Palladium-Catalyzed Cross-Coupling Reactions with Fluorinated

Communication pubs.acs.org/Organometallics

Palladium-Catalyzed Cross-Coupling Reactions with Fluorinated Substrates: Mechanistic Insights into the Undesired Hydrodehalogenation of Aryl Halides Meital Orbach,† Joyanta Choudhury,†,§ Michal Lahav,† Olena V. Zenkina,† Yael Diskin-Posner,‡ Gregory Leitus,‡ Mark A. Iron,‡ and Milko E. van der Boom*,† †

Departments of Organic Chemistry and ‡Chemical Research Support, The Weizmann Institute of Science, 76100 Rehovot, Israel S Supporting Information *

ABSTRACT: We report here that the undesired hydrodehalogenation in cross-coupling reactions with fluorinated substrates involves water as a possible hydrogen source. Moreover, the product distribution (hydrodehalogenation vs carbon−carbon coupling) can be controlled by varying the phosphine substituents. Significant hydrodehalogenation occurs prior to the formation of ArF−Pd(II)−Br complexes. DFT calculations were used to evaluate a direct hydrodehalogenation route with a phosphine and water. These findings provide new mechanistic insight into aryl−Br bond activation with fluorinated substrates and selective arene functionalization.

F

Chart 1. Molecular Structures of Compounds 1−7

luorinated compounds are widely used in the semiconductor and pharmaceutical industries. Their applications include electronic materials, solvents, lubricants, and phase-transfer catalysts.1 Despite their many applications, their formation is not trivial. The transition-metal-catalyzed direct arylation, olefination, and alkynylation of polyfluoroarenes have been reported recently.2 These and other cross-coupling reactions (e.g., Sonogashira, Heck, Suzuki) 3 to generate carbon−carbon bonds with fluorinated substrates are often hampered by the formation of strong metal−CF σ-bonds and other competitive processes.4 In 2001, Espinet and Milstein reported the first Heck catalysis with fluorinated aryl halides, 5 three decades after its initial discovery.6 Likewise, it took about two decades after the initial report on the Sonogashira reaction to apply it to fluorinated substrates.7 One commonly observed byproduct of cross-coupling reactions is hydrodehalogenation (ArF−X → ArF−H; X = halide) of fluorinated aryl halides, which affects the efficiency and selectivity of the overall catalytic process.5,8 Here we report insight into some of the key steps involved in the Sonogashira and related cross-coupling reactions with the fluorinated aryl halide 1 (Chart 1). We have previously used this type of compounds to study aspects of aryl halide oxidative addition.9,10 Here we present a study that examines (i) the importance of the phosphine ligand and (adventitious) water in controlling the product distribution (e.g., C−C bond formation versus hydrodehalogenation), (ii) the mechanism of a direct hydrodehalogenation route of the (polyfluoro)aryl bromides (without the need for a metal catalyst), and (iii) evidence that a radical-based mechanism is © 2011 American Chemical Society

unlikely to play a role in the metal-catalyzed hydrodehalogenation. We reacted compound 1 with phenylacetylene under Sonogashira cross-coupling conditions at 100 °C for 27 h with Pd(PEt3)4 as the catalyst (6 mol %) in anhydrous DMF (50 ppm of water; for details see the Supporting Information, Table S1). This reaction results in hydrodehalogenation of 1 as Special Issue: Fluorine in OrganometallicChemistry Received: September 27, 2011 Published: November 2, 2011 1271

dx.doi.org/10.1021/om200898t | Organometallics 2012, 31, 1271−1274

Organometallics

Communication

the major product (2, 67%) and C−C coupling as the minor product (3, 33%), as determined by 19F{1H} NMR, highresolution mass spectrometry (HRMS) and comparison with authentic samples. The single-crystal structure of compound 2 is included in the Supporting Information (Figure S1). Using Pd(PPh3)4 instead of Pd(PEt3)4 results in a substantial increase in the formation of the desired C−C coupling product (3, 77%) and only 23% of the hydrodehalogenation product (2). Furthermore, this reaction is complete in only 4 h. Thus, the product distribution can be significantly shifted by varying the phosphine (PEt3 versus PPh3). Hydrodehalogenation of fluorinated arenes has been reported with Zn/NH3, H2/catalyst, or Grignard reagents.11,12 It is likely in our case that phosphine ligands dissociate from the palladium catalyst and attack the substrate (1), generating a transient arylphosphonium ion that undergoes hydrolysis, which in turn generates the observed product of hydrodehalogenation (2). Indeed, reacting 1 with 3 equiv of PEt3 in THF/H2O (6:1 v/v) at room temperature results (after 5 min) in quantitative formation of 2. Hydrodehalogenation of 1 with PPh3 requires elevated temperatures and prolonged reaction times (e.g., 42% conversion after 43 h at 100 °C). Therefore, some of the hydrodehalogenation products in palladiumcatalyzed cross-coupling reactions might result from a combination of (adventitious) water and the use of nucleophilic phosphine ligands. Hydrodehalogenation was also observed when bromopentafluorobenzene was used under similar conditions (Scheme S1, Supporting Information), but not with bromobenzene. The reaction between either compound 1 or bromobenzene (in both cases hydrogen and fluorine substituted) and either PEt3 or PPh3 to give the corresponding hydrodehalogenated arene and phosphine oxide was examined using density functional theory (DFT) at the SMD(THF)-DSD-BLYP/ maug-cc-pV(D+d)Z-PP//DF−PBE+dv2/pc1 level of theory (Tables S2−S5; see the Supporting Information for full computational details). Four reaction steps were considered at both 298 and 373 K: (i) oxidative addition of the aryl bromide by the phosphine (PEt3 or PPh3), (ii) hydrolysis of the PV intermediate, (iii) the acid−base reaction between the HBr liberated in the previous step with free phosphine, and (iv) proton transfer from the hydroxyl group to the arene. Step iii was found to always be unfavorable, and thus the reaction was considered to result in free HBr. The first step is the organic equivalent of an oxidative addition of an aryl halide to the PIII center. The transition state (TS1) for the reaction of PEt 3 and bromopentafluorobenzene is shown in Figure 1 and is fairly

in which the phosphine as well as the bromine are bound to the ipso carbon, does not occur. Such a putative intermediate could not be found, but rather a σ−π complex is formed with the phosphine hovering over the aromatic ring. The product can be described as a trigonal-bipyramidal phosphonium salt with a weakly bound bromide (r (P−Br) = 2.878 Å). This allows the halide to be exchanged for OH−. Proton transfer from the hydroxyl group to the aryl moiety affords the experimentally observed arene and phosphine oxide. The hydroxyl intermediate and the proton-transfer transition state (TS2) are shown in Figure 2. The reaction profiles for the reaction of bromopentafluorobenzene and bromobenzene with PEt3 is shown in Figure 3. The reaction will not occur, even at elevated temperatures, in the nonfluorinated systems and varies from fast to sluggish with the fluorinated compounds.

Figure 2. Calculated intermediate (left) and transition state (TS2, right) for the proton transfer step in the reaction of bromopentafluorobenzene to PEt3 (color scheme: C, gray; H, white; F, light blue; O, red; P, orange).

Figure 3. Reaction profiles for the reactions of bromopentafluorobenzene (X = F) and bromobenzene (X = H) with PEt3 at 298 and 373 K.

Nonetheless, this direct hydrodehalogenation route with a phosphine and water is not the only possible pathway under catalytic conditions. If only such a process were to be operating, the amount of hydrodehalogenation would be limited by the amount of the phosphine and adventitious water. Reacting compound 1 under the aforementioned Sonogashira crosscoupling conditions without Pd but in the presence of PEt 3 (6 mol %) and all the other components (CuI, NEt3, alkyne) results in only 13% hydrodehalogenation (2). Without Pd(PEt3)4 and CuI no hydrodehalogenation was observed, whereas with Pd(PEt3)4 but without CuI formation of compound 2 was observed as the major product (∼70%). Moreover, no reaction is observed with PPh 3 . These observations show that the metal center also plays a critical role in catalyzing the hydrodehalogenation. Further mechanistic insight is provided by several stoichiometric reactions between Pd(PEt 3)4 or Pd(PPh3)4 with compound 1. Reacting Pd(PEt3)4 and 1 in dry THF at room

Figure 1. Calculated transition state (TS1, left) and product (right) for the oxidative addition of bromopentafluorobenzene to PEt3 (color scheme: C, gray; H, white; F, light blue; Br, red; P, orange).

similar for the other pairs of reactants. A nucleophilic aromatic substitution (SNAr) pathway, involving a discrete intermediate 1272

dx.doi.org/10.1021/om200898t | Organometallics 2012, 31, 1271−1274

Organometallics

Communication

temperature for 5 min results in the formation of complex 4 by oxidative addition of the ArF−Br moiety to the d10 metal center. The nature of this process could either be a concerted oxidative addition or involve a one-electron transfer from the Pd 0 complex to 1 followed by recombination of the PdI with the resulting aryl radical (vide infra). Complex 4 was formed nearly quantitatively (98%) with concurrent liberation of 2 equiv of PEt3. Traces of PdBr2(PEt3)2 and compound 2 were observed as well by 19F{1H} and 31P{1H} NMR spectroscopy. Performing this reaction at −70 °C and gradually raising the temperature to 20 °C reduced the selectivity, as complex 4 was formed in 86% yield. This product (4) was isolated and was fully characterized by 1H, 13C{1H}, 19F{1H}, and 31P{1H} NMR spectroscopy as well as by HRMS, elemental analysis (C, H, N), and single-crystal X-ray crystallography (Figure 4, left).

4 h results in the quantitative formation of the thermodynamically favored complex 5. No hydrodehalogenation of compound 1 was observed. Performing this reaction in THF/H2O (6:1 v/v) does not change the reaction outcome. Hydrodehalogenation is not observed when trans-4′-bromo4-stilbazole (8) (the nonfluorinated analogue of compound 1; see Scheme S2 in the Supporting Information) is used. Only selective η 2-CC coordination (9) with Pd(PEt3)2 in THF/ H2O (6/1 v/v) is observed by 31P{1H} NMR spectroscopy at room temperature. Thermolysis at 40 °C for 16 h results in the quantitative formation of the isostructural nonfluorinated analogue (10) of complex 4 (Scheme S2). Electrochemical measurements (cyclic voltammetry and differential pulse voltammetry) show that the redox potential of 1 (E1/2 = −0.94 V vs Ag/Ag+) is less negative than of the nonfluorinated compound 8 (E1/2 = −1.82 V), allowing for easier reduction of 1 (Figure S2, Supporting Information). The product distribution between C−Br bond activation and hydrodehalogenation is clearly controlled by the nature of the arene (ArF vs Ar). Our observations indicate that the product distribution with the fluorinated compound 1 can be directed by water or the nature of the phosphine. The hydrodehalogenation reaction proceeds via the formation of a phosphonium salt followed by hydrolysis with water, even in the presence of the palladium catalyst. The formation of phosphine oxides under exclusion of oxygen is in agreement with water activation. Indeed, the use of 17 O-enriched water results in Et3P17O. Other (parallel) pathways cannot be excluded for this model system. For instance, one could propose that an electron-rich d10 palladium center with three or four PEt3 ligands might undergo electron transfer with the electron-poor substrate 1 to afford an unobserved PdIBr(PEt3)x species and a radical (1•).14−16 The observed PdBr2(PEt3)2 would then be formed from a secondary reaction, whereas 2 is generated from hydrogen (or deuterium) abstraction from water by 1•. This mechanistic proposal is also in agreement with the different reactivities of the nonfluorinated substrate (8) with Pd(PEt 3)4 and of 1 with Pd(PPh3)4. However, these last two systems are less likely to undergo a one-electron transfer process. DFT calculations17 on an electron-transfer process show that the reaction Pd(PR3)4 + 1 → Pd(PR3)3Br + 1• + PR3 has a reaction energy of ΔG298(THF) = 11.4 kcal/mol for R = Et and 15.9 kcal/mol for R = Ph. Furthermore, it was shown (vide supra) that water and not THF is the hydrogen source, which would not be expected for a radical mechanism considering the large difference in the hydrogen bond dissociation energies (BDEs) of water (119 kcal/mol) and THF (92 kcal/mol).18 Thus, single-electron transfer/hydrogen transfer is not expected to occur. PdBr2(PEt3)2 could also result from a reaction of Pd(PEt3)4 with HBr formed by the reaction of 1 with free phosphine. This possibility was confirmed by a stoichiometric reaction between Pd(PEt3)4 and HBr, resulting in the formation of PdBr2(PEt3)2. It is noteworthy that the reactivity of PdBr2(PEt3)2 and complex 4 under Sonogashira cross-coupling conditions is similar to that of Pd(PEt3)4, suggesting that the substrateconsuming hydrodehalogenation process does not necessarily reduce the amount of active catalyst (for details see the Supporting Information, Table S1). In summary, we provide mechanistic insight into hydrodehalogenation of fluorinated aryl halides. The stoichiometric reactions indicate that this undesired process uses water as the hydrogen source and is affected by the nature of the phosphine

Figure 4. X-ray crystallography of complexes 4 (left) and 6 (right) with thermal ellipsoids at the 50% probability level. Hydrogen atoms are omitted for clarity, except for H1 of complex 6. Bond lengths and angles are provided in the Supporting Information.

Performing the reaction in THF-d8 containing traces of water isotopomers results also in the deuterated analogue of 2 (i.e., 2′). Compound 2′ is not observed when rigorously dried THFd8 is used. Thus, THF is not the hydrogen source in this reaction. Apparently, adventitious water plays a role in this hydrodehalogenation process. To further evaluate the possible role of water, we performed the room temperature reaction between Pd(PEt3)4 and 1 in THF/H2O (6:1 v/v). After 5 min, 19F{1H} NMR spectroscopy showed the complete conversion of compound 1 into compound 2 and the η 2-CC coordination complex 6 (Figure 4, right) in a ratio of 1.4:1. 31P{1H} NMR spectroscopy shows the formation of 6, PdBr2(PEt3)2, and Et3PO in a ratio of 3:1:1. These compounds were also identified by field-desorption mass spectrometry (FDMS), 1H and 31P{1H} NMR spectroscopy, and comparison with authentic samples. The use of THF/D2O (6:1 v/v) resulted in the formation of the ArF−D analogues 2′ and 6′, unambiguously demonstrating that water is the hydrogen source. In the absence of compound 1, Pd(PEt3)4 is stable under these reaction conditions.13 In addition, complex 4 is stable in the presence of an excess of H2O at 100 °C for 2 days. Therefore, the observed hydrodehalogenation process (1 → 2) occurs without intermediacy of complex 4 and this suggests that PdBr2(PEt3)2 and Et3PO are products formed from the reaction of water with transient species. Similar observations were made with bromopentafluorobenzene; selective oxidative addition occurs between this substrate and Pd(PEt3)4, whereas exclusive hydrodehalogenation takes place in THF/D2O (6:1 v/v) with either Pd(PEt3)4 or free PEt3 (Scheme S1, Supporting Information). In contrast, the reaction of Pd(PPh3)4 and compound 1 initially results in the η 2-CC coordination of 1 (7, 37% at room temperature) (in addition to unreacted starting materials). Thermolysis of this reaction mixture at 45 °C for 1273

dx.doi.org/10.1021/om200898t | Organometallics 2012, 31, 1271−1274

Organometallics

Communication

(c) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. (d) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (e) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (3) (a) Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to Catalysis; University Science Books, Sausalito, CA, 2010. (b) Collman, J. P., Hegedus, L. S., Norton, J. R., Finke, R. G. Principles and Applications of Organotransition Metal Chemistry; University Science Books: Mill Valley, CA, 2006. (c) Negishi, E. I. Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley: New York, 2002. (d) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525. (4) Clot, E.; Mégret, C.; Eisenstein, O.; Perutz, R. N. J. Am. Chem. Soc. 2009, 131, 7817. (5) (a) Albéniz, A. C.; Espinet, P.; Martı ́n-Ruiz, B.; Milstein, D. Organometallics 2005, 24, 3679. (b) Albéniz, A. C.; Espinet, P.; Martı ́nRuiz, B.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 11504. (6) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 14, 2320. (c) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581. (7) (a) Nguyen, B. V.; Yang, Z. Y.; Burton, D. J. J. Org. Chem. 1993, 58, 7368. (b) Neeman, T. X.; Whitesides, G. M. J. Org. Chem. 1988, 53, 2489. (c) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. (8) (a) Collings, J. C.; Burke, J. M.; Smith, P. A.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Org. Biomol. Chem. 2004, 2, 3172. (b) Nguyen, P.; Yuan, Z.; Agocs, L.; Lesley, G.; Marder, T. B. Inorg. Chim. Acta 1994, 220, 289. (9) Lucassen, A. C. B.; Shimon, L. J. W.; van der Boom, M. E. Organometallics 2006, 25, 3308. (10) (a) Zenkina, O. V.; Karton, A.; Shimon, L. J. W.; Martin, J. M. L.; van der Boom, M. E. Chem. Eur. J. 2009, 15, 10025. (b) Zenkina, O. V.; Karton, A.; Freeman, D.; Shimon, L. J. W.; Martin, J. M. L.; van der Boom, M. E. Inorg. Chem. 2008, 47, 5114. (c) Zenkina, O.; Altman, M.; Leitus, G.; Shimon, L. J. W.; Cohen, R.; van der Boom, M. E. Organometallics 2007, 26, 4528. (d) Strawser, D.; Karton, A.; Zenkina, O. V.; Iron, M A.; Shimon, L. J. W.; Martin, J. M. L.; van der Boom, M. E. J. Am. Chem. Soc. 2005, 127, 9322. (11) (a) Johnson, S. A.; Taylor, E. T.; Cruise, S. J. Organometallics 2009, 28, 3842. (b) Laev, S. S.; Shteingarts, V. D. J. Fluorine Chem. 1999, 96, 175. (c) Chambers, R. D.; Drakesmith, F. G.; Musgrave, W. K. R. J. Chem. Soc. 1965, 5045. (12) (a) For hydrodehalogenation of fluorinated arenes with P(NEt2)3: Bardin, V. V.; Pressman, L. S. Russ. Chem. Bull. 1997, 46, 786. (b) For hydrodehalogenation of p-halogenoperfluoroanilines: Kobayashi, H.; Sonoda, T.; Takuma, K.; Honda, N.; Nakata, T. J. Fluorine Chem. 1985, 27, 1. (13) Reacting Pd(PEt 3)4 in THF/H2O (6:1 v/v) at room temperature does not generate metal hydrides capable of hydrodehalogenation. (14) Pd(PEt3)4 and Pd(PPh3)4 undergo reversible phosphine dissociation: Mann, B. E.; Musco, A. J. Chem. Soc., Dalton Trans. 1975, 1673. (15) (a) Kraatz, H.-B.; van der Boom, M. E.; Ben-David, Y.; Milstein, D. Isr. J. Chem. 2001, 41, 163. (b) Hall, T. L.; Lappert, M. F.; Lednore, P. W. J. Chem. Soc., Dalton Trans. 1980, 1448. (c) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319. (16) For an example of Pd(I) complexes: Baya, M.; Houghton, J.; Konya, D.; Champouret, Y.; Daran, J.−C.; Almeida Leñero, K. Q.; Schoon, L.; Mul, W. P.; van Oort, A. B.; Meijboom, N.; Drent, E.; Orpen, A. G.; Poli, R. J. Am. Chem. Soc. 2008, 130, 10612. (17) PCM(THF)-PBE0/SDB-cc-pVDZ//PBE/SDD(d)/DFBS level of theory; see the Supporting Information for full computational details. (18) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC Press: Boca Raton, FL, 2003.

substituents. The electron-rich PEt3 ligand plays a double role. It can dissociate and directly hydrodehalogenate fluorinated aryl halides. In addition, it may generate reactive electron-rich metal centers capable of promoting nonselective processes. Electrochemical measurements confirm that the metal center of Pd(PEt3)4 more readily “donates” electrons in comparison to Pd(PPh3)4 (E 11/2 = −0.28 and 0.10 V vs Ag/Ag+, respectively; Figures S3 and S4 in the Supporting Information). Although electron-rich metal complexes are generally used in crosscoupling reactions with nonfluorinated substrates,3 they might be less efficient with fluorinated aryl halides. Furthermore, our findings show that hydrodehalogenation occurs prior to the formation of ArF−PdII−Br complexes. The DFT calculations suggest that single-electron transfer from Pd(PEt3)4 to 1 is disfavored by at about 12 kcal/mol. Therefore, such a process coupled with a hydrogen atom transfer pathway is not likely, and some, as of yet unknown, pathway involving proton or hydride transfer must be operating. Nonetheless, our study based on stoichiometric reactions does not take into account all components of the catalytic process (e.g., CuI, NEt3, alkyne). However, we have shown that under catalytic conditions Pd(PEt3)4 and not CuI induces hydrodehalogenation. Other parallel hydrodehalogenation processes might also be operating. Our observations are most likely not limited to the Sonogashira cross-coupling reaction with a model substrate presented here but are applicable to a wider range of processes with fluorinated aryl halides and platinum-group metals.

■

ASSOCIATED CONTENT * Supporting Information Text, figures, tables, and CIF files giving complete experimental and computational details and characterization data. This material is available free of charge via the Internet at http:// pubs.acs.org. S

■

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Present Address § Department of Chemical Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal 462023, India.

■

ACKNOWLEDGMENTS

■

REFERENCES

This research was supported by the Helen and Martin Kimmel Center for Molecular Design. J.C. thanks the EU (FP7 program) for an Incoming Marie Curie fellowship. Dr. A. C. B. Lucassen is acknowledged for his assistance. M.E.v.d.B. is the incumbent of the Bruce A. Pearlman Professorial Chair in Synthetic Organic Chemistry.

(1) (a) Gladysz, J. A. Catalysis Involving Fluorous Phases: Fundamentals and Directions for Greener Methodologies. In Handbook of Green Chemistry; Anastas, P., Crabtree, R. H., Eds.; Crabtree, R. H., Vol. Ed.; Wiley-VCH: Weinheim, Germany, 2009; Homogeneous Catalysis Vol. 1, pp 17−38. (b) Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992. (c) Reichenbaecher, K.; Suess, H. I.; Hulliger, J. Chem. Soc. Rev. 2005, 34, 22. (d) Kirsch, P. Modern Fluoroorganic Chemistry. Synthesis, Reactivity, Applications; Wiley: New York, 2004. (e) Clark, J. H.; Wails, D.; Bastock, T. W. Aromatic Fluorination; CRC Press: Boca Raton, FL, 1996. (2) (a) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850. (b) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377. 1274

dx.doi.org/10.1021/om200898t | Organometallics 2012, 31, 1271−1274