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Catalyst-counterion Controlled, Regioselective C-C Bond Cleavage in 1Azabiphenylene: Synthesis of Selectively Substituted Benzoisoquinolines David Frejka, Jan Ul#, Eric Assen B. Kantchev, Ivana Cisarova, and Martin Kotora ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01874 • Publication Date (Web): 24 Sep 2018 Downloaded from http://pubs.acs.org on September 24, 2018

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ACS Catalysis

Catalyst-counterion Controlled, Regioselective C-C Bond Cleavage in 1-Azabiphenylene: Synthesis of Selectively Substituted Benzoisoquinolines David Frejka,a Jan Ulč,a Eric Assen B. Kantchev,b* Ivana Císařová,c Martin Kotoraa* a

Department of Organic Chemistry, Faculty of Science, Charles University, Albertov 2030, 128

43 Prague 2, Czech Republic. b

School of Chemistry and Chemical Engineering, Hefei University of Technology, 193 Tunxi

Rd Hefei 230009 China c

Department of Inorganic Chemistry, Faculty of Science, Charles University, Albertov 2030,

128 43 Prague 2, Czech Republic

ABSTRACT: Catalytic C−C bond cleavage processes followed by further transformations are some of the most fascinating reactions in chemistry and valuable organic synthesis tools. Herein, we demonstrate that the regioselectivity of C−C bond cleavage in 1-azabiphenylene and its derivatives can be switched by using neutral or cationic transition metal catalysts. The use of the former leads to selective distal C−C bond cleavage (with respect to the position of the nitrogen atom), whereas the latter to selective proximal bond cleavage. This process enables synthesis of a variety of complex heterocycles by regioselective C−C bond cleavage switched on demand.

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Density functional theory calculations (SMD/M06/DGDZVP level of theory) show that the regioselectivity is a result of kinetically controlled oxidative addition into the C−C bond. In neutral complexes the transition states (TS) for distal cleavage have lower energy, in agreement with experiment. For the cationic catalyst, the proximal TSs are stabilized presumably by relieving the Cl−N dipole-dipole repulsion when the Rh-bound Cl is removed whereas the distal TSs remain largely unaffected.

KEYWORDS. C−C activation, catalytic cycloaddition, alkynes, regioselective catalysis, iridium, rhodium

Introduction Substituted arenes and heteroarenes are key structural motifs in numerous compounds of relevance to medicinal chemistry,1 crop protection2 and material sciences.3 The synthesis of decorated arenes and heteroarenes has evolved enormously over the past 60 years from using mostly conventional stoichiometric methods that proceed under harsh reaction conditions4 and generate high amounts of byproducts to more atom-economical and mild transition-metal catalyzed methods.5 Despite this remarkable progress, controlling regio- or site-selectivity in both classes of transformations remains challenging. One of the potentially powerful and hitherto rather unexplored approaches to substituted aromatics is the use of aromatic compounds possessing strained rings. Cleavage of C−C bonds therein followed by subsequent reactions with unsaturated substrates leads to products possessing expanded π-conjugated ring systems. However, controlling the site-selectivity of strained ring C–C bond activations is one of the main hurdles for the development of synthetically useful methodologies.


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ACS Catalysis

Strained carbocyclic compounds that contain 3 or 4 atoms integrated within larger ring systems are the ideal candidates for synthetic conversions driven by relief of the ring strain.6,7 The distortion of bond geometry in strained ring systems is inherently destabilizing and this makes them behave as ‘spring-loaded’ reagents that react efficiently and often form unique products.8 Such compounds include biphenylene and its derivatives. Biphenylene possesses strained hence rather weak σ-C–C bonds (BDE of 65 kcal mol-1) within a cyclobutadiene ring.9,10 In spite of that, its thermal cleavage requires rather high reaction temperatures. For instance, the reaction of biphenylene with diphenylacetylene proceeds with reasonable rate only at temperatures above 350 °C.11 The cleavage of the C−C bond in biphenylene is greatly facilitated by low-valent transition metal complexes to provide the corresponding dibenzometallacyclopentadienes.9,10 As typical examples, the insertion into the C−C bond can be accomplished with complexes of Fe,12,13 Co,14,15 Rh,14,16-18 Ir,16,17,19-21 Ni,22-28 Pd,29,30 Pt,31 and Au.32,33 Introduction of heteroatoms in the basic biphenylene system would result in complex heterocyclic compounds upon C−C cleavage, increasing the value of this transformation. However, there has been reported just one example of Ir-mediated cleavage of 1-(pyrid-2yl)biphenylene forming the corresponding cyclometalated complexes.34 Herein, we report the Ir and/or Rh catalyzed selective C−C bond cleavage in 1-azabiphenylene at the proximal or the distal C-C bond with subsequent reaction with alkynes giving rise either to benzo[h]quinolines or benzo[f]quinolines with very high selectivity (Scheme 1). This methodology represents a new approach to the catalytic synthesis of more complex conjugated planar azaaromatic systems and also demonstrates a unique example of a selective catalytic C−C bond cleavage.


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Scheme 1. Transition metal-induced cleavage of the distal or proximal C−C bonds in 1azabiphenylene.

Results and discussion At the outset of our study on the C−C bond activation in azabiphenylene, we focused on the optimal reaction conditions developed for cleavage of biphenylene by this laboratory,21 i.e. the use of Ir and Rh complexes with 1,2-bis(diphenylphosphino)ethane (dppe). The substrates were 6,7bis(trimethylsilyl)-1-azabiphenylene (1) and 1-azabiphenylene (2), which were prepared according to previously reported procedures.35 Diphenylethyne (3a) and 4-octyne (3b) were selected as representative alkynes. After screening numerous reaction conditions and carrying out the reaction at variable temperatures using both conventional heating and microwave irradiation (see Tables S1-S5), the best results were obtained in toluene under microwave heating to 170 °C. Firstly, it was found that neutral Ir or Rh complexes ([Ir(COD)Cl]2 or [Rh(COD)Cl]2) in combination with dppe catalyzed the reaction of bis(trimethylsilyl)azabiphenylene (1) with diphenylethyne (3a) at the distal C−C bond (the blue bond) giving rise solely to benzo[h]quinoline 4a in 82 and 84% yields, respectively (Table 1, Entries 1 and 2). On the other hand, the use of a cationic Rh-complex prepared from [Rh(COD)2]BF4 and dppe provided preferentially benzo[f]quinoline 5a by the proximal C−C bond (the red bond) cleavage in 43% yield (Entry 3). The structures of 4a and 5a were unequivocally


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ACS Catalysis

confirmed by a single crystal X-ray analysis (Figures 1 and 2). Similarly, the reactions of 1 with 3b catalyzed by the same Ir or Rh complexes gave benzo[h]quinoline 4b or benzo[f]quinoline 5b in 74 and 67% yields, respectively (Entry 4 and 5). It should be noted that although the use of cationic Rh complex preferentially afforded the benzo[f]quinoline derivatives 5a and 5b, formation of small amounts of the benzo[h]quinoline derivatives 4a and 4b could not be suppressed.

Table 1. Catalyst-controlled selective C−C bond cleavage in 1-azabiphenylene derivatives. R2 R1 R2

R2

3a, R2 = Ph 3b, R2 = Pr

1, R1 = TMS 2, R1 = H

R1

Catalyst A, B, C solvent, MW, 170 °C, 1 h

R1

N

R2

R1

R1

+ N

N R1

R2 R2 5, R1 = TMS 7, R1 = H

4, R1 = TMS 6, R1 = H

Entry

1 or 2

Alkyne 3

Catalystsa

4 or 6

Yield (%)b

5 or 7

Yield (%)b

1

1

3a

A

4a

82 (70)

5a

—c

2

1

3a

B

4a

84 (70)

5a

—c

3

1

3a

C

4a

7 (2)

5a

43 (37)

4

1

3b

A

4b

74 (44)

5b

—c

5

1

3b

C

4b

12 (9)

5b

67 (32)

6

2

3a

A

6a

26 (19)

7a

—c

7

2

3a

C

6a

—c

7a

4 (3)

8

2

3b

A

6b

33 (28)

7b

—c

9

2

3b

C

6b

—c

7b

8 (4)

a

Catalysts: A = [Ir(COD)Cl]2 (10 mol%), dppe (20 mol%), toluene; B = [Rh(CODCl)]2 (10 mol%), dppe (20 mol%), toluene; C = [Rh(COD)2]BF4 (10 mol%), dppe (10 mol%), THF. b 1H NMR yield, internal standard mesitylene. Isolated yields are in parentheses. c Not detected.


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The same set of experiments was carried out with azabiphenylene 2 under conditions A and B. The reactions proceeded with similar results, i.e. the use of the neutral Ir (conditions A, Entries 6 and 8) and the cationic Rh (conditions C, Entries 7 and 9) complexes provided exclusively either benzo[h]quinoline 6 or benzo[f]quinoline 7. However, the yields of the products were much lower indicating the lower reactivity of 2.

Figure 1. ORTEP drawings of the single-crystal X-ray structure of 4a. Thermal ellipsoids are shown at 30% probability.

Figure 2. ORTEP drawings of the single-crystal X-ray structure of 5a. Thermal ellipsoids are shown at 30% probability.


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With basic reaction conditions in hand, we investigated whether further tuning of the catalytic system by changing of the diphosphane ligand would have a beneficial effect on the course of the reaction (Table 2). Others and we have previously shown that by changing the coordination sphere environment by ligand variation is possible not only to control the yield but also regioselectivity (e.g. in cyclotrimerization reaction36). These effects are generally considered to be associated with the ligand’s bite angle and hence the geometry of the reactive intermediates. In addition to dppe, the following bidentate ligands were tested: bis(diphenylphosphino)methane (dppm), 1,3bis(diphenylphosphino)propane

(dppp),

1,4-bis(diphenylphosphino)butane

(dppb),

1,2-

bis(diphenylphosphino)benzene (dppbe), 1,1’-bis(diphenylphosphino)ferocene (dppf), and (rac)2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP). The reaction of 1 with diphenylethyne (3a) under the standard conditions (toluene, MW, 170 °C, 1h) was tested for cleavage of the distal C−C bond with the neutral Ir catalyst (A: ligand (20 mol%), [Ir(COD)Cl]2 (10 mol%, toluene) and for cleavage of the proximal C−C bond with the cationic Rh catalyst (B: ligand (10 mol%), [Rh(COD)2]BF4 (10 mol%), THF). The original conditions for cleaving the distal C−C bond in 3a using dppe provided solely regioisomer 4a in 82% yield (Entry 3). Higher yields (94 and 93%) were obtained with dppbe (Entry 2) and dppp (Entry 4) that have bite angles (83 and 91°, respectively) similar to dppe (85°). Dppm, a ligand with a considerably smaller bite angle (72°) gave rise to 3a in a good yield (77%, Entry 1) as well. On the other hand, ligands with larger bite angles (BINAP, 92°; dppf, 96°; dppb, 98°) failed (113% yields, Entries 5-7). Gratifyingly, in all cases only 4a was detected. A similar trend was also observed in the cleavage of the proximal C−C bond in 3a under Rhcatalysis. The original conditions using dppe provided predominantly 5a in 43% yield (Entry 3). Higher yields were obtained with dppbe, dppp and BINAP (50, 74, and 50%, respectively; Entries


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2, 4, and 5) whereas the use of dppf and dppb failed to provide products (Entries 6 and 7). With dppm, 5a was formed in 29% yield (Entry 1). Since these results clearly showed that dppp was the optimal ligand, all further experiments were carried out with it.

Table 2. Ligand effects in the selective C−C cleavage.

[Ir(COD)Cl]2,

toluene

[Rh(COD)2]BF4

THF

Entry Ligand

Bite angle 4a, Yield (%)a

5a, Yield (%)a 4a, Yield (%)a

5a, Yield (%)a

1

dppm

72°

77

—b

3

29

2

dppbe

83°

94

—b

4

50

3

dppe

85°

82

—b

7

43

4

dppp

91°

93

—b

14

74

5

BINAP

92°

13

—b

4

50

6

dppf

96°

1

—b

—b

—b

7

dppb

98°

2

—b

—b

5

a 1H

NMR yield (mesitylene as the internal standard). b Not detected.

The reaction of 1 with diphenylethyne 3a was also performed with a stoichiometric amount of [Ir(COD)Cl]2 (50 mol%)/dppp (100 mol%) and [Rh(COD)2]BF4 (100 mol%)/dppp (100 mol%). In the former case, as expected, only regioisomer 4a was detected in the reaction mixture in 80% yield (1H NMR) and isolated in 76% yield. In the latter case, regioisomer 5a was detected in 85% yield (isolated in 79% yield) along with traces of 4a (~2%) according to 1H NMR.


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In addition, the reaction of 1 with diphenylethyne (3a) was carried out at different catalytic loadings (see Table S3). The results indicate that high yields of 4a (87-91%) could be obtained even by using 5 mol%, but prolonged reaction time of 4 h was required (Entries 3 and 4). Yields of 4a were in the range of 28-31% by using 1 mol% of the catalyst regardless of the reaction time (Entries 5-8). With optimized reaction conditions and ligand at hand, the selective C−C bond cleavage and reactions with various disubstituted alkynes under Ir and Rh-catalysis was evaluated. The distal C−C bond cleavage proceeded well under Ir-catalysis. Notably, the proximal bond cleavage leading to products 5 was not observed in all cases (Figure 3). Thus the reaction with bis(4trifluoromethylphenyl)ethyne

(3c),

bis(4-bromophenyl)ethyne

(3d),

and

bis(4-

methoxyphenyl)ethyne (3e) gave rise to the corresponding benzo[h]quinolines 4c , 4d, and 4e in good yields (67, 57, and 78%, respectively). The structure of 4e was unequivocally confirmed by a single crystal X-ray analysis (see Figures S5). The expected product 4f was also obtained with bis(2-thienyl)ethyne (3f), albeit in a somewhat lower yield of 37%. The reaction with 1phenylpropyne (3g) furnished as 4.7/1 mixture of 4g and 4g’ regioisomers in the combined 91% yield. The structures of 4g and 4g’ were unequivocally confirmed by a single crystal X-ray analysis (see Figures S3 and S4). A similar result was obtained with 1-(4-trifluoromethylphenyl)-2-(4methoxyphenyl)ethyne (3h) where regioisomers 4h and 4h’ were formed in 1/1.5 ratio and overall yield of 76%.


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F3C

CF3

Br

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Br

TMS

MeO

OMe

TMS

TMS

N

N

N

TMS 4c, 67% (51%)

TMS 4d, 57% (35%)

TMS 4e, 78 (63%)

S S

Me

Ph

Ph

TMS N

TMS N

TMS 4f, 37% (25%) MeO

Me

TMS N

TMS 4g, 75% (68%) CF3

+

TMS 4g', 16% (12%)

F3C

OMe

TMS N

TMS N

TMS 4h, 30% (16%) + 4h', 46% (27%)

TMS

Figure 3. The distal C−C bond cleavage in 1a under Ir-catalysis. Reaction conditions: [Ir(COD)Cl]2 (10 mol%) dppp (20 mol%), toluene, MW, 170 °C, 1 h. 1H NMR yields (mesitylene was used as the internal standard), isolated yields are in parentheses. Next, the proximal C−C bond cleavage was attempted (Table 3). Compared to the Ir-catalyzed distal bond cleavage, the Rh-catalyzed proximal cleavage proceeded with lower regioselectivity. The results obtained with diphenylethyne (3a) and 4-octyne (3b) are displayed in Table 1. The reactions with symmetrically substituted alkynes such as bis(4-trifluoromethylphenyl)ethyne (3c), bis(4-methoxyphenyl)ethyne (3e), and bis(2-thienyl)ethyne (3f) furnished predominantly the corresponding benzo[f]quinolines 5c, 5e, and 5f in moderate yields (39, 36, and 31%, respectively)


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ACS Catalysis

(Entries 1, 3, and 4). Small amounts of the distal cleavage products, benzo[h]quinolines 4c, 4e, and 4f, were also detected (6, 9, and 3%, respectively). Interestingly, the reaction with bis(4bromophenyl)ethyne (3d) proceeded preferentially through the distal bond cleavage giving rise to benzo[h]quinoline 4d in 22% yield, whereas the expected benzo[f]quinoline 5d was detected in only 4% yield (Entry 2). Although the reaction with 1-phenylpropyne (3g) proceeded with a high overall yield (78%), it provided a mixture of all possible regioisomers. The desired regioisomeric benzo[f]quinolines 5g and 5g’ were formed in 24 and 28% yields, whereas the regioisomeric benzo[h]quinolines − 4g and 4g’ − were both formed in 13% yield. The structure of 5g’ was unequivocally confirmed by a single crystal X-ray analysis (see Figure S6). In the case of reaction of 1-(4-trifluoromethylphenyl)-2-(4-methoxyphenyl)ethyne (3h) formation of regioisomer 5h’ was observed in 10%. Other products (5h, 4h, and 4h’) were not detected in the reaction mixture.


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Table 3. Catalyst-controlled selective C-C bond cleavage in 1-azabiphenylene derivatives. TMS

TMS

TMS

TMS N

N [Rh(COD)2]BF4 (10 mol%) dppp (10 mol%) THF, 170 °C, 1 h, MW

R1

R2 5

R1

R2

+

1 R1

R2 3 (1 eq)

R2

R1 5'

R2

R1

TMS N 4

a 1H

TMS N

TMS

4'

TMS

Entry Alkyne 3

R1

R2

5

Yield (%)a

4

Yield (%)a

1

3c

4-CF3-C6H4

4-CF3-C6H4

5c

39 (29)

4c

6 (4)

2

3d

4-Br-C6H4

4-Br-C6H4

5d

4 (2)

4d

22 (19)

3

3e

4-MeOC6H4

4-MeOC6H4

5e

36 (30)

4e

9 (-)b

4

3f

2-Thienyl

2-Thienyl

5f

31 (26)

4f

3 (-)b

5

3g

Ph

Me

5g + 5g’ 24 (19) + 28 (27) 4g + 4g’ 13 (10) + 13 (10)

6

3h

4-MeOC6H4

4-CF3-C6H4

5h + 5h’ ― c +10 (6)

4h + 4h’ ― c

NMR yield (mesitylene as the internal standard). b Products were not isolated. c Not detected.

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ACS Catalysis

Although the results of the C−C bond cleavage reaction with azabiphenylene 2 with diphenylethyne (3a) and 4-propyne (3b) indicated its lower reactivity in comparison with 1 (see results in Table 1), reactions were carried out also with bis(thien-2-yl)phenylethyne (3f) (Scheme 2). As far as regioselectivity was concerned, it proceeded as expected: the reaction catalyzed by the neutral Ir complex gave product of the distal cleavage 7 and the reaction using the Rh cationic complex furnished the product of the proximal cleavage 8, but in low yields of 3 and 22%, respectively. No other products were isolated or detected in the respective reaction mixtures.

Scheme 2. Reaction of di(thien-2-yl)phenylethyne 3f with 2 under Ir or Rh catalysis. 1H NMR yields (mesitylene was used as the internal standard), isolated yields are in parentheses. Since the reactions with azabiphenylene 2 proceeded with lower yields than with 6,7bis(trimethylsilyl)azabiphenylene 1, indicating that the presence of electron-donating trimethylsilyl

groups

enhances

reactivity,

we

investigated

the

reactivity

of

6,7-

dichloroazabiphenylene 9 (prepared by the reaction of 1 with NCS) to evaluate the effect of electron-withdrawing substituents (Table 4). The reaction of 9 with diphenylethyne 3a in the presence of the neutral Ir-catalyst (Entry 1) furnished benzo[h]quinoline 10 in 57% (1H NMR) and


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49% isolated yield. The presence of benzo[f]quinoline 11 was not detected. As expected, the reaction of 9 with 3a in the presence of the cationic Rh-catalyst (Entry 2) gave rise to a mixture of regioisomers 10 and 11 in 4/3 ratio and the combined yield of 19% (1H NMR) and 13% isolated yield along with other intractable side products. Unlike the previous reactions carried out in the presence of stoichiometric amounts of Ir and Rh complexes, the desired compounds were obtained in rather low yields along with a number of intractable side-products. The reaction of 9 with 3a using a stoichiometric amount of the Ir-catalyst (Entry 3) proceeded with full conversion of the starting material. However, the expected product 10 was detected in only 10% yield (1H NMR). Unexpectedly, workup of the reaction mixture furnished a solid substance in 80% yield (1H NMR) and isolated in 69% yield. Its recrystallization from dichloromethane/cyclohexane and X-ray analysis of a single crystal revealed this product to be a stable, coordinatively saturated (18e-) octahedral Ir complex (10-Ir ; Figure 4) formed by C-H activation of 10 by the Ir-catalyst; 10-Ir is a rare example of an Ir hydride compound (Ir-H, 1H NMR δ -16.99 (t, JH-P = 16.1 Hz) ligated with bidentate phosphanes.37 It reasonable to assume that the higher acidity of the C-H bond orthoto Cl38.39 substantially contributed to its easy formation. This clearly demonstrated full conversion of 9 into products having the benzo[h]quinolone framework. The same reaction carried out in the presence of a stoichiometric amount of the cationic Rh-catalyst (Entry 4) provided a mixture in which only regioisomer 11 was detected in 25% yield (1H NMR).


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ACS Catalysis

Table 4. C−C cleavage in 9 by catalytic or stoichiometric amounts of Ir- and Rh-catalysts. Ph

Ph

Cl

Ir or Rh complex Cl solvent, 170 °C, 1 h, MW N

Cl 9

3a (1 eq)

Cl Cl or/and N N 10

Cl

Ph

11

Ph

Entry Catalytic system

10, Yield (%)a

11, Yield (%)a

1

[Ir(COD)2Cl] (10 mol%) dppp (20 mol%), toluene

57 (49)

―b

2

[Rh(COD)2]BF4 (10 mol%) dppp (10 mol%), THF

11 (8)

8 (5)

3

[Ir(COD)2Cl] (50 mol%) dppp (100 mol%), toluene

10 (7)

―b

4

[Rh(COD)2]BF4 (100 mol%) dppp (100 mol%), THF

―b

27 (23)

a 1H

NMR yield (mesitylene as the internal standard). Isolated yields in parentheses. b Not detected.

Figure 4. ORTEP drawings of the single-crystal X-ray structure of 10-Ir. Thermal ellipsoids are shown at 30% probability.


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Modeling of regioselectivity by DFT calculations As far as individual steps the reaction mechanism of the C−C bond cleavage are concerned, earlier studies have shown that the existence of η6-arene (coordination to the aromatic ring) and η4-dibenzocyclobutadiene complexes might precede the C−C bond cleavage. These complexes were observed by NMR studies of one case of Rh-catalyzed process and also supported by DFT calculations.18 Recently, a η6-arene complex was also identified in one case of Au-catalyzed process.32 Formation of both η6- and η4-complexes and their fluxional behavior was observed in the case polyphenylene Co-complexes.40 The putative catalytic cycle involves oxidative addition (OA) into the 4-mebered ring, migratory insertion of the alkyne (MI), and reductive elimination (RE); each substrate binds before the first and the second steps (Scheme 3).

1/2 [Rh(COD)Cl]2 R

COD

R

Ph2P

PPh2

Ph2P

PPh2 Rh Cl CAT

reductive elimination (RE) Ph2P Rh Cl

PPh2 R

SM oxidative addition (OA)

Ph2P PPh2 Cl Rh

R

OA-P R R migratory insertion (MI)

Scheme 3. The putative catalytic cycle of C-C bond cleavage in biphenylene This cycle is supported by the corresponding metallacycles having been isolated in many cases and their structure confirmed by a single crystal X-ray diffraction methods (vide supra). The


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ACS Catalysis

regioselectivity (proximal vs. distal, Scheme 1) of the 4-membered ring cleavage in the case of 1azabiphenylene (2) is determined during oxidative addition (OA) provided it is irreversible. In order to probe the thermodynamics and selectivity of OA, we performed DFT calculations using the state-of-the-art, dispersion interaction-corrected general purpose M06 functional41 combined with the full-electron, DFT-optimized DeGauss double-ζ + valence polarization (DGDZVP) basis set.42 The solvent (toluene) was modeled implicitly by the recent SMD variant43 of the Polarisable Continuum Model (PCM). The OA Gibbs energy profile was calculated at 120 °C for biphenylene (12) as the starting material (SM) and [(dppe)RhCl] (13) as the putative catalyst (CAT; Figure 5a). The product of the reaction (OA-P) is a penta-coordinate, square-pyramidal Rh(III) complex that could exist in two possible isomers, with the Cl occupying either one of the 4 base coordination sites or the apex. The relative Gibbs energy of the former (16a) is -18.1 kcal mol-1 whereas that of the latter (16b) is 3.3 kcal mol-1. This indicates that: 1) OA is irreversible; 2) the product is the Clbasal isomer. The Gibbs energy for OA-TS (15) leading to the Cl-basal product is 17.4 kcal mol-1 (no such TS could be located leading to the endergonic Cl-apical product). The OA-TS arises from the π−complex of biphenylene and [(dppe)RhCl] (CPL). In the case described here, πcomplexation was found to occur in η2-fashion as expected for square-planar, 16-e- Rh(I) complexes. Five such complexes (14a-e) (see SI) differing by the position of the Rh atom relative to biphenylene could be located. The ∆G for these complexes range from -0.7 to 2.7 kcal mol-1. Among these, the (C1-C8b)→Rh complex (14a) derived from intrinsic reaction coordinate (IRC: see SI file) calculation staring from TS 12 was the most stable. However, complexes arising from π-coordination at the 4-membered ring could not be found. This indicates that biphenylene complexation is reversible hence the selectivity of the OA depends only on the relative energies of the competing regioisomeric transition states (kinetic


ACS Catalysis

a)

20

b)

17.4 15

12 15 13 = [(dppe)RhCl] (CAT)

Cl apical

10 15

5 ∆G (kcal mol-1)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

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3.3

2.7 0

0.0

1.4 1.3

0.8

14b- e

16b

CH

N

dist

12 + 13 –0.7 14a

prox

-5

-10 CAT + -15 SM

-20

CPL

OA-TS OA-P –18.1

16a Cl basal

down 17a

up

down

up

17b

17c

17d

Figure 5. a) Oxidative addition reaction profile for the reaction of [(dppe)RhCl] and biphenylene. b) Substrate change from biphenylene to 1-azabiphenylene increases the number of OA pathways from 1 to 4.


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ACS Catalysis

Table 5. Oxidative addition barriers (∆G‡, kcal mol-1). ∆G‡ (kcal mol-1)b

Pathwaya

neutral

cationic

py-coordinatedc

-

17.4/21.3 (15)

-

-

dist/down

15.2/19.2 (17a) 15.8/17.6 (20a)

7.3/11.4 (23a)

dist/up

16.0/20.0 (17b) 16.1/18.1 (20b)

5.5/9.8 (23b)

prox/down 18.6/22.7 (17c)

11.3/13.8 (20c)

-0.2/4.7 (23c)

prox/up

21.1/24.9 (17d) 12.6/14.8 (20d)

3.3/7.5 (23d)

dist/down

14.7 (24a)

16.0 (25a)

6.7 (26a)

dist/up

16.0 (24b)

17.0 (25b)

5.5 (26b)

prox/down 17.5 (24c)

11.9 (25c)

-2.5 (26c)

9.8 (25d)

1.6 (26d)

prox/up

20.1 (24d)

a

Defined on Figure 5b. b Calculated at SMD(toluene, 393.15K)/M06/DGDZVP level of theory. For substrates 12 and 2, values calculated at SMD(toluene)/M06/def2-TZVP//SMD (toluene, 393.15K)/M06/DGDZVP are also shown after the solidus. ∆G‡ = ∆G(OATS) - (∆G(CAT) + ∆G(SM)). CAT = [(dppe)RhCl] (13) for “neutral”, [(dppe)Rh]+ (19) for “cationic”, and “py-coordinated”. Selected examples are shown on Figure 5. c[(dppe)Rh]+ + py → [(dppe)Rh(py)], ∆G = -15.6/-14.2 kcal mol-1.


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Page 20 of 32

control). Substituting biphenylene C1 to N (as in 2) multiples the number of OA pathways from 1 to 4 due to: 1) the two 4-member ring C−C bonds becoming non-equal (proximal, prox vs. distal, dist); 2) lowering of the symmetry (up vs. down defined as the position of the pyridine N relative to the Rh(I) coordination plane when the structure is viewed so that the Cl atom is positioned frontleft and the dppe ligand occupies the back; Figure 5b). OA at the distal C−C bond proceeds by a pair of dist OA-TSs having ∆G (Table 5) of 15.2 and 16.0 kcal mol-1, for the down (17a) and up (17b) isomers, respectively, leading to the corresponding OA products (18a,b) having ∆G of -20.7 and -21.0 kcal mol-1, respectively. That is, the major pathway is the one of kinetically-controlled distal cleavage giving a slightly less stable product, despite the possibility of initial Rh-pyridine coordination steering OA towards proximal cleavage. This selectivity predicted by DFT agrees with the experiment. The removal of the chloride leads to a reversal of the cleavage selectivity from the distal to the proximal C-C bond both in vitro as well in silico. Unsurprisingly, the selectivities in stoichiometric cleavage experiments were much closer to those predicted by DFT calculations, which are also stoichiometric by default. Calculating of the corresponding cationic, coordinatively saturated TSs arising from the cationic form of the catalyst [(dppe)Rh]+ (19) showed that the Gibbs energies of the dist OA-TS pair (Table 4) changed only slightly (down: from 15.2 to 15.8 (20a), up: from 16.0 to 16.1 (20b)) whereas those of the prox OA-TS pair were significantly lowered (down: from 18.6 to 11.3 (20c), up: from 21.1 to 12.6 (20d)). This suggests that the selectivity is not a consequence of substrate bias, but rather arises in the course of the reaction under the influence of the catalyst. The regioselectivity reversal can be most likely explained by relief of the strong dipole-dipole repulsion between the relatively negatively charged Cl and pyridine N. The Mulliken charges for the dist/down, dist/up, prox/down, and prox/up OA-TSs are -0.527, -0.525, -0.526, and -0.526


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ACS Catalysis

Figure 6. Structural plots and selected bond lengths of the lowest-energy OA-TSs.


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Page 22 of 32

for Cl, respectively, and -0.248, -0.259, -0.198, and -0.185 for N, respectively. This repulsive interaction is strongly distance dependent. The Cl-N interatomic distances in the dist OA-TS pair (down: 5.7869 Å, up: 5.7738 Å) are much longer than those in the prox pair (down: 3.4826 Å, up: 3.4996 Å). The cationic complexes being coordinatively unsaturated could coordinate the pyridine fragment found in the starting material as well as the products. To evaluate the effect of this phenomenon, we performed calculations on added coordination by simple pyridine (21). The Gibbs energy of the catalyst dropped by 15.6 kcal mol-1 upon coordination of a pyridine molecule to [(dppe)Rh]+ (16) to give [(dppe)Ph(py)]+ (22). The corresponding 4 py-coordinated OA-TSs (23a-d) underwent a change that was identical in direction but somewhat smaller in magnitude leading to an increase in the reaction barriers (Table 4). These results suggest that the OA (and, presumably, subsequent steps) with cationic catalysts proceeds by a series of pyridinecoordinated Rh (and, presumably, Ir) structures. However, pyridine coordination appears to increase the OA barrier in line with the observed diminished total yields with cationic catalysts. Nevertheless, the calculated barriers are of reasonable height suggesting OA is most likely not the rate-determining step of the catalytic cycle. The relatively low sensitivity of product yields and distribution on the electronic effect of substrate substituents indirectly confirms this notion. Additionally, the barriers associated with TSs 15, 17, 20, and 23 were recalculated at SMD(toluene)/M06/def2-TZVP//SMD(toluene, 393.15K)/M06/DGDZVP in order to improve the data accuracy. Def2-TZVP44 is a recent effective core potential (ECP) triple-ζ basis set recommended for quantitative DFT calculations of reaction energies. For all 4 TSs, there was a small, systematic increase of ∆∆G‡, confirming the selectivity trends determined with the smaller DGDZVP basis set. ∆∆G‡ for TS 17 for C-C bond cleavage in biphenylene (12) by the neutral increased by 3.9 kcal mol-1 from 17.4 to 21.3 kcal mol-1. The barriers associated with the analogous


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ACS Catalysis

4 isomeric TSs for C-C bond cleavage of substrate 2 by the neutral catalyst (17a-d) also increased by 3.8 - 4.1 kcal mol-1, confirming the preference for proximal cleavage. The barriers associated with the 4 isomeric TSs for C-C bond cleavage of substrate 2 by the cationic catalyst (17a-d) increased by 1.8 - 2.5 kcal mol-1, confirming the preference for distal cleavage. Pyridine coordination to the cationic catalyst was exothermic by 14.2 kcal mol-1 with def2-TZVP vs. 15.6 kcal mol-1 with DGDZVP. The barriers for the respective py-coordinated TSs 23a-d were again systematically increased by 4.1-4.9 kcal mol-1 with def2-TZVP relative to DGDZVP, without change in selectivity. Finally, we compared the OA-TSs arising from the di(trimethylsilyl) analog of 2, 1. The two silyl substituents had almost no effects on the barriers for the neutral complexes (Table 4). On the other hand, both cationic and py-coordinated OA-TSs experienced modest (

Catalyst-Counterion Controlled, Regioselective C ... - ACS Publications

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