Origins of regioselectivity of the palladium-catalyzed (aromatic)CH bond metalation–deprotonation

Coordination Chemistry Reviews 257 (2013) 153–164

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Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr

Review

Origins of regioselectivity of the palladium-catalyzed (aromatic)C H bond metalation–deprotonation Serge I. Gorelsky Centre for Catalysis Research and Innovation, University of Ottawa, 30 Marie Curie, Ottawa, ON K1N 6N5, Canada

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Palladium-catalyzed C H bond cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Arene C H bond cleavage by Pd–carboxylate catalysts: concerted or not? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Distortion–interaction analysis of CMD transition states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Arene distortion energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Catalyst–arene interaction energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Reactivity of arenes with fluoro- and chloro-substituents. C H bond acidities and metal carbon bond energies . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Reactivity of pyridine N-oxides and related heteroarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Reactivity of azoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Reactivity of thiophenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

a r t i c l e

i n f o

Article history: Received 26 February 2012 Received in revised form 18 June 2012 Accepted 19 June 2012 Available online 27 June 2012 Dedicated to Professor Edward Solomon on the occasion of his 65th birthday. Keywords: Direct arylation Cross-coupling Palladium-catalyzed reactions Concerted metalation–deprotonation Distortion–interaction analysis

153 154 155 157 157 159 160 161 162 163 163 164 164

a b s t r a c t A comprehensive understanding of the C H bond cleavage step in direct arylation is important in further development of cross-coupling reactions using transition metal catalysts. Analysis of Pd-catalyzed C H bond cleavage of a wide range of (hetero)arenes via the concerted metalation–deprotonation (CMD) pathway allows one to quantify various contributions to the activation barriers and to identify activation characteristics of different substituent groups. In general, the CMD activation barriers do not show correlation with C H bond acidities and metal aryl bond energies. Regioselectivity of arylation for many (hetero)arenes, especially electron-deficient arenes, can be predicted from the C H bond acidities. Regioselectivity of arylation for different (hetero)arenes can be understood from the distortion and electronic interaction contributions to the CMD activation barriers. The effects of remote substituents and metal coordination to heteroarenes on reactivity and regioselectivity are discussed. Electron-withdrawing substituents and metal coordination to heteroatoms increase acidities of (hetero)arene C H bonds, making those bond more reactive in the CMD process. © 2012 Elsevier B.V. All rights reserved.

1. Introduction The site-selective formation of carbon carbon bonds through functionalization of carbon hydrogen bonds is a very attractive

Abbreviations: CMD, concerted metalation–deprotonation; EMD, electrophilic metalation–deprotonation; SE Ar, electrophilic aromatic substitution; DFT, density functional theory; HOFO, highest occupied fragment orbital; LUFO, lowest unoccupied fragment orbital; NPA, natural population analysis; TS, transition state. E-mail addresses: [email protected], [email protected] 0010-8545/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ccr.2012.06.016

method for synthesis of complex organic molecules for a variety of applications (medicinal compounds, light-emitting diodes, liquid crystals, etc.) [1]. Biaryl cross-coupling reactions based on arene preactivation have revolutionized synthetic chemistry [1,2]. These reactions are dependent on preactivation of two arene fragments with halides or similar functionalities (X) and electropositive groups M (Scheme 1). Incorporation of these functional groups requires additional synthetic steps and creates waste. Transitionmetal catalyzed functionalization of (hetero)arene C H bonds has emerged over the past few years as a rapidly growing and increasingly reliable alternative to conventional cross-coupling reactions [3–13].

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2. Palladium-catalyzed C H bond cleavage

base). In the SE Ar mechanism, the reaction proceeds via the Wheland intermediate (also known as the  complex) [14]. In the Wheland intermediate of the C H bond cleavage mechanism, a metal ion is bound to the carbon atom of the arene via a covalent bond. It is expected that this Wheland intermediate is similar to a Wheland intermediate after the proton attack on the arene. Formation of the additional covalent bond at the carbon atom in the Wheland intermediates causes a disruption of the conjugated ␲ system of the arene and the bond orders [15] of the C C bonds in the arene ring deviate significantly from a value of 1.5 (Fig. 1). The charges of the carbon atoms derived from the natural population analysis (NPA) [16,17] also show

In contrast to the conventional cross-coupling reactions, direct arylation and oxidative cross-coupling reactions (Scheme 1) eliminate the necessity of pre-functionalization of arenes. Multiple investigations have focused on the understanding of the C H bond cleavage mechanism for different substrates and several pathways have been proposed [13]. Electrophilic aromatic substitution (SE Ar) and the concerted metalation–deprotonation (CMD) are two mechanisms (Fig. 1) that have received the most attention for Pd-catalyzed direct arylation reactions under the standard conditions (a metal-phosphine catalyst and a carbonate/carboxylate

Scheme 1. Conventional cross-coupling reactions, direct arylation, and oxidative arene cross-coupling reactions.

[M] [M]

Ar +

L

H

L

Ar [M]

H

CMD Mechanism

Ar

L H [M]

[M] SEAr Mechanism

L

Ar

L

Ar H

H

Wheland Intermediate -0.25 1.55 +0.05 1.32 1.10 +0.04 -0.58

H H

-0.25

+0.05

Fig. 1. Concerted metalation–deprotonation (CMD) and electrophilic aromatic substitution (SE Ar) pathways for C H bond cleavage using metal–carboxylate catalysts (M-L). Mayer bond orders for C C bonds and NPA-derived charges for carbon atoms (B3LYP/TZVP calculations) are shown in blue and red respectively for the Wheland intermediate C6 H7 + .

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155

Fig. 2. The lowest-energy CMD transition state structures for C H bond cleavage for benzene (A) and N-methylimidazole (C5 H bond, B) using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst. The relevant internuclear distances (Å) in the 6-member cycle are shown. Arrows indicate atomic movements that correspond to a normal mode with an imaginary frequency in the direction towards a product. Mayer bond orders for C C bonds of the benzene substrate in the CMD TS structure are shown in blue.

characteristic positive values at ortho and para positions of the benzene ring (Fig. 1). These changes in the C C bond orders and the C atomic charges can be explained by considering three resonance forms of the Wheland intermediate (Fig. 1). These SE Ar signatures are important to distinguish the Wheland intermediate from other structures with similar geometries (for example, ␲ complexes). In special situations when properties of the metal catalyst are tuned to lower the activation barriers for alternative reaction pathways and/or to increase the CMD activation barriers, other mechanisms can be at play. For example, it has recently been shown that Heck-type arylation becomes the lowest-energy pathway for arylation of thiophene using the Pd catalyst with the bulky fluorinated phosphine ligand P(OCH(CF3 )2 )3 [18]. Instead of C␣ arylation that is characteristic for the CMD pathway [19,20], this Heck-type arylation pathway leads to C␤ arylation. Mechanistic studies on the palladium-catalyzed direct arylation and related C H bond cleavage reactions were conducted on various substrates including benzene [21,22], pyridine [23], tethered arenes [24] and diarenes [25,26], and electron deficient arenes such as fluorobenzenes [27,28], pyridine N-oxide [29,30], and CF3 -, Acand CO2 Me-substituted benzenes [31]. The results of these studies supported the CMD mechanism [13,19,20] as did the earlier investigations of Pd-catalyzed cyclometalation [24,25,32]. In a CMD transition state (Figs. 1 and 2), a carboxylate ligand of a catalyst abstracts a proton from a C H bond while, at the same time, a metal carbon bond is being formed. Instead of CMD, alternative names such as ambiphilic metal–ligand activation [33] or internal electrophilic substitution [34] have also been used in the literature. In contrast to arene substrates in the Wheland intermediates (Fig. 1), the arene substrates in the CMD transition states and in the pre-transition state energy minima (␲ complexes) [20] do not loose the C C aromatic conjugation (Fig. 2) and do not feature a buildup of significant positive charge on the carbon atoms at the ortho and para positions. Using density functional theory (DFT) calculations, activation barriers for cleavage of different C H bonds using a palladium–acetate catalyst [Pd(C6 H5 )(PMe3 )(OAc)] [19,20], were evaluated and it was demonstrated that the C H bond cleavage for a wide range of (hetero)arenes (Fig. 3) by the PdII –acetate complex proceeds by the CMD pathway [19,20]. The calculated barriers for the CMD pathway are consistent with the experimental regioselectivity of the palladium-catalyzed direct arylation. The calculated barriers are also in agreement with the relative reactivity of various arenes [35].

2.1. Arene C H bond cleavage by Pd–carboxylate catalysts: concerted or not? In the mechanistic studies investigating C H bond cleavage of various (hetero)arenes by metal–carboxylate complexes, the stepwise SE Ar mechanism or a single-step concerted process (Fig. 1) were discussed. Electrophilic metalation–deprotonation (EMD) mechanism, an intermediary process between the two, has also been proposed [37]. This proposal goes along with the idea of a possible continuum for the mechanisms of the C H bond cleavage by transition metal–carboxylate complexes. At one end of this continuum lies the SE Ar pathway in which the metal carbon bond is formed in the Wheland intermediate before the C H bond is cleaved and the O H bond is formed. At the other end lies a fully concerted process in which the M C and O H bonds are formed as the C H bond is cleaved. The mechanism of (hetero)arene C H bond cleavage using different transition-metal catalysts can fall in between these two limiting scenarios. A More O’Ferrall–Jencks diagram [38,39], in which both the O H and M C bond formations and the C H bond breaking in the transition state structures are characterized by corresponding bond orders (Fig. 4), can be used to verify the “continuum” proposal [20]. In the transition states with the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst, the bond orders of the forming O H bonds are situated in the 0.52–0.59 range. The C H bond orders in the TS structures range from 0.31 to 0.41. The Pd C bond orders are somewhat more dependent on the nature of the arene, they range from 0.30 to 0.62. Fairly small deviations of the bond orders from the expected trend (dashed lines in Fig. 4) for the concerted formation of the M C and O H bonds at the expense of the C H bond for different arenes do not provide support for the idea of a switch in the mechanism for cleavage of C H bonds in electron-poor and electron-rich arenes using the PdII –carboxylate catalysts. A comprehensive understanding of the governing parameters influencing the reactivity and regioselectivity of the C H bond cleavage is required in order to utilize arylation reactions successfully for a broad range of substrates. Finding conditions under which it will be possible to switch reactivity from one C H bond to another is also an important goal of research. Fluorine [25,27,28,40], chlorine [41], and nitro [42] functional groups have an activating influence on arene C H bonds toward metalation. Remote substituents at the C6 position of 1-methylindoles [43] and at the C2 position of thiophenes [20] affect the arylation reactivity of the C H bonds of indoles at the C2 site and thiophenes at the C5

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Fig. 3. Gibbs free energies of activation (G‡ 298 K ) of the cleavage of C H bonds for different (hetero)arenes in the CMD process using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst (B3LYP/TZVP(DZVP for Pd) level of theory) [19,20,29,36]. Only symmetry-unique C H bonds are shown and C H bonds with the lowest CMD activation barriers are shown in blue.

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2.2. Distortion–interaction analysis of CMD transition states

1.0

O-H Bond Order

0.8 0.6

pyrazine

C6H6

C6Cl5H

SEAr

C6F5H

0.4

CMD 0.2 0.0 Wheland intermediate

C-H Bond Order

0.8 CMD

0.6

C6F5H

0.4

SEAr

C6Cl5H

0.2 0.0 0.0

157

pyrazine

0.2

0.4

C6 H6

0.6

0.8

1.0

M-C Bond Order Fig. 4. Mayer bond orders for metal C(arene), (acetate)O H and C H(arene) bonds of the lowest-energy CMD TS structures for (hetero)arenes using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst. The dashed black lines represent the expected trend for the perfectly concerted formation of M C and O H bonds and cleavage of the C H bond. The gray and black boxes indicate expected bond order regions that correspond to the SE Ar transition states and the Wheland intermediates, respectively. Red, green, and open circles are for the lowest-energy TS structures with class I, class II, and class III (hetero)arenes, respectively [20]. Black circles are for TS structures of arene substrates with a single type of C H bond.

site (Fig. 5). Thiophenes with electron withdrawing groups, such as nitrile and ester, are the most reactive substrates along with thiophene containing a strongly electron-donating N-pyrrolidine substituent. Thiophenes with weak electron-donating groups are the less reactive substrates along with the thiophene possessing the acetyl substituent. This trend is not in agreement with SE Ar reactivity but in agreement with the CMD reactivity (Fig. 5). Herein, we discuss the parameters that govern the activation barriers of the C H bond cleavage in (hetero)arenes via the CMD mechanism with a PdII –carboxylate catalyst.

Fig. 5. Experimental reactivity of C2-substituted thiophenes toward arylation. Values below the structures correspond to the Gibbs free energies (G‡ 298 K , kcal mol−1 ) for CMD activation barriers for C5 H bonds using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst [20].

The distortion–interaction analysis [44–46] is a useful method to identify geometric and electronic contributions to activation barriers. This analysis has been applied to understand reactivity and regioselectivity of arylation of arene C H bonds (Fig. 6). First, there is the energetic cost (distortion energy, Edist ) associated with the distortion of the catalyst and the (hetero)arene from their ground state structures (I and II) to their geometries (III and IV) in the TS structure V. Second, there is the energy gain (electronic interaction energy, Eint ) resulting from the electronic interaction of fragments III and IV to form the TS structure V. These factors allowed for the classification of the arenes into three categories (Fig. 7) [20]. Class I includes (hetero)arenes for which the regioselectivity of C H bond metalation is controlled by the difference in the arene distortion energies, Edist (ArH). It can be seen that most of class I (hetero)arenes contain electronwithdrawing substituents (fluorine, chlorine, methoxy group, N-oxide group, etc.). 1-Methylpyrazole belongs to class I and its C5 H bond is more reactive than the C3 H and C4 H bonds in the CMD process due to lower distortion energy of the arene at the C5 site (41.3 kcal mol−1 for C5 arylation vs. 43.6 kcal mol−1 for C3 arylation and 45.3 kcal mol−1 for C4 arylation, Fig. 8). This difference in distortion energies prevails over the difference in the catalyst–substrate interaction energies in the CMD TS (−45.0 kcal mol−1 at the C4 site vs. −41.9 kcal mol−1 at the C5 site), making the C4 site, the most nucleophilic site of this heteroarene, less reactive than the C5 site, the site with the most acidic C H bond (gas-phase acidities of C H bonds of 1-methylpyrazole are 414.5 kcal mol−1 , 409.9 kcal mol−1 , and 396.2 kcal mol−1 for C3 H, C4 H, and C5 H bonds respectively). Class II includes (hetero)arenes, for which catalyst–arene electronic interaction energies define the most reactive C H bonds. Furan is an example of class II heteroarene. In arylation of furan, C␣ H bonds are more reactive than C␤ H bonds in the CMD process due to more negative interaction energy at the C␣ site (−44.8 kcal mol−1 for C␣ arylation vs. −40.0 kcal mol−1 for C␤ arylation, Fig. 8). Class III includes (hetero)arenes for which both the arene distortion and catalyst–arene interaction energies enhance the CMD cleavage of a given C H bond. An example of such heteroarene is thiophene for which C␣ H bonds are more reactive than C␤ H bonds in the CMD process due to lower arene distortion energy at the C␣ site (39.9 kcal mol−1 for C␣ arylation vs. 41.8 kcal mol−1 for C␤ arylation, Fig. 8) and the more favorable catalyst–arene interaction energy at the C␣ site (−41.4 kcal mol−1 for C␣ arylation vs. −37.8 kcal mol−1 for C␤ arylation, Fig. 8). Regioselectivity of arylation and C H acidity of free (hetero)arenes show an interesting trend: for 12 class I arenes (out of 15), the arylation occurs at the C H bond with the lowest heterolytic dissociation energy (Fig. 7). For 5 class III arenes (out of 8), the arylation also occurs at the most acidic C H bond. Finally, only for 3 class II arenes (out of 10), the arylation occurs at the most acidic C H bond. This points to a conclusion that C H bond acidity is a most important contributor to reactivity in class I arenes. For class III and class II arenes, C H bond acidity becomes an increasingly less important factor.

2.2.1. Arene distortion energy The energy cost associated with the distortion of the (hetero)arenes into their CMD transition state geometries can be separated into two components: (1) the C H bond stretching from an equilibrium bond distance to an elongated distance in the CMD TS structure, and (2) the out-of-plane bending of the C H bond of the arene. Evaluation of the C H bond elongation and out-of-plane bending of the C H bond as contributions to Edist (ArH) for different

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Fig. 6. Distortion–interaction analysis for the CMD transition states. The TS structure for the C H bond cleavage at the C2 site of azole is shown as an example.

Fig. 7. Classification of (hetero)arene substrates in terms of contributions to regioselectivity of C H bond metalation via the CMD pathway based on their reactivity with the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst (B3LYP/TZVP(DZVP for Pd) level of theory) [19,20,29,36]. C H bonds with the lowest activation energies for the CMD cleavage are shown in bold. The circled H atoms indicate the cases where the C H bond with the lowest CMD activation barrier corresponds to a C H bond with the lowest gas-phase electronic energy of heterolytic dissociation.

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159

50

Edist(ArH) / kcal mol-1

45

Class I Class II Class III other

C6H6

correlation

40 pyrazine

35

C6Cl5H

30 C6F5H 25 350

360

370

380

390

400

410

420

EC-H / kcal mol-1

Fig. 8. Gibbs free energies of activation (G‡ 298 K ), arene distortion energies and catalyst–arene interaction energies for cleavage (via the CMD pathway) of C H bonds in 1-methylpyrazole, furan, and thiophene using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst.

(hetero)arenes (Fig. 9) showed that average out-of-plane bending distortion energy is 13.5(±2.0) kcal mol−1 . (Hetero)arene distortion energies appear to show some relationship with the energies for heterolytic C H bond cleavage of free arenes, the deprotonation energies of the C H bonds (Fig. 10). The C H bond deprotonation energy, EC H , is calculated by removing the proton from the corresponding C H bond of the arene and optimizing the structure of the resulting anion [20]. For all (hetero)arenes in Fig. 3, the linear regression analysis of the correlation between Edist (ArH) and EC H (correlation coefficient R = 0.79) leads to an approximate expression (Eq. (1)): Edist (ArH) = 0.34(±0.04)EC–H − 93(±17)

(1)

2.2.2. Catalyst–arene interaction energy The fragment molecular orbital analysis [44] of the electronic interactions between the PdII –OAc catalyst and the (hetero)arene substrates indicates that two types of donor–acceptor interactions are responsible for the formation of new Pd C(arene) and

Fig. 10. (Hetero)arene distortion energies for the lowest-energy CMD TS structures with the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst and electronic energies of heterolytic dissociation of C H bonds (red squares for class I arenes, green squares for class II arenes, black squares for class III arenes, and black circles for other arenes).

O(acetate) H(arene) bonds. The O H bond is formed by charge donation from the acetate-based occupied molecular orbital (the highest occupied fragment orbital (HOFO) of the metal–acetate fragment, Fig. 11) to the C H ␴* anti-bonding molecular orbital (the lowest unoccupied fragment orbital (LUFO) of the arene fragment, Fig. 11). The Pd C(arene) bond is formed by charge donation from one or more occupied ␲ orbitals of the arene fragment to the metal-localized unoccupied orbital of the PdII –acetate fragment [19]. In the case of the C5 H bond cleavage of N-methylimidazole, the largest contribution to the Pd C bond formation in the CMD transition state comes from charge donation from the HOFO of the azole fragment [36]. This fragment orbital changes its electron population by 17.8% when the interaction with PdII is “turned on” (Fig. 11). For other arenes, it is frequently not the HOFO of the arene that is most important donor orbital for the metal carbon bond formation but one or more deeper-lying occupied fragment orbitals.

Edist of ArH / kcal mol-1

50 C6H6

45 40

pyrazine

35 30

C6Cl5H C6F5H

25

Edist(C-H stretch)

20 15 0.25

0.30

0.35

0.40

ΔdC-H / A Fig. 9. Arene distortion energies (red squares for class I arenes, green squares for class II arenes, black squares for class III arenes, and black circles for pyrazine, C6 H6 , C6 F5 H, and C6 Cl5 H) and the C H bond distortion energies (black triangles) for the lowest-energy CMD TS structures with the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst as a function of the C H bond elongation.

Fig. 11. Simplified orbital interaction diagram for charge transfer interactions between the palladium–carboxylate catalyst and arene (N-methylimidazole) in the CMD TS structure. Black arrows indicate charge donation from the acetate base to the C H ␴* anti-bonding orbital and green arrows indicate charge transfer from an arene ␲ orbital to a PdII acceptor orbital. Percentages next to arrows indicate changes in orbital populations when the donor–acceptor interaction between the fragments is “turned on”.

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Fig. 12. Gibbs free energies of activation (G‡ 298 K , kcal mol−1 ) of C H bond cleavage via the CMD pathway for benzene, fluoro- and chloro-substituted benzene, benzothiophene, benzofuran and their fluoro- and chloro-substituted derivatives using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst. NPA-derived atomic charges of the carbon atoms of the most reactive C H bonds and the neighboring atoms in the arene ring are shown in italics.

2.3. Reactivity of arenes with fluoro- and chloro-substituents. C H bond acidities and metal carbon bond energies The realization that electron-deficient arenes such as fluorinated arenes can be fairly reactive substrates in direct arylation reaction with PdII –carboxylate catalysts was an important step that led to the recognition of the importance of the CMD mechanism. The relative reactivities and site selectivities for fluoro-substituted benzenes (Fig. 12) in direct arylation reactions indicated that most reactive C H bonds were the bonds with higher acidity [27]. Thus, C H bond acidity was deemed to be a significant parameter. In the follow-up study of direct arylation of C6 H6−n Fn (n = 0–5), Perutz and Eisenstein [28] showed that the CMD activation barriers correlate with the energies of heterolytic C H cleavage (slope 0.25 ± 0.02, correlation coefficient 0.980). However, if one moves from fluorosubstituted benzenes to a larger set of (hetero)arenes (Fig. 3), the correlation is lost (Fig. 13). For fluoro-substituted benzenes, another correlation was reported between the CMD activation barriers and homolytic metal aryl bond energies (slope −0.63 ± 0.04, correlation

CMD Free energy barrier / kcal mol-1

35

coefficient 0.984) [28] showing that the CMD barrier is expected to decease if the strength of the Pd C bond formed in the CMD step increases (Pd Ar bond strengths were calculated in the [Pd(C6 H5 )(PMe3 )(AcOH)(Ar)] intermediates). In the CMD step, the Pd C bond is made and the C H bond is cleaved in heterolytic manner by the base ligand. Perutz and Eisenstein [28] concluded that a fluorine substituent on the arene, especially at the ortho position, favors both transformations because it strengthens the Pd C bond as well as increasing the acidity of the arene. However, if we look at strength of the electronic interaction between the Pd–acetate catalyst and the arene in the transition state structures, Eint (Fig. 14), it is hard to see the evidence to conclude that fluoro-substitution strengthens the Pd C(arene) bond. When going from benzene to C6 H5 F to C6 F5 H, −Eint decreases from 35.9 kcal mol−1 to 35.1 kcal mol−1 to 32.2 kcal mol−1 . Moreover, the evaluation of PdL–Ar dissociation energies for heterolytic cleavage, DPdL–Ar (PdL = Pd(C6 H5 )(PMe3 )(AcOH)), in the [Pd(C6 H5 )(PMe3 )(AcOH)(Ar)] intermediates (Table 1) leads to a conclusion that fluorine and chlorine substitution

pyrazine

C6H6 30

C6Cl5H

25

20

15 350

C6F5H

360

370

Class I Class II Class III other 380

390

400

410

420

EC-H / kcal mol-1 Fig. 13. Gibbs free energies of activation (G‡ 298 K ) of cleavage of C H bonds (via the CMD pathway) for different (hetero)arenes using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst and electronic energies of heterolytic dissociation of C H bonds in (hetero)arenes (red squares for class I arenes, green squares for class II arenes, black squares for class III arenes, and black circles for other (hetero)arenes).

Fig. 14. Gibbs free energies of activation (G‡ 298 K ), arene distortion energies and catalyst–arene interaction energies for lowest-energy C H bond cleavage (via the CMD pathway) of benzene, fluorobenzene, 1,3-difluorobenzene, and pentafluorobenzene using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst.

S.I. Gorelsky / Coordination Chemistry Reviews 257 (2013) 153–164 Table 1 Heterolytic PdL–Ar dissociation energies (kcal mol−1 ) and Pd CAr bond orders in the [Pd(C6 H5 )(PMe3 )(AcOH)(Ar)] intermediates from the B3LYP/TZVP (DZVP for Pd) calculations. Ar

DPdL–Ar a

B(Pd–CAr )b

Ar

DPdL–Ar a

B(Pd–CAr )b

C6 H5 C6 H4 F C6 H3 F2 C6 F5

156.2 146.6 137.4 122.6

0.714 0.698 0.652 0.619

C6 H4 Cl C6 H3 Cl2 C6 Cl5

142.8 131.0 117.4

0.600 0.477 0.402

a Pd Ar bond dissociation energy in the [Pd(C6 H5 )(PMe3 )(AcOH)(Ar)] intermediate after the cleavage of the most reactive C H bond in the arene. b Mayer bond order for the Pd CAr bond.

CMD Gibbs free energy barrier / kcal mol-1

weakens the Pd C bond. For the [Pd(C6 H5 )(PMe3 )(AcOH)(Ar)] intermediates after the CMD step at the most-reactive C H bond, DPdL–Ar decreases from 156.2 kcal mol−1 for Ar = C6 H5 to 146.6 kcal mol−1 for Ar = C6 H4 F to 137.4 kcal mol−1 for Ar = C6 H3 F2 to 122.6 kcal mol−1 for Ar = C6 F5 (Table 1). Thus, fluoro-substitution reduces heterolytic dissociation energies of the Pd aryl bonds while it increases the homolytic dissociation energies. Fluorine and chlorine substituents on the arene, especially at the ortho position, favor the CMD transformation despite the fact that they reduce the interaction energy between palladium(II) and the aryl anion. Looking at the relationship of the CMD activation barrier with heterolytic DPdL–Ar for other substrates (Fig. 15), the correlation between the two energies for a broad range of (hetero)arenes is rather weak. It has been shown [20] that (hetero)arene distortion energies in the CMD step and C H bond acidities are linked to each other (Section 2.2.1). For electron-deficient substrates, the distortion energy is a dominant factor in determining the most reactive C H bond for CMD cleavage [20]. Fluorine substitution lowers the arene distortion energy of the neighboring C H bond most dramatically (Fig. 14). When going from C6 H6 to C6 H5 F, Edist (arene) is lowered by 5.7 and 1.6 kcal mol−1 for ortho and meta C H bonds respectively while Edist (arene) for the C H bond at the para position remains unchanged. Electronic interaction energies between the catalysis and the arene at the ortho and meta site of C6 H5 F are 0.8 kcal mol−1 smaller than that for benzene while Eint at the para site of C6 H5 F is 1.6 kcal mol−1 larger than that for benzene. As a result, activation of the C H bonds at the ortho positions is exclusively due to the lower distortion energy of the arene and this, in turn, is linked to the

35

30

C6H6 pyrazine

C6Cl5H

25

20

C6F5H

Class I Class II Class III other

15 110

120

130

140

150

160

170

DPdL-Ar / kcal mol-1 Fig. 15. Gibbs free energies of activation (G‡ 298 K ) of cleavage of the most reactive C H bonds (via the CMD pathway) for different (hetero)arenes using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst and electronic energies of heterolytic dissociation of Pd Ar bonds in the [Pd(C6 H5 )(PMe3 )(AcOH)(Ar)] intermediates (red squares for class I arenes, green squares for class II arenes, black squares for class III arenes, and black circles for other (hetero)arenes).

161

Table 2 Heterolytic dissociation energies (kcal mol−1 ) of C H bonds of free arenes (at the B3LYP/TZVP level of theory). ArH

C6 H6 C6 H5 Xb 1,3-C6 H4 X2 b C6 X5 H

EC

H

a

X=F

X = Cl

412.6 398.8 385.0 365.3

396.3 381.9 365.6

a Electronic energy of heterolytic dissociation of a C H bond in a free arene in the gas phase. b A C H bond at the C2 site.

Fig. 16. Gibbs free energies of activation (G‡ 298 K ), arene distortion energies and catalyst–arene interaction energies for C H bond cleavage (via the CMD pathway) at the C2, C3, and C4 sites of benzene, fluorobenzene, and chlorobenzene using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst.

increased acidity of the ortho C H bond (Table 2). This increased acidity originates from the fact that electron-withdrawing fluorine pulls the electron density away from the carbon atom of the C F bond creating a positive charge which stabilizes a more negative charge of the carbon atom at the ortho position (Fig. 12). Putting additional fluoro substituents on the arene amplifies this effect (Fig. 14) and leads to a lower arene distortion energy and, thus, a lower CMD activation energy. As a result, among fluorinated benzenes, pentafluorobenzene C6 F5 H is most reactive (Fig. 12). (Hetero)arenes with chlorine substituents inhibit the similar behavior to (hetero)arenes with fluorine substituents (Fig. 12). However, the activating effect of the chlorine group is weaker relative to the fluorine group (Fig. 15). This weaker activating affect cannot be attributed to lower C H bond acidity of chlorinesubstituted arenes (relative to fluorine-substituted arenes, Table 2). Comparison of the electronic interaction energies between the Pd–acetate catalyst and the arene in the transition state structures, Eint (Fig. 15), for benzene, C6 H5 F, and C6 H5 Cl shows that the chlorine group makes the arene less nucleophilic and weakens the metal aryl bond interaction (Table 1 and Fig. 4). This decrease in the strength of the metal aryl interaction explains to a lower activating effect of the chlorine group relative to the fluorine group (Fig. 16). 2.4. Reactivity of pyridine N-oxides and related heteroarenes Until recently, arylation of unprotected pyridines has remained a challenge due to the fact that the C H bonds in pyridine and similar N-heterocycles (such as quinolines) are fairly unreactive (Fig. 3) and a nonproductive N-bound coordination with metal centers can

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Fig. 18. Gibbs free energies of activation (G‡ 298 K , kcal mol−1 ) of C H bond cleavage via the CMD pathway for N-methylimidazole and oxazole (with and without coordination to CuI ), and thiazole using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst.

Fig. 17. Gibbs free energies of activation (G‡ 298 K ), arene distortion energies and catalyst–arene interaction energies for cleavage (via the CMD pathway) of C2 H and C3 H bonds of pyridine, pyridine N-oxide, and [CuCl(pyridine)] using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst [19,20,36].

hamper arylation [23]. In 2011, the first example of Pd-catalyzed, C3-selective arylation of unprotected pyridines has been developed by employing a catalytic system consisting of Pd(OAc)2 and 1,10-phenanthroline [23]. The preference for C3 arylation and the observation that pyridine is a more reactive substrate than benzene is consistent with the CMD reactivity (Figs. 3 and 17). The Gibbs free energy barrier for CMD cleavage at the C3 site (32.6 kcal mol−1 ) is 1.3 kcal mol−1 lower than the corresponding barrier for benzene (Fig. 3). The cleavage of the C3 H bond has a lower barrier than the C2 H bond due to higher nucleophilicity of the C3 site (Eint is −33.9 kcal mol−1 at the C3 site relative to Eint of −32.4 kcal mol−1 at the C2 site). Similar effects are observed for C H bond cleavage in quinoline and isoquinoline (Fig. 3). Arylation of pyridines at the C2 site and other N-heteroarenes at the ortho C H bond can be achieved by employing N-oxide derivatives [6,29,47–50]. Similar to a fluorine substituent, N-oxide functionality dramatically lowers the distortion energy of the C H bond at the ortho site due to the increase of the acidity of this bond. For example, when going from pyridine to pyridine Noxide, the C2 H bond heterolytic cleavage energy decreases from 413.1 kcal mol−1 to 393.1 kcal mol−1 and Edist (arene) decreases by 3.9 kcal mol−1 (Fig. 17). However, unlike CMD TS structures with fluoro-substituted benzenes, the corresponding CMD TS structure with pyridine N-oxide shows an increase in the interaction energy between the arene and the catalyst (−32.4 kcal mol−1 for a TS with pyridine and −35.7 kcal mol−1 for a TS with pyridine N-oxide, Fig. 17). This enhances the CMD reactivity further. As a result, Noxide derivatives of pyridine, pyrazine, isoquinoline, and thiazole are classes I and III arenes (Fig. 7) and have significantly lower (by 7–9 kcal mol−1 ) CMD activation barriers of C H bond cleavage than the original N-heterocycles (Fig. 3). Coordination of CuCl to pyridine (Fig. 17) [36] has a similar effect on the reactivity and regioselectivity of the CMD bond cleavage as N-oxide functionalization.

high reaction temperatures (110–150 ◦ C) are required [51–53]. This reactivity is consistent with the calculated CMD barriers for Nmethylimidazole, oxazole and thiazole (Fig. 18). Arylation at the C2 site using a palladium–carboxylate catalyst can be achieved through a N-oxide substrate [54] or by using a CuI additive [52,55–58]. The higher reactivity with a change of regioselectivity (C2 > C5 > C4) for thiazole N-oxide [54] and the effect of CuI additives has been rationalized using the CMD pathway [19,20]. The calculated CMD barriers for the three C H bonds of azoles indicate that the most reactive C H bond for PdII -catalyzed arylation is at the C5 site (Figs. 18 and 19). The Gibbs free energy barrier for the CMD cleavage of the C2 H bond is ∼1.5 kcal mol−1 higher than the cleavage of the C5 H bond. The C5 H bond is more reactive than the other two C H bonds due to the stronger electronic interaction between the PdII –acetate catalyst and the azole at the C5 site (−49.3 kcal mol−1 for C5 vs. −42.5 and −42.6 kcal mol−1 for C2 and C4 in N-methylimidazole) [36]. This is a signature of class II arenes for which the nucleophilicity of the arene carbon sites controls the regioselectivity of arylation [20]. In agreement with this, the Pd C5 bond order in the CMD transition state with the C5 H bond being cleaved has the highest value relative to the Pd C bond orders in the CMD TS structures with C2 H and C4 H bonds being cleaved [36]. When electron-withdrawing groups (such as an ester group) is attached to azoles at the C4 position, the gap between the CMD activation energies at the C2 and C5 sites are reduced to such an extent that changing the solvent and the PdII ligand can result in poor C2/C5 selectivity [59]. When N-methylimidazole is coordinated to CuI , all C H bonds become activated for the CMD process (Figs. 18 and 19). Cleavage of the C H bond at C2 site becomes the

2.5. Reactivity of azoles Understanding the reactivity of azoles comes from recognizing that the C5 site is the most nucleophilic site while the C H bond at the C2 site is considered to be the most acidic among the three C H bonds [36,37,51]. Noteworthy that the DFT calculations for free N-methylimidazole and oxazole showed that the gas-phase acidity of the C H bonds at the C2 and C5 are very close [36]. In most cases, arylation at C5 is preferred and fairly

Fig. 19. Gibbs free energies of activation (G‡ 298 K ), arene distortion energies and catalyst–arene interaction energies for cleavage (via the CMD pathway) of C2 H and C5 H bonds of N-methylimidazole and CuCl(N-methylimidazole) using the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst.

S.I. Gorelsky / Coordination Chemistry Reviews 257 (2013) 153–164 Table 3 Activation barriers and distortion–interaction analysis (kcal mol−1 ) for CMD C5 H bond cleavage of C2 substituted thiophenes with the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst.

NC4 H8 CN F Cl OMe CO2 Me Ph H Me Ac

G‡ 298 K

E‡

Edist (PdL)a

Edist (ArH)b

Eint c

23.2 23.9 24.0 24.4 24.5 25.2 25.2 25.6 25.8 25.9

12.3 14.1 13.8 14.3 14.0 15.6 15.3 15.9 15.6 16.0

20.0 16.4 17.6 17.4 18.5 17.8 17.4 17.3 17.8 16.4

47.6 34.8 39.6 37.9 42.4 37.3 39.3 39.9 40.7 36.5

−55.3 −37.1 −43.4 −41.0 −46.9 −39.5 −41.4 −41.4 −42.9 −37.0

Data for nonsubstituted thiophene are shown in bold. a The distortion energy for the [Pd(C6 H5 )(PMe3 )(OAc)] catalyst. b The distortion energy of the arene substrate. c The electronic interaction energy between the catalyst and the arene substrate.

lowest-energy process due to decrease of the arene distortion energy from 41.0 kcal mol−1 for N-methylimidazole to 33.7 kcal mol−1 for the adduct of N-methylimidazole with CuCl and increase in the electronic interaction energy between the catalyst and the substrate (−44.9 kcal mol−1 for [CuCl(N-methylimidazole)] vs. −42.6 kcal mol−1 for N-methylimidazole). Similar change in reactivity is observed when oxazole is coordinated to CuI (Fig. 17). The significant decrease in the distortion energy can be explained by very dramatic increase of azole C H bond acidities after coordination to CuI [36]. The most significant change in the acidity is at the C2 site, followed by the C4 site and then by the C5 site. The charge donation from the azole ligand to CuI induces this increase in C H bond acidities. Since the arylation reactivity of other azoles is similar to that of N-methylimidazole and oxazole [58], these results (activation of C H bonds for CMD cleavage by metal coordination and switch in regioselectivity from C5 to C2) apply to other azoles as well. The discovery of a highly efficient catalytic system utilizing a PdII /CuI cocatalyst for arylation of benzothiazoles [60] is in good agreement with this proposal. 2.6. Reactivity of thiophenes The arylation of thiophenes under standard CMD reaction/catalyst conditions always results in functionalization of C␣ H bonds (Figs. 3 and 8). Competition experiments for direct arylation at the C5 site of C2 substituted thiophenes provided the data required for comparison of the experimental reactivity of these thiophenes with the calculated barriers of C H bond cleavage (Fig. 5). The distortion–interaction analysis of the CMD TS structures for thiophenes highlights the influence of the substituents on both the distortion energy of the arene and the arene–catalyst interaction energy (Table 3). ␲-Nucleophilic thiophenes benefit from more negative Eint although this effect is partially counterbalanced by an increase in the arene distortion energy, Edist (ArH). Electronwithdrawing groups, such as acetyl, ester, fluorine and nitrile, reduce the energetic penalties for the arene distortions, but also reduce the magnitude of the interaction energy between the substrate and the catalyst. A closer examination of the distortion–interaction parameters revealed a correlation with the nature of the C2 substituent. Indeed, plotting of −Eint as a function of Hammett  p constants for the substituent highlights the relationship between the ␲-nucleophilicity of the arenes and their interaction with the palladium–acetate catalyst (Fig. 20, black circles). The beneficial effects of electron donating groups on the Eint values are partially offset by the

60 -Eint

50

E / kcal mol-1

C2 substituent

163

40

Edist(ArH)

30 20

Edist(PdL)

10 -1.0 -0.8 -0.6 -0.4 -0.2

σp

0.0

0.2

0.4

0.6

Fig. 20. Distortion–interaction parameters (kcal mol−1 ) for the PdII -catalyzed cleavage of the C5 H bonds (via the CMD pathway) as a function of  p values for C2 substituted thiophenes. The solid lines show the linear correlations.

increased Edist (ArH) penalties (Fig. 20, open squares). The third factor is Edist (PdL) (Fig. 20, black squares). The small dependence of Edist (PdL) on the arene nucleophilicity can be rationalized by the fact that arenes with high nucleophilicity and, thus, with stronger catalyst–arene interaction are expected to cause greater distortion of the metal–acetate catalyst to accommodate the incoming substrate. 3. Conclusions and outlook In the last five years, great progress has been achieved in understanding crucial steps of direct arylation mechanism. One important step in the advancing this chemistry was a realization that, under the standard reaction conditions with palladium–carboxylate catalysts, the CMD mechanism is not just applicable for electron-deficient arenes, but for a very wide range of arene substrates. Moreover, we also have learned that direct arylation reactions catalyzed by other transition metal catalysts have many common features and contributions to reactivity with Pd-catalyzed direct arylations [61,62]. However, the story is far from being complete. New discoveries in understanding the finer details of the reaction mechanism are being made [22,30,63] and they allow us to push the success of direct and oxidative arylation reactions to new frontiers. The distortion–interaction analysis of the C H bond cleavage of a wide range of (hetero)arenes through the concerted metalation–deprotonation pathway allows us to quantify the contributions to reactivity. Based on this analysis, (hetero)arenes can be divided into three classes. For class I arenes, the regioselectivity of C H bond functionalization is controlled by the difference in the arene distortion energies. Class II includes the (hetero)arenes for which interaction energies with the metal catalyst are the determining factor in reactivity. Class III arenes are the (hetero)arenes in which both the distortion and interaction energies enhance the functionalization of one particular C H bond. For most class I and III (hetero)arenes, regioselectivity of arylation can be derived from C H acidity of free arenes: the arylation occurs at the most acidic C H bond. Functional groups, such as fluoro- and chloro-substituents, and N-oxide derivatives, activate one or more C H bond of arene towards cleavage by lowering the distortion energy of arene. There is a relationship between the distortion energies of arenes in the CMD process and the deprotonation energies of the C H bonds (C H bond acidities): arenes with acidic C H bonds have low distortion energies for the CMD process. Electron-deficient arenes exhibit smaller C H bond elongation in the CMD TS structures than the electron-rich arenes. The C H bond out-of-plane

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bending energy penalty for different arenes have a fairly constant value. The nucleophilicity of thiophenes evaluated by the Hammett  p values correlates with not just the catalyst–substrate interaction energies but also with the distortion energies of the substrate and of the catalyst. The reactivity and regioselectivity of direct arylation of heteroarenes is also tuned by metal coordination. Similar to the effect of non-metallic electron-withdrawing groups, metal coordination to heteroarene activates C H bonds of arene towards cleavage by lowering the distortion energy of arene. One example of such a case is the CMD reactivity of azoles. In the absence of CuI -azole coordination, the most reactive C H bond is at C5 site. When the N atom of azole is bound to CuI , all C H bonds undergo activation for the CMD process due to a significant increase in C H bond acidities but the most reactive C H bond is now at the C2 site. This type of substrate activation and tuning of regioselectivity by metal coordination to heteroarenes can potentially be used in direct arylation and related reactions [64] with C H bond cleavage of other heteroarenes. Acknowledgments The author would like to thank the Centre for Catalysis Research and Innovation (CCRI) and the University of Ottawa for supporting this work. References [1] J. Hassan, M. Savignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 102 (2002) 1359. [2] F. Diederich, P.J. Stang (Eds.), Metal-Catalyzed Cross-Coupling Reactions, WileyVCH, New York, 1998. [3] D. Alberico, M.E. Scott, M. Lautens, Chem. Rev. 107 (2007) 174. [4] I.V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 36 (2007) 1173. [5] T. Satoh, M. Miura, Chem. Lett. 36 (2007) 200. [6] L.C. Campeau, D.R. Stuart, K. Fagnou, Aldrichim. Acta 40 (2007) 35. [7] G.P. McGlacken, L.M. Bateman, Chem. Soc. Rev. 38 (2009) 2447. [8] X. Chen, K.M. Engle, D.H. Wang, J.Q. Yu, Angew. Chem. Int. Ed. 48 (2009) 5094. [9] A.A. Kulkarni, O. Daugulis, Synthesis (2009) 4087. [10] F. Bellina, R. Rossi, Tetrahedron 65 (2009) 10269. [11] L. Ackermann, A. Althammer, S. Fenner, Angew. Chem. Int. Ed. 48 (2009) 201. [12] T.W. Lyons, M.S. Sanford, Chem. Rev. 110 (2011) 1147. [13] L. Ackermann, Chem. Rev. 111 (2011) 1315. [14] J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, Wiley-Interscience, New York, 1985. [15] I. Mayer, Chem. Phys. Lett. 97 (1983) 270. [16] A.E. Reed, L.A. Curtiss, F. Weinhold, Chem. Rev. 88 (1988) 899. [17] A.E. Reed, R.B. Weinstock, F. Weinhold, J. Chem. Phys. 83 (1985) 735. [18] S.-Y. Tang, Q.-X. Guo, Y. Fu, Chem. Eur. J. 17 (2011) 13866. [19] S.I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 130 (2008) 10848. [20] S.I. Gorelsky, D. Lapointe, K. Fagnou, J. Org. Chem. 77 (2012) 658. [21] M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 128 (2006) 16496.

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