[f,j]picene (7.8 mg, 13%) was isolated as a white solid as well as a mixture of dibenzopicene trimers (17.7 mg, 30%) as an orange solid. A solution of this material in Ph₂O (2 mL) was heated at 270 °C for 24 h, and then it was filtrated through SiO₂ eluted with hexanes/CH₂Cl₂ (70:30). The resulting material was dissolved in CHCl₃ and the slow evaporation of this solution at room temperature, afforded tiny single crystals of compound **4**, suitable for X-ray diffraction. In practice, we have not been able to record suitable characterization data for this compound (e.g., clean NMR data), except for its MS MALDI-TOF with *m/z* = 1128.0 (see Supporting Information) and its SCXRD data (see section 4.3.2.), because of the too low amount of crystalline material isolated from our experiments.

**4.3.2. Single crystal X-ray diffraction of 4**

Single crystals of dibenzopicene trimer **4** were obtained by slow evaporation of a CHCl₃ solution at room temperature. Suitable crystals were selected and mounted on a Bruker D8 VENTURE PHOTON-III 14 diffractometer. Crystals were kept at 100 K during data
collection. The structure was solved with *SHELXT*[41a] program and refined with *SHELXL*. [41b]
CCDC 2365063 contains the supplementary crystallographic data for **4**.

**Supporting Information & Data availability**

Copies of spectra, tabulated crystallographic structural data, and supplementary computational
data are available free of charge as a downloadable Supporting Information file (PDF) on the
Wiley Online Library (see https://doi.org/10.1002/adsc.202500338) or from the authors.
Deposition Number(s) 2403133 (for **3a**), 2365063 (for **4**) and 2403132 (for **5**) contain(s) the
supplementary crystallographic data for this paper. These data are provided free of charge by
the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe
Access Structures service.

All computational data concerning reaction mechanisms and conformational analyses have
been deposited to the ioChem-BD repository[³⁹] and are available free of charge from ioChem-
BD (see DOI: 10.19061/iochem-bd-4-82).

**Acknowledgements**

The authors gratefully acknowledge financial support from the French Agence Nationale de la
Recherche (ANR) through grant ANR-19-CE07-0041, from the Spanish MCIN/AEI/
10.13039/501100011033 through grants PID2022-140845OB-C62 and PID2022-139933NB-
I00, from the European Union (EU) through grant ERC SyG MolDAM (951519), from Xunta
de Galicia (Centro de Investigación do Sistema Universitario de Galicia accreditation 2023-
2027, ED431G 2023/03), and from the European Regional Development Fund (ERDF). A.A.
acknowledges the Spanish Ministerio de Universidades and the EU for a Margarita Salas
grant (REQ2021_A_02) and European Union's Framework Programme for Research and
Innovation Horizon Europe under the Marie Skłodowska-Curie Grant Agreement No.
101106492 (project title: Full-Fission). M.A.O. acknowledges the Xunta Distinguished
Researcher program (ED431H 2020/21) funded by Xunta de Galicia and the Ramón y Cajal
program (RYC2022-035453-I) funded by MICIU/AEI/10.13039/501100011033 and FSE+.
The authors thank the use of RIAIDT-USC analytical facilities for the SCXRD analysis of **4**.
The authors acknowledge the CSUC ("Consorci de Serveis Universitaris de Catalunya"),
CESGA ("Centro de Supercomputación de Galicia") and the Centre Régional de
Compétences en Modélisation Moléculaire (Aix Marseille Univ) for providing generous
computational resources.
Present addresses:

Dr. Albert Artigas: Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona (UdG), Facultat de Ciències, C/ Maria Aurèlia Capmany, 69, 17003 -Girona, Catalunya, Spain.

Dr. Manuel A. Ortuño: Departamento de Química Física, Universidad de Alicante, 03080 Alicante, Spain.

Dr. Jesús Castro-Esteban: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Received: March 25, 2025

Revised: May 7, 2025

Published online: July 4, 2025

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In the presence of a Pd⁰ catalyst, large π-extended arynes trimerize in an unusual manner to forge extremely compact and strained chiral benzenoids. This new trimerization reaction involves a 1,7-Pd isomerization, a rare and poorly understood process that was elucidated.

Albert Artigas, Manuel A. Ortuño, Jesús Castro-Esteban, Michel Giorgi, Diego Peña*, Dolores Pérez*, Yoann Coquerel*

Water-mediated 1,7-Palladium Aryl-to-Aryl Migration in an Unusual Aryne
Trimerization Enables the Synthesis of Multihelicenes with Profoundly Hindered
Stereogenic Axes

<figure><img src="image_11.png" /></figure>