Roles of Base in the Pd-Catalyzed Annulative Chlorophenylene Dimerization

Li-Ping Xu,a,b Brandon E. Haines,c Manjaly J. Ajitha,a Kei Murakami,d Kenichiro Itami,*,d and Djamaladdin G. Musaev*,a

a Cherry L. Emerson Center for Scientific Computation, Emory University, Atlanta, Georgia 30322, USA b School of Chemistry and Chemical Engineering, Shandong University of Technology, Zibo, 255000, China c Westmont College, Department of Chemistry, Santa Barbara CA, 93108, USA d Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, and JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464- 8602, Japan

KEYWORDS: Palladium catalyst, polycyclic aromatic hydrocarbon, C-H functionalization, DFT, base effect

ABSTRACT By using computation, the detailed mechanism of the Pd-catalyzed annulative chlorophenylene dimerization has been elucidated and the roles of the base have been identified. It is shown that the initial steps of this reaction are the active catalyst formation and the first C–Cl bond activation proceeds via the “base-assisted oxidative addition” mechanism. Overall, these steps of the reaction proceed via 16.2 kcal/mol free energy barrier for the C–Cl bond activation and are highly exergonic. Importantly, the base directly participates in the C–Cl bond cleavage introduces a mechanistic switch of the Pd(0)/Pd(II) oxidation and makes the reaction more exergonic. The following steps of the reaction are palladacycle and Pd-aryne formations, among which the palladacycle formation is found to be favorable: it proceeds with a moderate C–H activation barrier and is slightly exergonic. Although the Pd-aryne formation requires a slightly lower energy barrier, it is highly endergonic: therefore, the participation of the Pd-aryne complex, or its derivatives, in the Pd- catalyzed annulative chlorophenylene dimerization in the presence of Cs2CO3 seems to be unlikely. Again, base plays important roles in the palladacycle formation: it participates in the “bay” C–H bond activation, and facilitates the driving of the reaction forward by removing a proton to the solution via the bicarbonate-to-carbonate exchange mechanism. Addition of the second C– Cl bond to palladacycle intermediate, i.e. Pd(II)/Pd(IV) oxidation, is a rate-limiting step of the entire Pd-catalyzed annulative chlorophenylene dimerization in the presence of Cs2CO3: it occurs with 35.8 kcal/mol free energy barrier and is exergonic by 25.1 kcal/mol. The following polycyclic aromatic hydrocarbon (PAH) formation is a multi-step process and requires less free energy barriers. An alternative pathway, namely, cyclooctatetraene (COT) formation requires a higher energy barrier and is not feasible. This finding is consistent with experiments that show no COT

1 product in the utilized conditions. The calculations also indicate that the observed diminishing of the yield of the Pd-catalyzed annulative chlorophenylene dimerization reaction upon the use of Na-carbonate instead of Cs-carbonate is the result of not only poor solubility of Na-carbonate in the used experimental conditions, but also of a prohibitively large free energy barrier required for the second C–Cl activation, i.e. Pd(II)-to-Pd(IV) oxidation.

Introduction The high π-electron density, low redox potentials, strong π-π stacking interactions, and high stability of the polycyclic aromatic hydrocarbons (PAHs) make them potentially attractive materials for use in optoelectronic, fluorescent bioimaging, pharmaceutical, and agrochemical industries.1 Ongoing extensive research has (a) revealed that the physicochemical properties of PAHs are functions of the topology of their ring structures and degree of π-extension,1 and (b) identified multiple synthetic strategies for the control over the preparation of PAHs or other π- extended aromatic materials. Current synthetic toolbox for this purpose includes (but is not limited to) cross-coupling, Diels-Alder, cyclodehydrogenation (such as Scholl reaction), and cyclotrimerization.2 However, recent advances in transition metal catalyzed selective C–H functionalization3 have opened new horizons for effective synthesis of PAHs and related species. A prominent example of this is the annulative π-extension (APEX) of unfunctionalized aromatics, reported by Itami and coworkers.4 This step- and atom-economic synthesis allows direct transformation of easily available unfunctionalized arenes to PAHs and nanographenes. Briefly, it n is shown that the use of PdCl2 as a catalyst, P Bu(Ad)2 as a ligand, and Cs2CO3 as a base facilitates the annulative dimerization of chlorophenylenes through double C(sp2) – H bond 4 functionalization. Fascinatingly, the change of base from Cs2CO3 to Na2CO3 decreases yield of the reaction from 82% to 0%, and the use of sterically less bulkier phosphines is shown to be less effective (see Scheme 1).

Scheme 1. The Pd-catalyzed Annulative Chlorophenylene Dimerization Reaction, Reported by Itami and Coworkers (see ref. 4).

Ph Ph Ph PdCl2 (5.0 mol%) Ligand (10 mol%) CPME 140 οC, 18h Cl

Cs2CO3 (3.0 equiv): 82% yield 2 1 Na2CO3 (3.0 equiv): 0% yield Inspiring work by Shi and coworkers has shown that the product, i.e. polyaromatic hydrocarbons (PAHs) vs arene-fused cyclooctatetraenes (COTs) formation, via the C–H bond functionalization,

depends on the reaction conditions. For example, they have reported that Pd(OAc)2 catalyzed direct arylation and cyclization of o-iodobiaryls forms tetraphenylenes or arene-fused cyclooctatetraenes 5 (COTs) (Scheme 2a). In this reaction, the use of neither Cs2CO3 nor KHCO3 gives higher yield than NaHCO3, and the use of bulky phosphine ligand (Davephos) has a negative impact on the reaction yield. Intriguingly, performing the reaction under argon gas, instead of air, and switching 6 the base from NaHCO3 to KHCO3 has led to formation of PAHs instead of COTs (Scheme 2a).

Scheme 2. Selected Examples for the Synthesis of Polycyclic Aromatics Compounds.

2 (a) Arylation and cyclization of o-iodobiaryls (3) to tetraphenylenes (4) and PAHs (5), reported by Shi and coworkers (see ref. 5 and 6)

cat. Pd(OAc)2 (5mol%) NaHCO3 (2.4 eq.)

I DMF, 130 oC, air, 36h 4

DMA, 150 oC, Ar, 36h

3 cat. Pd(OAc)2 (2.5mol%) KHCO3 (1.1 eq.)

(b) Palladium-catalyzed APEX reaction of indoles and pyrroles with diiodobiaryls, reported by Itami and coworkers (see ref. 7a)

Ar Ar cat. Pd(OPiv)2 I Ag CO + 2 3 N I DMF/DMSO, 80 oC Ar R Ar N 6 8 R indoles 7 nitrogen-containing polycyclic or pyrrols aromatic compounds (N-PACs)

(c) Synthesis of heteroarene-fused cyclooctatetraenes: reported by Miura and coworkers (see ref. 7b) Ph Ph Ph S S S cat. Pd(OAc)2 (10 mol%) AgOPiv (2.0 eq.) PhCO2H (50 mol%) toluene, 120 oC, 12h

S S S Ph Ph Ph 9 10 Growing number of the transition metal catalyzed synthesis of PAHs and related species via the selective C-H functionalization (as example, see Scheme 2b and 2c)7 make it critical to better understand the mechanism and controlling factors of the reported catalytic annulative coupling reactions. It is conceivable to expect that the understanding of details of these reactions will enable us to improve the yield and product selectivity, and will broaden the substrate scope. Previously, the Itami group have proposed a multistep mechanism for the Pd-catalyzed annulative dimerization of chlorophenylene (1) that includes (i) oxidative addition of the C–Cl bond to Pd(0) to form Pd- aryl intermediate A, (ii) the first C-H bond activation, either of ‘bay’ C–HB or ‘ortho’ C–HO bonds, leading to formation of the palladacycle B or Pd-aryne C intermediates, respectively, (iii) C–Cl oxidative addition of a second equivalent of substrate 1 to either palladacycle B or Pd-aryne C intermediates leading to the formation of intermediates D or E, respectively, and (iv) reductive elimination or insertion to form intermediates S and T, (v) the second C–H bond activation, and (vi) reductive elimination to form the final product 2 (see Scheme 3).4 However, this proposed mechanism left several key questions unanswered , including (a) What is the nature of the catalytic active species?, (b) What are the barriers, reaction energies, and the rate-limiting and selectivity- determining steps of the reaction?, (c) What are the factors controlling the stability and formation of the proposed palladacycle and aryne intermediates?, and (d) What is a true nature of the proposed intermediates. Furthermore, it is critical to elucidate roles of the base in the reaction, and

understand reasons of diminishing of the yield of the reaction upon changing the base from Cs2CO3 to Na2CO3. In order to answer these questions and improve the efficiency of the Pd-catalyzed annulative chlorophenylene dimerization, we launched a comprehensive computational and mechanistic study. Briefly, we have elucidated the mechanism of the Pd-catalyzed annulative chlorophenylene

3 dimerization, and shed lights on the role of the base in the reaction. We expected that the findings of these computational studies will enable the further development of the synthesis of versatile PAHs.

Scheme 3. The Proposed Mechanism for the Pd-catalyzed Annulative Chlorophenylene (1) Dimerization Reaction.

Ph Ph Ph 1 1 'bay' HO oxidative 'ortho' C-HB activation O oxidative addition C-H activation PdL PdX(L) addition PdIIL HB O B HBX H X Ph Ph A C L Ph L Ph oxidative X = Cl or addition Pd CsCO3 1 Pd X

PdL2 L X L=PBu(Ad)2 E reductive D insertion elimination reductive Ph reductive Ph elimination elimination Ph L L Ph L X Ph Pd Ph Ph Pd Ph L Ph L X HX Pd HX T S Ph 2 second C-H second C-H Pd activation activation L U W

Computational Methods Geometry optimizations and frequency calculations for all reported structures were performed with the Gaussian 09 suite of programs8 at the B3LYP-D3BJ/[6-31G(d,p) + Lanl2dz (Pd, Cs)] level of theory with the corresponding Hay-Wadt effective core potential for Pd and Cs, and Grimme’s empirical dispersion-correction (D3) with Becke-Johnson (BJ) damping for B3LYP9 (below, called as B3LYP-D3BJ/BS1). Frequency analysis was used to characterize each minimum with zero imaginary frequency and each transition state (TS) structure with only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations were performed for all TSs to ensure their true nature. Bulk solvent effects were incorporated for all calculations using the self- consistent reaction field polarizable continuum model (IEF-PCM).10 As a solvent we chose dichloromethane (with dielectric constant of 8.93) which is a closest alternative of the cyclopentyl- methyl-ether (CPME, with dielectric constant of 4.76) used in the experiments. The calculated Gibbs free energies are corrected to the experimentally-used temperature, 413.15 K (G413). In the text, the B3LYP-D3BJ/BS1 results at 413.15 K (G413) will be primarily used, while the G298 values will be discussed where that will be appropriate and will be included in Supporting Information. In order to validate the [B3LYP-D3BJ]/BS1 calculated results we also performed single point energy calculations (i.e. at the [B3LYP-D3BJ]/BS1 calculated geometries) for selected intermediates and transition states by utilizing an extended basis set BS2 = 6-311+G(d,p) + SDD (Pd and Cs), and Stuttgart effective core potential for Pd and Cs11 (below, called as [B3LYP- D3BJ]/BS2 approach). Since both the [B3LYP-D3BJ]/BS2 and [B3LYP-D3BJ]/BS1 methods led to same conclusions, here we discuss only [B3LYP-D3BJ]/BS1 results because of their

4 completeness, while the data obtained for the selective structures at the [B3LYP-D3BJ]/BS2 are included in Supporting Information.

Results and Discussion A. Catalyst generation and the first C–Cl bond addition. As it could be expected, the mixing of PdCl2 with phosphine ligands and base leads to formation of the Pd(0)-phosphine pre- reaction complex. Previously, the role of phosphine ligands in the Pd(0)/Pd(II) oxidation by aryl halides has been extensively studied.12 Our computational data, presented below, are consistent n with findings of previous investigations and show that in the mixture of Pd[P Bu(Ad)2]2 (below, called as PdP2) and 2-Cl-diphenyl (Cl-diPh or chlorophenylene, 1a), the C–Cl oxidative addition does not occur prior to the dissociation of one of phosphine ligands, i.e. formation of the monophosphine Pd-complex, PdP.

Cl Cl ΔG/ΔH (kcal/mol) in solvent, at 413K Pd 26.1/42.3 Pd 21.1/44.5 Cl-diPh TS1 P P PdP TS1 P 14.0/34.1 Cl INT1 Pd 0.0/0.0 n Ad Bu P PdP2 P Cl-diPh = P = Cl -3.4/15.1 Ad 1a INT2 Figure 1. The calculated free energy surface of the PdP2 + 1a oxidative addition reaction.

As shown in Figure 1: (a) the PdP2 ® PdP + P reaction is endergonic by 21.1 kcal/mol, (b) the coordination of one equivalent of 1a to Pd-monophosphine complex PdP is 7.1 kcal/mol exergonic, and (c) the C–Cl bond activation at the transition state TS1 requires 12.1 kcal/mol free energy barrier calculated relative to the pre-reaction complex, INT1. The overall process PdP2 + 1a ® PdP + P + 1a ® TS1 ® ClPdP(Ar) + P (1) requires a total of 26.1 kcal/mol free energy and is exergonic by 3.4 kcal/mol. However, until now, little is known about the impact of base on the Pd(0)/Pd(II) oxidation by aryl halides. Partly, because this is a very complex issue and depends both on solubility and aggregation states of the base in the course of the reaction. Here, in our computational study, we assumed that Cs-carbonate is soluble in experimental conditions, i.e. the Cs2CO3 molecules exist in the reaction mixture. In this case, the initial step of the above discussed C–Cl oxidative addition is found to be coordination of base to PdP2: the PdP2 + Cs2CO3 ® [Cs2CO3]PdP2 reaction is calculated to be exergonic by 8.3 kcal/mol (see Figure 2a). The subsequent phosphine dissociation from the resulting [Cs2CO3]PdP2 adduct is only 5.5 kcal/mol endergonic, instead of 21.1 kcal/mol for the base-free process. Thus, in the presence of Cs2CO3, the formation of mono-phosphine complex, i.e. reaction

PdP2 + Cs2CO3 ® [Cs2CO3]PdP2 ® [Cs2CO3]PdP + P (2)

is 2.8 kcal/mol exergonic. Close analysis of [Cs2CO3]PdP (below called as compound A_Cs) revealed the presence of two stabilizing interactions: i) an unusual Pd–Cs (which has been 13 previously reported by Schaefer and coworkers ), and ii) Pd–CO3 interactions with distances of Pd–Cs = 3.823Å and Pd–O = 2.138Å (see Figure 2b). Thus, the presence of Cs2CO3 in the reaction

5 mixture changes the nature of catalytic active species from PdP to [Cs2CO3]PdP (i.e. A_Cs), and makes its formation energetically favorable.

(a) Cs 7.9/2.8 Cs Cl O O Pd P TS1_Cs 4.1/1.8 Cs C Cl-diPh O O Pd 0.0/0.0 A_Cs INT1_Cs O O Cs P PdP2 -2.8/2.5 P TS1_Cs A_Cs Cs Cl Cs CO 2 3 -8.3/-25.2 Cs O O Pd [Cs CO ]PdP 2 3 2 O O P O 5 INT1_Cs B ΔG/ΔH (kcal/mol) -19.5/-21.3 H Cs O Pd in solvent, at 413K INT2_Cs HO 2 Ad nBu P P B_Cs P = Cl-diPh = Ad Cl CsCl 1a -49.5/-40.2 B_Cs ligand exchange first C-Cl activation

2.458 (b) 3 B 1 Cl 2.288 O H Cs 3.575 O2 C5 Cs1 C4 Cs1 1 2.148 O 3 2.015 1 C 3.823 1 C C Pd 2.005 2.135 2 1 2.190 C O Pd Pd 2.301 HO Cl-diPh, 1a 1 O 2.396 2.138 2.237 P Cs2 P Cs2 P CsCl

[Cs CO ]PdP (A_Cs) TS1 (C-Cl addition) [CsCO ]PdP(η1–C H Ph) 2 3 3 6 4 (B_Cs) Figure 2. (a) Free energy surface for ligand exchange and first C–Cl bond addition steps; (b)

Structures and important geometry parameters (distances are in Å) of the reactant [Cs2CO3]PdP, C–Cl addition transition state TS1_Cs, and product of the 2-electron oxidation reaction II 1 [Cs2CO3]PdP + 1a ® [CsCO3]Pd P(h –C6H4Ph) + CsCl. The subsequent C–Cl oxidative addition by intermediate A_Cs (at the transition state TS1_Cs, see Figure 2) occurs with a 10.7 kcal/mol free energy barrier, relative to A_Cs + 1a. Intriguingly, in the presence of Cs2CO3, the Pd(0) and Cs-cation act collectively to activate the C–Cl bond. Subsequent IRC calculations confirm that the product of the C–Cl bond cleavage is complex II 1 [(ClCs)(CsCO3)]Pd P(h –C6H4Ph), INT2_Cs. Thus, while the C–Cl cleavage at the TS1_Cs leads to two-electron, i.e. Pd(0)/Pd(II), oxidation of Pd-center, it results in the formation of Pd–C(aryl), II Pd–O(from CO3) and Cs–Cl bonds, but Pd–Cl bond. The resulted Pd intermediate INT2_Cs is II 1 metastable: It releases CsCl molecule and rearranges to product complex [CsCO3]Pd P(h – 14 C6H4Ph), B_Cs. The overall reaction PdP2 + Cs2CO3 + 1a ® A_Cs + P + 1a ® B_Cs + P + CsCl (3) is highly (by 49.5 kcal/mol) exergonic. In summary, if Cs-carbonate is soluble at the utilized reaction conditions, then the chlorophenylene C–Cl addition in the mixture of PdP2, 1a and Cs2CO3 is a highly exergonic process, proceeds via the “base-assisted oxidative addition” mechanism (which resembles the 15 concerted nucleophilic aromatic substitution SNAr mechanism ) and leads to intermediate

6 II 1 [(CsCO3)]Pd P(h –C6H4Ph), B_Cs. Importantly, the presence of Cs2CO3 in the reaction mixture is critical for success of this step of the studied Pd-catalyzed annulative coupling reaction. It not only facilitates the active catalyst generation, but also directly participates in the C–Cl bond cleavage, and introduces mechanistic switch of Pd(0)/Pd(II) oxidation from the traditional oxidative addition to the “base-assisted oxidative addition.” B. Formation of the Palladacycle and Pd-aryne intermediates. Previously,4 the activation of either C–HB (i.e. “bay”) or C–HO (i.e. “ortho”) bonds – leading to the formation of palladacycle and Pd-aryne intermediates, respectively – were proposed to be next, but alternative, steps of the studied Pd-catalyzed annulative chlorophenylene dimerization reaction. However, our extensive calculations have convincingly shown that the next step of this reaction, initiated from the intermediate B_Cs can be very complex and is subject to the chemical nature of both the used base and its aggregation state (i.e. full or partial solubility), as well as the electronic properties of the intermediate species (for example, complex B_Cs). Indeed, if the base molecule has a low aggregation capability (i.e. high solubility), then the Pd-aryne and palladacycle formation can be directly initiated from the complex B_Cs. In contrast, if the base molecule has a relatively higher aggregation capability in the presence of intermediate B_Cs (i.e. if it is prone to the aggregate formation), then prior the C–H bond activation complex B_Cs may add one (or several, which were not pursued) more Cs2CO3 molecule(s) to form “Cs-cluster-complex”. For example, calculations show that the addition of one molecule of Cs2CO3 to intermediate B_Cs, i.e. reaction II 1 B_Cs + Cs2CO3 ® [Cs3(CO3)2]Pd P(h –C6H4Ph), C_Cs, is exergonic by 11.4 kcal/mol. As seen in Figure 3, the generated [Cs3(CO3)2] fragment of C_Cs has a well-defined “cage-type” of structure and is bidentately coordinated to Pd-center with the Pd–O1 = 2.159 Å and Pd–O2 = 2.159 Å bonds. Previously, we have reported similar “Cs-cluster-complex” in the study of Ni-dcype catalyzed C–H/C–O coupling of benzoxazole and naphthalen-2-yl pivalate in the presence of 16 Cs2CO3.

Cs2 2.414 Cs Cs1 O2 5 B 4 O2 B O H 3 H 1 O1 Pd 5 Cs O1 2.159 C 2 3 O 3 C 3 Cs Pd C1 O HO O3 Cs O P 2.555 2 O C 2.159 H Pd–C1 = 2.015 P Pd–P = 2.306

1 [Cs3(CO3)2]PdP(η –C6H4Ph) (C_Cs) 1 Figure 3. The proposed “Cs-cluster-complex” [Cs3(CO3)2]PdP(h –C6H4Ph) (i.e. C_Cs) with its important geometry parameters (distances are in Å). Thus, next step of the studied Pd-catalyzed annulative chlorophenylene dimerization reaction can be initiated from either B_Cs or C_Cs intermediates with CsCO3 or Cs3(CO3)2 fragments, respectively. Below, we discuss mechanism of the reaction initiated from the “Cs-cluster- II 1 complex” [Cs3(CO3)2]Pd P(h –C6H4Ph), C_Cs. Nevertheless, we also studied mechanism of the Pd-catalyzed annulative chlorophenylene dimerization reaction directly initiated from the complex B_Cs with the CsCO3 fragment, and included all data and related discussion into the Supporting Information (Figure S1). Here, we will compare differences of these two sets of reactions if that would be critically important.

7 2 Close examination of C_Cs shows that the O -center of the bidentately coordinated CO3-group 3 2 B and O -center of another CO3-group are within hydrogen bonding distances (O -H = 2.414Å and O3-HO = 2.555Å) from the phenyl groups of the di-phenyl ligand. Thus, these atoms can act as proton acceptors either from the C5–HB (leading to the palladacycle intermediate) or C2–HO (leading to the Pd-aryne formation) bonds. Therefore, below, we study the palladacycle and Pd- aryne formation in the cluster-complex C_Cs. Here, we wish to mention that the calculations (see Figure S2 in Supporting Information) have discounted the second C–Cl bond activation by intermediate C_Cs because of the required extremely large energy barrier.

B.1. Palladacycle formation. In intermediate C_Cs, the palladacycle formation occurs via the 17 5 B 2 concerted-metalation-deprotonation (CMD) of the C –H bond by the O -center of the CO3-unit at the transition state TS2_Cs (see Figure 4). Consistently, in TS2_Cs the weak Pd–O2 bond is completely broken (see Figures 3 and 4), the activated C5–HB bond is elongated to 1.393Å, and, consequently, the emerging O2–HB and Pd–C5 bonds are formed with 1.297 and 2.317 Å bond distances, respectively. The calculated free energy barrier is 31.4 kcal/mol, relative to pre-reaction complex C_Cs. 2 5 Cs 1.297 Pd–C = 2.317 B 2 H 1 1 Cs Pd–C = 2.062 1 Pd–C = 1.997 Cs 1.393 Pd–C5 = 2.038 Pd–P = 2.340 HB O1 O2 5 O3 C5 1 C O 1 2.148 Cs3 Pd C O3 Pd 2.176 2 C Cs1 1 HO P C Cs3 HO P Pd–O1 = 2.148 Pd–P = 2.525 2 [Cs3(CO3)(HCO3)]PdP[η –(C6H4)2] TS2_Cs (C1_Cs)

1 Figure 4. Transition state and product of the palladacycle formation in [Cs3(CO3)2]PdP(h –

C6H4Ph) with their important geometry parameters (distances are in Å). The IRC calculations from the transition state TS2_Cs led to intermediate II 2 [Cs3(CO3)(HCO3)]Pd P[h –(C6H4)2] (C1_Cs_cf1, see Figure S3 of Supporting Information), which later isomerized to its most stable conformer C1_Cs. The overall cyclopalladation reaction is found to be endergonic by only 4.2 kcal/mol, relative to complex C_Cs. In order for the reaction to proceed further the resulting palladacycle C1_Cs should either react with another equivalent of substrate with less than 27.2 kcal/mol energy barrier (this energy is required for the reverse reaction) or undergo another kinetically and thermodynamically favorable transformations. Calculations show that reaction of C1_Cs with the second equivalent of substrate 1a requires a significant free energy barrier and cannot be next step of the reaction (see Figure S3 of Supporting Information). Satisfyingly, we have identified multiple potentially enabling transformations (see Scheme S1 of Supporting Information) leading to the thermodynamically most favorable products II 2 II 2 [Cs2CO3]PPd [h –(C6H4)2], D1_Cs, and [Cs2CO3]Pd [h –(C6H4)2], D2_Cs (see Figure 5), both of them are result of replacement of the protonated base, i.e. the [Cs3(CO3)(HCO3)] fragment, by another equivalent of Cs2CO3 [this can be considered as one of the possible ways of proton (or acid) removal from the catalytic mixture which previously was proposed to facilitate forward reaction18]. Calculations show that regardless of their formation pathways (dissociative or

8 associative) the resulting intermediates D1_Cs and D2_Cs are thermodynamically favorable by 6.6 and 10.4 kcal/mol, respectively (relative to the initial complex C1_Cs): thus, the [Cs3(CO3)(HCO3)]-to-Cs2CO3 ligand exchange in complex C1_Cs is a facile and thermodynamically favorable process and provides much needed driving force to the palladacycle formation in course of the Cs-carbonate mediated and Pd-catalyzed annulative chlorophenylene dimerization reaction.

II 2 Figure 5. The calculated thermodynamically most favorable [Cs2CO3]PPd [h –(C6H4)2], D1_Cs, II 2 and [Cs2CO3]Pd [h –(C6H4)2], D2_Cs, palladacycles resulted by the [Cs3(CO3)(HCO3)]-to- Cs2CO3 ligand exchange in the complex C1_Cs.

1 1 O2 Cs Pd–O1 = 2.145 Pd–C = 2.008 Pd–C5 = 2.003 3.812 Pd–Cs2 = 3.893 1 O 2 2 Pd Cs Cs C5 P C1 Cs1 P 2.500 2 O 2.168 C5

3 1 1 O 2.188 Pd C Pd–C = 2.049 O1 Pd–C5 = 2.035 2 [(Cs2CO3)]Pd[η –(C6H4)2] (D2_Cs)

2 [Cs2CO3]PPd[η –(C6H4)2] (D1_Cs)

II 2 Comparison of these intermediates shows that dissociation of P ligand from [Cs2CO3]PPd [h – II 2 (C6H4)2], D1_Cs, to form complex [Cs2CO3]Pd [h –(C6H4)2], D2_Cs, is thermodynamically slightly favorable and may proceed via a lower energy barrier (which was not identified). A close examination shows that the entropy is a major factor in this favorable phosphine dissociation. In summary (see Figure 6), the palladacycle formation in B_Cs, i.e. reaction:

B_Cs + 2Cs2CO3 ® C_Cs + Cs2CO3 ® TS2_Cs + Cs2CO3 ® C1_Cs + Cs2CO3 ® D1_Cs + [Cs2(CO3)(CsHCO3)] ® D2_Cs + [Cs2(CO3)(CsHCO3)] + P (4) is kinetically and thermodynamically feasible: indeed, the D1_Cs and D2_Cs formations are 13.8 and 17.6 kcal/mol exergonic and proceed via overall 31.4 kcal/mol free energy barrier at the transition state TS2_Cs. Thus, the D1_Cs and D2_Cs complexes are the products of the cyclopalladation process. Data presented in the Supporting Information (Figure S1) for the palladacycle formation directly from intermediate B_Cs (i.e. without the “Cs-cluster complex” formation) show that it proceeds via a very similar mechanism with a 30.5 kcal/mol free energy barrier for the C–H activation and is exergonic by 7.7 kcal/mol. Comparison of these data with those (i.e. with 31.4 and 17.6 kcal/mol, respectively) for the reaction occurring via the “Cs-cluster complex” formation pathway shows that the proposed “Cs-cluster complex” formation has no critical impact to the palladacycle formation from the product of the first C–Cl activation, i.e. intermediate B_Cs. Thus, if Cs- carbonate is soluble under the used experimental conditions to drive the first C–Cl activation in the Pd-catalyzed annulative chlorophenylene dimerization reaction, the following palladacycle formation is independent from the aggregation state of base.

9 2 Cs O Cs 2 O HB O Cs O 2 Cs Cs 5 O HB 1 Cs O O1 Pd 5 5 O1 1 O1 1 O 2 Pd Pd 3 O Cs O Cs O O TS2_Cs 2 2 H HO P -29.5/-37.9 3 O Cs O O HO O3HO P TS2_Cs P TS3_Cs C2_Cs -37.5/-46.9 P ΔG/ΔH (kcal/mol) -41.2/-48.3 -41.1/-23.7 in solvent, at 413K TS3_Cs D2_Cs_benz C2_Cs D1_Cs_benz -43.3/-50.2 -44.2/-49.9 Cs2CO3 Cs3(CO3)(HCO3) C1_Cs_cf1 Cs

-49.5/-40.2 O P O B 1 B_Cs H O Pd Cs Cs 5 Cs O 2 O1 O D1_Cs_benz 1 -56.7/-63.2 Cs2CO3 O Pd C_Cs 3 Cs O 2 C1_Cs -63.3/-72.0 P -60.9/-69.4 O Cs2CO3 D1_Cs – P C1_Cs_cf1 B Cs3(CO3)(HCO3) Cs OH D2_Cs 2 O Cs O -67.1/-51.8 O B Cs H O1 5 5 O Cs 1 3 1 II O O O O Pd Pd 1 5 O 2 O 1 3 2 Cs Pd Cs O O Cs H O Cs P P O P C1_Cs D1_Cs C_Cs Figure 6. Free energy surfaces of the palladacycle (in black) and Pd-aryne (in red) formation. B.2. Palladium-aryne formation. As discussed above, the alternative pathway initiated from 2 C_Cs (or B_Cs, see above) is the formation of Pd-aryne complex [Cs2(CO3)(CsHCO3)]PdP(h – 2 O 3 C6H3Ph), C2_Cs, that occurs by deprotonation of the C -H bond by O -center of another (i.e. second) CO3-group of the Cs3(CO3)2 fragment (see Figures 3 and 7, as well as Scheme 4). Pd- aryne is not a common intermediate in the Pd(II)-catalyzed C–H functionalization chemistry but has been extensively studied and proposed in various organic and organometallic transformations.19 The performed IRC calculations from the associated transition state TS3_Cs confirmed that the Pd-aryne formation occurs via an asymmetric (i.e. “proton abstraction then Pd– C bond formation”) mechanism (see Scheme 4 for proposed concept of the aryne formation based on the performed calculations) with 23.4 kcal/mol free energy barrier, calculated relative to C_Cs. At the transition state TS3_Cs, the C2–HO bond is elongated (to 1.495Å) and the nascent O3–HO, Pd–C2 and C1ºC2 bonds are formed with 1.144, 2.918 and 1.391 Å bond distances, respectively. In the product complex C2_Cs, the aryne ligand (i.e. C6H3Ph) is coordinated to Pd-center via its C1ºC2 bond (with C1–C2 = 1.354Å). Based on the analyses (see Scheme 4) we conclude that complex C2_Cs is a Pd(0)-aryne complex, the calculated geometry parameters of which are in good agreement with those [Pd–C1=2.042(6) Å, Pd–C2=2.032(6) Å, and C1-C2=1.324(8)Å] 2 19a reported previously for the Pd(h -C6H4)(PCy3)2 complex in X-ray studies. As shown in Figure 6, the Pd-aryne formation is 19.7 kcal/mol endergonic (relative to pre- reaction complex C_Cs). All our efforts to identify transformation that can provide additional thermodynamic stability (i.e. driving force) to the formed Pd-aryne intermediate were 2 unsuccessful. The dissociation of phosphine ligand from [Cs3(CO3)(HCO3)]PdP(h –C6H3Ph) to generate D2_Cs_benz is a thermoneutral process, and the [Cs3(CO3)(HCO3)]-to-Cs2CO3 exchange to form D1_Cs_benz is only 3.0 kcal/mol exergonic. Furthermore, moderate (with a 47.5 kcal/mol free energy) stability of the formed D1_Cs_benz complex relative to the aryne dissociation [i.e. relative to the [Cs2(CO3)]PdP + C6H3Ph dissociation limit], also excludes the formation of free aryne molecule during this reaction. Thus, it is conceivable to conclude that participation of the Pd-aryne complex, or its derivatives, in the studied Pd-catalyzed and Cs-carbonate mediated

10 annulative chlorophenylene dimerization is less likely: even though it occurs with a lower (23.4 vs 31.4 kcal/mol) free energy barrier than the competing palladacycle formation, it lacks the driving force to proceed.

Cs2 3.201 1 1 3 O Cs Cs2 Cs 3 Cs O2 O3 2.198 3.198 3 B 3 O 2.198 H Cs 3 HO HO 2.024 O 2 2.300 Cs1 1.144 C C1 3.804 O1 2 O1 Pd 2 P C 1.495 C Pd 2.082 2.183 O4 Pd 1.351 Cs2 1.354 2.009 2.021 2.407 C1 2.195 2 P 1 O C P 3.779 3.063

Cs1 Cs3–O1 = 3.260 Pd–P = 2.338 Pd–C1 = 2.014 C1–C2 = 1.391 Pd–C2 = 2.918 (C2_Cs) (D2_Cs_benz) 2 [Cs (CO )(HCO )]Pd( 2–C H Ph) TS3_Cs [Cs3(CO3)(HCO3)]PdP(η –C6H3Ph) 3 3 3 η 6 3 1 Figure 7. Transition state and intermediates of the Pd-aryne formation in [Cs3(CO3)2]PdP(h – C6H4Ph) with their important geometry parameters (distances are in Å). In order to rationalize the difference in the calculated energy barriers and thermodynamicity of the palladacycle and Pd-aryne formation reactions in the Pd-catalyzed and Cs-carbonate mediated annulative chlorophenylene dimerization, we closely compare the structures of the associated intermediates, products and transition states. Analyses shown that these differences are due to several major factors. First, C–HO bond is more activated than C–HB bond because of direct bonding of cationic Pd(II) to the phenyl ring R1 of C_Cs with the C–HO bond (see Scheme 4). Second, in order to participate in the C–HB activation, O2-center has to be dissociated from the Pd(II)-center which introduces large distortion to the well-defined square-planar geometry of the Pd(II)-center (see Figures 4 and 7, and Figure S6 in Supporting Information). Third, difference of the Pd-ligand bonding in the D1_Cs and D1_Cs_benz products: as shown in Scheme 4, although the Pd–C bond distances are very similar in D1_Cs and D1_Cs_benz, the much shorter C1–C2 bond distance (and smaller [C1,Pd,C2] bond angle) in D1_Cs_benz induces a ring-strength and destabilizes Pd–C bonds. Data presented in Supporting Information (Figure S4) for the Pd-aryne formation directly from the intermediate B_Cs (i.e. without the “Cs-cluster complex” formation) show that it proceeds with a 38.6 kcal/mol energy barrier and is endergonic by 26.4 kcal/mol. Comparison of these data with those (23.4 and 19.7 kcal/mol, respectively) for the reaction initiated from the “Cs-cluster complex” C_Cs shows that the “Cs-cluster complex” formation may significantly facilitate the Pd-aryne formation process. Thus, based on the above presented findings, while the palladacycle formation in intermediate C_Cs is independent from the aggregation state of base, the Pd-aryne formation turns to be facilitated by the “Cs-cluster complex” formation (i.e aggregation state of base). In summary, above presented data clearly show that the Pd-catalyzed and Cs-carbonated mediated chlorophenylene C–Cl and C–H bond activation leads to the thermodynamically more favorable palladacycle intermediates D1_Cs and D2_Cs.

Scheme 4. Selected Geometry Parameters (distances are in Å, and angles are in deg.) and Schematic Presentation of the Stable Palladacycle (C1_Cs) and Pd-aryne (C2_Cs) Complexes, as well as a Concept of the Pd-aryne Formation. Here X Stands for the [Cs3(CO3)2] Fragment.

11 Pd - C1 = 2.015 R2 R2 R2 B 5 5 P H P HB HB 5 P e II 1 II 1 X Pd Pd 1 R1 R1 II R1 XHO 2 Pd 2 O 2 .. .. H HOX e C_Cs SIMULTANIOUS deprotonation Electron transfer Decoupling spins 2 O of C -H by X from C2 to Pd of Pd–C1 bond deprotonation of C5-HB by X R2 Pd0 HB 5 II R2 C1 - C2 = 1.354 Pd 1 5 1 Pd - C1 = 2.021 Pd - C = 2.062 O 2 H X R1 HBX 1 Pd - C5 = 2.038 Pd - C = 2.082 1 2 2 (C1,Pd,C5) = 80.2 (C ,Pd,C ) = 38.7 R1 P 2 P Palladacycle C1_Cs C2_Cs Pd-aryne

C. The second equivalent of substrate addition to the palladacycle or competing PdII/PdII ® Pd0/PdIV transmetalation. As anticipated, the next step of the reaction is the formation of IV 2 1 intermediate [CsCO3]Pd [h –(C6H4)2](h –C6H4Ph) (INT4_Cs). This, in general, can be achieved either via the second equivalent of substrate coordination to the energetically most stable palladacycle D2_Cs and following C-Cl bond activation or by the PdII/PdII ® Pd0/PdIV transmetalation. Calculations show that the substrate coordination to D2_Cs leads to the formation of II 2 intermediate [Cl-C6H4Ph)]-(Cs2CO3)Pd [h –(C6H4)2], INT3_Cs, which may have several isomers. Since INT3_Cs is only 0.9 kcal/mol stable relative to the reactants D2_Cs + 1a, and unlikely to critically contribute to the reaction outcome, for the sake of simplicity, we report all of its calculated isomers in the Supporting Information (Figure S7). Briefly, in INT3_Cs (a) Cl-atom weakly interacts with one of the Cs-cations, and (b) the phosphine ligand dissociates with no (or insignificant) energy barrier.

1 Pd–O = 2.147 Pd–C5 = 2.025 Pd–O2 = 2.170 Pd–C2 = 1.988 Pd–C5 = 2.005 6 2.239 6 C Cl C Pd–C1 = 2.007 2.030 3.626 2.362 Pd–Cl = 3.165 1 5 C C Cl C5 Pd 2 1 O C 1 2 Cs1 Pd O2 Pd–O = 2.222 Cs O1 2 O1 Pd–O = 2.225 3.489 1 2 Cs O3 Cs O3 3.030

IV 2 1 TS3a_Cs [(CsCl)CsCO3)]Pd [η –(C6H4)2](η –C6H4Ph) (E1_Cs) Figure 8. Structures along with important geometry parameters (distances are in Å) of the transition state TS3a_Cs and product E1_Cs of the second C-Cl bond activation by palladacycle D2_Cs. The following C–Cl cleavage (i.e. in INT3_Cs) occurs, again, via the “base-assisted oxidative addition” mechanism at the transition state TS3a_Cs and leads to PdIV-complex IV 2 1 [(CsCl)CsCO3]Pd [h –(C6H4)2](h –C6H4Ph) (E1_Cs) (see Figure 8). The associated free energy barrier with this process is 35.8 kcal/mol, and reaction INT3_Cs ® E1_Cs is exergonic by 1.9 kcal/mol (Figure 9).20 Comparison of this barrier with 31.4 kcal/mol (or 30.5 kcal/mol for the pathway occurring without the “Cs-cluster complex” formation) free energy barrier required for the first C–Cl cleavage (i.e. for the Pd(0)/Pd(II) oxidation) show that the second C–Cl bond

12 addition (i.e. the Pd(II)/Pd(IV) oxidation) is more energy demanding process. From the Pd(IV)- complex E1_Cs, the CsCl dissociation occurs with only 0.9 kcal/mol free energy and leads to the INT4_Cs intermediate.21

Cl 6 Cs -32.2/-23.5 Cl 6 O Pd ΔG/ΔH (kcal/mol) TS3a_Cs Cs in solvent, at 413K O O O Pd

Cs O O TS3a Cs Cs E1_Cs O3 6 -69.0/-46.1 D2_Cs -68.0/-58.3 INT4_Cs O Pd 2 -67.1/-51.8 Cl 6 O INT3_Cs 1 Cs -69.9/-60.2 O O Cl-diPh CsCl 1a O Pd E1_Cs O Cs Cs

O O Cs2CO3 F_Cs Cs INT3_Cs -92.2/-90.5 F_Cs Figure 9. Free energy surface for the second C–Cl activation by the D2_Cs intermediate.

The energetically most favorable, among the alternative PdII/PdII ® Pd0/PdIV transmetalation processes, is presented in Scheme 5. Calculations show that even this process is thermodynamically more demanding than the substrate coordination to D2_Cs and following C– Cl bond cleavage pathway discussed above. Therefore, below we will not discuss the PdII/PdII ® Pd0/PdIV transmetalation in more details, while we include all related structures to Supporting Information together with their energies.

Scheme 5. Schematic Presentation of the Energetically Most Favorable PdII/PdII ® Pd0/PdIV Transmetalation Reaction. Energies Are Given in kcal/mol.

Cs O Cs O 5 O Cs2CO3 O 5 O 5 O O O 1 II Cs II IV Pd 1 + Pd + Pd Cs O 1 Pd0 P P Ph P P B_Cs D1_Cs INT4_Cs 0 IV PdII/PdII Pd /Pd ΔG = 0.0 / ΔH = 0.0 ΔG = 37.6 / ΔH = 40.6

D. Product Formation. In the presence of base with a relatively higher aggregation capability, intermediate INT4_Cs IV 2 1 may rearrange to the complex [Cs3(CO3)2]Pd [h –(C6H4)2](h –C6H4Ph) (F_Cs): the reaction INT4_Cs + Cs2CO3 ® F_Cs is calculated to be exergonic by 23.2 kcal/mol. Thus, product formation, either cyclooctatetraene (COT) or polycyclic aromatic hydrocarbon (PAH) (see structures 4 and 5 in Scheme 2a), can be initiated from either intermediate INT4_Cs (if the base has a low aggregation capability) or complex F_Cs (if the existing base molecules can form higher- level aggregates).

Scheme 6. Comparison of Three Different Reaction Pathways Leading to the PAH (path-1, blue) and COT (path-2 and path-3, red) Products. Energies (given in kcal/mol) Are Calculated Relative

13 to the (a) PdP2 + 2xCs2CO3 + 2x[Cl-C6H4Ph] Limit for Intermediates and Products, and (b) Corresponding Pre-reaction Complexes for the Transition States.

PdLH

C-H activation II C-C coupling Path 1 LPdII Pd LH G = 22.7 ΔG = 14.4 trans C-C Δ TS5_Cs TS6_Cs couplingΔG = 23.4 TS4_Cs G_Cs H_Cs PAHs I_Cs ΔG = -126.6 ΔG = -138.2 ΔG = -142.8 PdIVL cis C-C coupling

ΔG = 19.5 C-H activation cis C-C coupling F_Cs TS4a_Cs LH PdLH ΔG = -92.2 Path 2 LPdII ΔG = 43.1 PdII ΔG = 30.5 - TSN_Cs L=Cs3(CO3)2 TSP_Cs C-H activation P_Cs Q_Cs R_Cs ΔG = 30.2 COTs G = -137.4 ΔG = -124.7 ΔG = -125.7 Δ TSM_Cs

Path 3 cis C-C coupling PdIVL ΔG = 37.8 TSL_Cs J_Cs ΔG = -91.3

Our extensive studies have shown that PAH formation in F_Cs (we also studied PAH and COT formations initiated from the complex INT4_Cs, see Figure S10 in Supporting Information) proceeds via path-1 (see Scheme 6, also see PES of this reaction in Figure S11 of Supporting Information) that includes reductive elimination (i.e. trans C–C coupling at the transition state TS4_Cs), C–H bond activation (at the transition state TS5_Cs), and the second C–C coupling (at the transition state TS6_Cs) steps. The first C–C coupling, i.e. F_Cs ® TS4_Cs ® G_Cs or Pd(IV)/Pd(II) 2-electron reduction, requires 23.4 kcal/mol free energy barrier and is exergonic by 12.1 kcal/mol. [These values are 18.3 kcal/mol and 28.0 kcal/mol, respectively, if this process will be initiated directly from the INT4_Cs]. The following C–H bond activation and the second C–C coupling occur with the 22.7 and 14.4 kcal/mol energy barriers and lead to the final product I_Cs [These values are 31.8 and 5.8 kcal/mol, respectively, if this process is initiated directly from the INT4_Cs]. As shown in Figure 10, in the product complex I_Cs, Pd(0)-center is only loosely coordinated to the formed PAH molecule. Overall PAH formation from intermediate F_Cs is exergonic by 50.6 kcal/mol (57.5 kcal/mol, if this process is initiated directly from the INT4_Cs). The above presented data show that (a) if the reaction proceeded via the “Cs-cluster complex” formation pathway (initiated from intermediate F_Cs), it would require a 7-8 kcal/mol smaller energy barrier and would be ca 7 kcal/mol less exergonic than if that will proceed via the “no Cs- cluster complex” pathway (initiated from directly from the intermediate INT4_Cs). Regardless, the second C–Cl activation step remains the rate-limiting step of entire Cs-carbonate mediated and Pd-catalyzed annulative chlorophenylene dimerization reaction. Alternative product of the studied annulative chlorophenylene dimerization reaction could be cyclooctatetraene (called as product R_Cs), which, in general, is formed from intermediate F_Cs (with “Cs-cluster complex”) or INT4_Cs (if reaction proceeds via without “Cs-cluster complex” formation mechanism) via paths 2 and 3, as shown in Scheme 6. Path-2 follows via the cis C–C coupling (at the transition state TS4a_Cs), the C–H bond activation (at the transition state TSP_Cs), and the second cis C–C coupling (at the transition state TSN_Cs). An alternative pathway, i.e. path-3, starts with the C–H bond activation (at the transition state TSM_Cs), and

14 follows via the two consequent cis C–C coupling steps (at the transition states TSL_Cs and TSN_Cs). Calculations show that paths 2 and 3 occur with very high free energy barriers at the C–H activation (with 43.1 and 40.5 kcal/mol energy barriers, if the reaction is initiated from F_Cs and INT4_Cs, respectively) and the second reductive elimination (37.8 and 36.2 kcal/mol, if the reaction will be initiated from F_Cs and INT4_Cs, respectively) steps, respectively. Based on the above presented data it is conceivable to conclude: the COT formation cannot compete with the PAH formation in the studied Pd-catalyzed annulative chlorophenylene dimerization in the presence of Cs2CO3, regardless of aggregation states of the base. This finding is consistent with experiments showing no COT products at the utilized conditions (see Supporting Information for more details).

1 Pd–O = 2.162 Pd–C1 = 2.015 Pd–O3 = 2.179 Pd–C6 = 2.045 5 7 Pd–O5 = 2.247 O –H = 1.981 C7–H7 = 1.097 Cs1 6 6 C C O5 O5 C5 Pd H7 C7 1 O 5 5 O Pd 1 C C 1 2 1 Cs O 5 3 Cs 1 Pd C O 1 O C 3 1 Cs O3 Pd–O = 2.097 O1 5 Pd–O3 = 2.166 1 Pd–C = 2.009 3 Pd–O = 2.057 7 2 Cs 1 Pd–C = 2.410 3 Cs Pd–C = 2.081 Pd–O2 = 2.198 Cs2 Cs 2 Cs Pd–C6 = 2.191 6 1 (F_Cs) TS4_Cs C –C = 1.949 (G_Cs)

1 Pd–O = 2.120 Pd–O3 = 2.260 Pd–O1 = 2.203 Pd–C7 = 2.172 1 2 Pd–O = 2.274 Pd–O = 2.176 7 7 Pd–C8 = 2.169 O –H = 1.390 Pd–C7 = 2.032 7 7 1 5 C –H = 1.249 C –C = 1.479 5 7 Pd–C = 2.038 H 5 C1–C8 = 1.436 O5 O 6 C7 C C1–C5 = 1.913 C1 H7 C7 C5 7 Cs1 C C8 Cs3 Cs3 Pd 5 C C7 C5 C5 O2 Cs1 1 1 2 Pd Pd–O = 2.098 1 5 2 Cs Pd O O Pd–C = 2.011 Cs 1 2 7 Cs2 Pd Cs O1 Pd–O = 2.200 Pd–C = 2.234 Pd–C5 = 2.011 2 3 Cs 7 Cs2 O1 Cs Pd–C = 2.002 O3 O1 Cs3 (I_Cs) TS6_Cs (H_Cs) TS5_Cs Figure 10. Structures and important geometry parameters (distances are in Å) of reactants, intermediates, transition states and products of the energetically most favorable polyaromatic hydrocarbons (PAHs) formation pathway, i. e. path-1.

E. Impact of the Cs2CO3 ® Na2CO3 substitution on the reaction outcome. To validate, once again, the role of base in the Pd-catalyzed annulative chlorophenylene dimerization, we calculated free energy surfaces of all elementary reactions, reported above, also in the presence of Na2CO3. Here, we chose Na2CO3 because experiments have shown that the yield of the reaction reduces from 82% to 0% upon the Cs2CO3 ® Na2CO3 substitution. In our computational modeling, at first, we assumed the Na-carbonate to be soluble and studied the impact of the presence of Na2CO3 in the reaction mixture to the reaction outcome. Briefly, we found that while the coordination of Na2CO3 to complex PdP2, unlike Cs2CO3 (for comparison, see Figure 2a) is endergonic (by 9.5 kcal/mol), it also facilitates the phosphine dissociation from PdP2, and consequently, the formation of active catalyst (See Figure S14 in Supporting Information). Indeed, the free energy required for one of phosphine ligands dissociation from PdP2 is almost two times smaller in the presence of Na2CO3 than in the absence of Na2CO3, 10.4 kcal/mol vs 21.1 kcal/mol, respectively. Thus, as in the Cs2CO3 case, in the

15 presence of Na2CO3 the active catalyst of the reaction is intermediate [Na2CO3]PdP (below called as A_Na).The following oxidative addition of C–Cl bond of 1a to intermediate A_Na proceeds with a moderate (11.7 kcal/mol) energy barrier at the “base-assisted oxidative addition” transition state and leads to the complex [NaCO3]PdP (below called as B_Na). Thus, if the sodium-carbonate were soluble under the utilized experimental conditions, then the catalytic active species formation and following C–Cl addition (or Pd(0)/Pd(II) oxidation), like in the presence of Cs2CO3, would occur with a moderate (22.1 kcal/mol) free energy barrier and would be exergonic (by 25.5 kcal/mol, see Supporting Information). In other words, the observed dramatic difference in the reaction yield upon the Cs2CO3 to Na2CO3 substitution can be explained neither by the active catalyst formation nor the first C–Cl oxidative addition, while it could be result of poor solubility of the Na-carbonate.

ΔG/ΔH [Na (CO )(NaHCO )]PdP(η2-C H Ph) 2 3 3 6 3 (40.3/31.2) (in kcal/mol) C2_Na at t =413.15 K TS3b_Na (22.8/5.7)

“cluster” (32.6/23.9) (12.3/-9.2) TS3a_Na TS2_Na [Na (CO )(HCO )]Pd(η2-(C H ) ) 1 3 3 3 6 4 2 [NaCO3]PdP(η -C6H4Ph) D2a_Na “non-cluster” B_Na P (1.6/1.7) (0.0/0.0) Na Cl -25.5/-11.7 (-2.6/-21.0) 6 O Na2CO3 Na3(CO3)(HCO3) Na C1_Na O 2 OH O Pd [Na (CO )(HCO )]PdP(η2-(C H ) ) 3 3 3 6 4 2 O O1 Na2CO3 (-6.7/-24.9) Na O 2- O H [Na2(CO3)]PdP(η (C6H4)2) TS3b_Na D1_Na Na Na 5 O1 Na 1 O Cl 6 O Pd O 3 5 (-24.4/-42.8) O 2 C_Na O Na Na P Na Pd 1 1 O O Pd [Na3(CO3)2]PdP(η -C6H4Ph) C1_Na P D1_Na O O

Na TS3a_Na Figure 11. Free energy surfaces of the palladacycle (in black) and Pd-benzyne (in red) formation in the complex B_Na. For details of the reactions initiated from intermediates D1_Na and D2a_Na see Supporting Information.

Next, we investigated palladacycle and Pd-aryne formation in the presence of Na2CO3 (see Figure 11). Similar to the case with Cs2CO3, these steps of the Pd-catalyzed annulative chlorophenylene dimerization in the presence of Na2CO3 can be initiated either directly from complex B_Na (if the base molecule has a low aggregation capability, i.e. is highly soluble) or II 1 from the “Na-cluster-complex” [Na3(CO3)2]Pd P(h –C6H4Ph), C_Na, (if the base molecule were prone to form a highly aggregated Na-carbonate species). Again, here, we studied both mechanistic scenarios, while below we discuss only the reaction initiated from the complex C_Na. Calculated data for the reaction from B_Na are included into the Supporting Information (Figure S15), and will be compared when it becomes important.

Compared with the Cs2CO3 case (see Figure 6), we found (see Supporting Information for more details) that (a) the coordination of the second equivalent of Na2CO3 to B_Na and formation of the “Na-cluster complex” C_Na is highly exergonic (by 24.4 kcal/mol), more so than the same reaction in the presence of Cs2CO3: this finding indicates that Na-carbonate is prone to form high aggregation species, i.e. is less soluble, than Cs-carbonate, (b) the palladacycle (C1_Na)

16 formation in C_Na has ca 5-6 kcal/mol more energy barrier (36.7 kcal/mol) and is endergonic by 21.8 kcal/mol, and (c) the Pd-aryne formation in C_Na is highly (by 47.2 kcal/mol) endergonic (therefore, we did not calculate the Pd-aryne formation transition state). Most importantly, neither the following (from the palladacycle C1_Na) [Na3(CO3)(HCO3)]-to-Na2CO3 exchange nor phosphine dissociation leading to the D1_Na and D2a_Na complexes, respectively, are thermodynamically feasible. Thus, the palladacycle formation (we also expect the Pd-aryne formation) initiated from the “Na-cluster complex” C_Na occurs over a much higher energy barrier and is more endergonic than that initiated from the “Cs-cluster complex” C_Cs. These findings could be explained by larger stability of the “Na-cluster complex” C_Na compared to the “Cs-cluster complex” C_Cs, i.e. by weaker solubility of Na2CO3 compared to Cs2CO3. As expected, the second C–Cl oxidative addition to the thermodynamically unfavorable palladacycles, either D1_Na or D2_Na, is going to be a highly energy demanding process. Indeed, the calculated C–Cl activation barriers (relative C_Na) are as high as 57.0 and 64.7 kcal/mol, for the following “cluster” and “non-cluster” pathways, respectively (see Figure 11 and Figure S17 in Supporting Information). Thus, the second C-Cl addition in the presence of Na2CO3 requires a prohibitively high energy barrier and is unlikely to proceed. This conclusion is consistent with our previous experiments showing zero yield in the presence of Na2CO3.

Conclusion Based on the rigorous computations presented here, a modified mechanism of the Pd-catalyzed annulative chlorophenylene dimerization was proposed (see Scheme 7, here for the sake of clarity we omit suffix “_Cs” of the labels of the presented structures): 1. Initial steps of this reaction are: (a) the active catalyst A formation, (b) the first C–Cl bond activation via the “base-assisted oxidative addition” mechanism, and (c) the formation of intermediate B. Overall, these steps of the reaction proceed via 16.2 kcal/mol free energy barrier for the C–Cl bond activation and are highly exergonic. Importantly, the presence of base molecules (i.e. Cs2CO3) in the reaction mixture is critical for success of these steps of the studied reaction: Base directly participates in the C–Cl bond cleavage, introduces mechanistic switch of the Pd(0)/Pd(II) oxidation, and makes reaction more exergonic. 2. Among the following palladacycle and Pd-aryne formation pathways, the palladacycle formation is favorable: it proceeds with a moderate C–H activation free energy barrier (~30-31 kcal/mol) and is slightly exergonic. Although the Pd-aryne formation may require slightly lower C–H activation barrier, it is a highly endergonic process and lacks the driving force to proceed: thus, the participation of the Pd-aryne complex, or its derivatives, in the studied Pd-catalyzed annulative chlorophenylene dimerization in the presence of Cs2CO3 is unlikely. Again, the presence of the base molecule (i.e. Cs2CO3) in the reaction mixture is important for the palladacycle formation: it (a) participates in the “bay” C–H bond activation, and (b) facilitates the driving of the reaction forward by removal of proton to the solution via the cesium(bicarbonate)- to-cesium(carbonate) exchange mechanism. We show that if base is soluble under the used experimental conditions to drive the first C–Cl activation, the following palladacycle formation is independent from the aggregation state (or solubility) of base; 3. The next step of the reaction is the second C–Cl bond addition to palladacycle D2 via another “base-assisted oxidative addition” mechanism and formation of intermediate F. Overall, this step, i.e. Pd(II)® Pd(IV) oxidation, is a rate-limiting step of entire Pd-catalyzed and Cs-carbonate mediated annulative chlorophenylene dimerization: it occurs over a 35.8 kcal/mol free energy barrier and is exergonic by 25.1 kcal/mol.

Scheme 7. The Proposed Mechanism of the Pd(0)-catalyzed and Cs2CO3-mediated Annulative Chlorophenylene Dimerization.

B Cs C–H B 5 Cl-C H Ph 5 OH Cs2CO3 5 6 4 (CMD) (II) O O HB 4 O Pd (II) (0) 3 O Pd (Cs2CO3)Pd P O O Pd(II) 1 1 O Cs O P 1 CsCl 2 Cs B Cs (A) O CsCO3H base-assisted P H O O and P H (B) H (C1) oxidative add. Palladacycle (D2) P REGARDLESS OF AGGREGATION STATE OF BASE Cs CO Cl-C6H4Ph 2 3 Cs2CO3 Cs2CO3 (II) (IV) 5 Pd /Pd (0) Pd P Cs B base-assisted 2 O H Cs2(CO3)(HCO3) O oxidative add. Pd(II) and P

Regeneration Catalyst 1 B 5 Cs O C–H 7 1 2 (CMD) O P O 8 6 O H Ph (I) Cs Cl 6 O (C) Cs PAH 5 O Pd(IV) HB O O Cs O 1 O O Cs (0) 5 O Pd O HO 7 1 Pd(0) Cs O (E1) O Cs 8 6 Cs O O O P OH Cs CO O Cs Cs 2 3 O (C2) Pd-aryne (CsCl) REGARDLESS OF AGGREGATION STATE OF BASE Pd(II)/Pd(0) Ph 6 O

C-C coupling 7 OH O (IV) (II) 5 O O Pd /Pd O Pd(IV) Cs (II) 5 (II) 5 Pd 1 Cs Pd 1 O 1 O 7 O H7 2nd C–H C-C Cs Cs Cs 6 Cs 7 6 O 8 (CMD) O coupling O O Ph O O Ph Cs O Cs O Cs O (H) (F) (G)

4. The final stage of the reaction is the product formation from intermediate F. Calculations show that polycyclic aromatic hydrocarbon (PAH) formation via the subsequent trans C–C coupling, C–H bond activation, and the second C–C coupling steps, requires lower free energy barriers. This process is exergonic by 50.6 kcal/mol. Alternative pathway, namely, cyclooctatetraene (COT) formation from F requires a higher free energy barrier and is not feasible. This finding is consistent with experiments shown no COT product in the utilized conditions. 5. Calculations indicate that the observed dramatic change in the yield of the Pd-catalyzed annulative chlorophenylene dimerization reaction (from 82 % to 0%) upon use of Na-carbonate instead of Cs-carbonate is result of not only poor solubility of Na-carbonate in the used experimental conditions, but also a prohibitively large free energy barrier required for the second C–Cl activation, i.e. Pd(II)-to-Pd(IV) oxidation.

ASSOCIATED CONTENT

Supporting Information. Energies and Cartesian coordinates for all reported structures. This material is available free of charge via the Internet at http://pubs.acs.org AUTHOR INFORMATION

18 Corresponding Author *E-mail: [email protected] (D.G.M.) *E-mail: [email protected] (K.I.) Notes The authors declare no competing financial interests. ACKNOWLEDGMENT This work was supported by the National Science Foundation under the CCI Center for Selective C–H Functionalization (CHE-1700982). D.G.M. gratefully acknowledges the NSF MRI-R2 grant (CHE-0958205) and the use of the resources of the Cherry Emerson Center for Scientific Computation at Emory University. L.P.Xu acknowledges the National Science Foundation of China (NSFC 21702126) and China Scholarship Council for support. REFERENCES 1. (a) Watson, M. D.; Fechtenkötter, A.; Müllen, K., Big Is Beautiful−“Aromaticity” Revisited from the Viewpoint of Macromolecular and Supramolecular Benzene Chemistry. Chem. Rev. 2001, 101, 1267-1300; (b) Allard, S.; Forster, M.; Souharce, B.; Thiem, H.; Scherf, U., Organic Semiconductors for Solution-Processable Field-Effect Transistors (OFETs). Angew. Chem. Int. Ed. 2008, 47, 4070-4098; (c) Facchetti, A., π-Conjugated Polymers for Organic Electronics and Photovoltaic Cell Applications. Chem. Mater. 2011, 23, 733-758; (d) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D., Semiconducting π-Conjugated Systems in Field-Effect Transistors: A Material Odyssey of Organic Electronics. Chem. Rev. 2012, 112, 2208-2267. 2. (a) Harvey, R. G., Polycyclic Aromatic Hydrocarbons. Wiley-VCH: New York 1997; (b) Wu, J.; Pisula, W.; Müllen, K., Graphenes as Potential Material for Electronics. Chem. Rev.2007, 107, 718-747; (c) Segawa, Y.; Ito, H.; Itami, K., Structurally uniform and atomically precise carbon nanostructures. Nat. Rev. Mater. 2016, 1, 1-14; (d) Tsefrikas, V. M.; Scott, L. T., Geodesic Polyarenes by Flash Vacuum Pyrolysis. Chem. Rev. 2006, 106, 4868-4884; (e) Chen, L.; Hernandez, Y.; Feng, X.; Müllen, K., From Nanographene and Graphene Nanoribbons to Graphene Sheets: Chemical Synthesis. Angew. Chem. Int. Ed. 2012, 51, 7640-7654; (f) Sun, Z.; Ye, Q.; Chi, C.; Wu, J., Low band gap polycyclic hydrocarbons: from closed-shell near infrared dyes and semiconductors to open-shell radicals. Chem. Soc. Rev. 2012, 41, 7857-7889; (g) Ito, S.; Tokimaru, Y.; Nozaki, K., Benzene-Fused Azacorannulene Bearing an Internal Nitrogen Atom. Angew. Chem. Int. Ed. 2015, 54, 7256-7260; (h) Yokoi, H.; Hiraoka, Y.; Hiroto, S.; Sakamaki, D.; Seki, S.; Shinokubo, H., Nitrogen-embedded buckybowl and its assembly with C60. Nat. Commun. 2015, 6, 8215; (i) Tokimaru, Y.; Ito, S.; Nozaki, K., A Hybrid of Corannulene and Azacorannulene: Synthesis of a Highly Curved Nitrogen-Containing Buckybowl. Angew. Chem. Int. Ed. 2018, 57, 9818-9822; (j) Cai, J.; Ruffieux, P.; Jaafar, R.; Bieri, M.; Braun, T.; Blankenburg, S.; Muoth, M.; Seitsonen, A. P.; Saleh, M.; Feng, X.; Müllen, K.; Fasel, R., Atomically precise bottom-up fabrication of graphene nanoribbons. Nature 2010, 466, 470-473; (k) Maekawa, T.; Segawa, Y.; Itami, K., C–H activation route to dibenzo[a,e]pentalenes: annulation of arylacetylenes promoted by PdCl2–AgOTf–o-chloranil. Chem. Sci. 2013, 4, 2369-2373. 3. (a) Lyons, T. W.; Sanford, M. S., Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions. Chem. Rev. 2010, 110, 1147-1169; (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q., Palladium(II)-Catalyzed C-H Activation/C-C Cross-Coupling Reactions: Versatility and Practicality. Angew. Chem. Int. Ed. 2009, 48, 5094-5115; (c) Arockiam, P. B.;

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22 Table of Context Use

Roles of base in the Pd-Catalyzed Annulative Chlorophenylene Dimerization

Li-Ping Xu, Brandon E. Haines, Manjaly J. Ajitha, Kei Murakami, Ken Itami,* and Djamaladdin G. Musaev*

Pd-Phosphine Catalyzed Annulative Coupling The Presence of Cs2CO3 is critical

"Cs cluster" COT

PAH

Palladacycle vs Aryne Formation