Bond Activation and Catalysis by Ruthenium Pincer Complexes

Review pubs.acs.org/CR

Bond Activation and Catalysis by Ruthenium Pincer Complexes Chidambaram Gunanathan*,† and David Milstein*,‡ †

School of Chemical Sciences, National Institute of Science Education and Research (NISER), Bhubaneswar 751005, India Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel

‡

3.7. Activation of CO Bonds and Reversible C− C Bond Formation 3.8. Activation of Carbon Dioxide 4. Catalysis 4.1. Dehydrogenation Reactions 4.1.1. Dehydrogenation of Alkanes 4.1.2. Dehydrogenation of Alcohols 4.1.3. Dehydrogenation of Amines 4.1.4. Dehydrogenation of Amine-boranes 4.2. Transfer Hydrogenation Reactions 4.2.1. Mechanism of THs 4.3. Dehydrogenative Functionalization Reactions 4.3.1. Selective Deuteration of Arenes and Alcohols 4.3.2. Synthesis of Acids from Alcohols Using Water in the Absence of Added Oxidant 4.3.3. Dehydrogenative Coupling of Alcohols To Form Esters and H2 4.3.4. Synthesis of Acetals from Alcohols 4.3.5. Synthesis of Amides 4.3.6. Synthesis of Amines from Alcohols and Ammonia 4.3.7. Synthesis of Alcohols from Amines and Water 4.3.8. Synthesis of Secondary Amines from Primary Amines 4.3.9. Synthesis of Imines from Primary Amines 4.3.10. Synthesis of Lactams from Cyclic Amines Using Water 4.3.11. Synthesis of Imines from Alcohols and Amines 4.3.12. Synthesis of Heteroaromatics from Amino Alcohols 4.4. Hydrogenation/Hydrogenolysis Reactions 4.4.1. Hydrogenation of Aldehydes and Ketones 4.4.2. Hydrogenation of Carboxylic Acid Derivatives 4.4.3. Hydrogenation of Carbonic Acid Derivatives 4.4.4. Hydrogenation of Carbon Dioxide to Methanol and Formates 4.4.5. Hydrogenation of Nitriles to Amines 4.4.6. Hydrogenation of Nitriles to Imines 4.4.7. Hydrogenation of Imines to Amines 4.4.8. Hydrogenation of Azide to Ammonia

CONTENTS 1. Introduction 2. Synthesis, Reactivities, and Structure of Ruthenium Pincer Complexes 2.1. Synthesis of Ruthenium Pincer Complexes 2.1.1. Ruthenium Pincer Complexes with L3 Pincer Ligands 2.1.2. Ruthenium Pincer Complexes with L2X Pincer Ligands 2.1.3. Ruthenium Pincer Complexes with LX2 Pincer Ligands 2.2. Deprotonation−Dearomatization Reactions 2.3. Metal−Ligand Cooperation (MLC) by Ruthenium Pincer Complexes 2.3.1. MLC Based on Aromatization−Dearomatization Process 2.3.2. Long-Range MLC in Acridine-Derived Pincer Complexes 2.3.3. MLC by Amine−Amide Interconversion 2.4. Uncommon Unsaturated Pincer Complexes 2.4.1. Square-Planar 16e− Ru(0) Pincer Complexes 2.4.2. Square-Planar 14e− Ru(II) Pincer Complexes 2.4.3. Trigonal Pyramidal 14e− Ru(II) Pincer Complexes 3. Bond Activation 3.1. Activation of the H−H Bond 3.2. Activation of C−H Bonds 3.3. Activation of N−H Bonds 3.4. Activation of O−H Bonds 3.4.1. O−H Bond Activation of Alcohols 3.4.2. O−H Bond Activation of Water 3.5. Activation of B−H Bonds 3.6. Activation of Si−H and Si−Cl Bonds

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Received: May 25, 2014 Published: November 14, 2014 © 2014 American Chemical Society

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Chemical Reviews 5. Miscellaneous Usages 5.1. Hydroboration of Terminal Alkynes 5.2. Asymmetric Alkynylation of Aldehydes 5.3. Conjugate Addition of Alkynes to α,βUnsaturated Carbonyl Compounds 5.4. Decarbonylation of Acetone and Carbonate 5.5. Reduction of Hydrazine to Ammonia 6. Conclusions and Outlook Author Information Corresponding Authors Notes Biographies Acknowledgments References

Review

pincer complexes with platinum group metals, attracted the early attention and were reviewed by Albrecht and Van Koten in 20018 and by van der Boom and Milstein in 2003.10 Since then, this field underwent rapid growth and was periodically reviewed by several groups in different contexts.11−30 Recently, the chemistry of iridium pincer complexes was reviewed23 by the groups of Goldman and Brookhart, and palladium pincer complexes were reviewed24 by Szabó and Selander in Chemical Reviews. In this Review, we consider ruthenium pincer complexes of type B (saturated) and C (unsaturated) developed since 2003 from the perspective of bond activation and catalysis. These coordinatively saturated and unsaturated ruthenium pincer complexes with heteroaromatic and aliphatic backbones developed in recent years exhibit new reactivities, activate strong chemical bonds, and act as efficient catalysts for several synthetic methods including unprecedented green transformations, the pivotal interest of this Review. At the outset we describe the synthesis, important reactivities like deprotonation−dearomatization, MLC (metal−ligand cooperation), and electronic structure of unusual ruthenium pincer complexes. Various bond activation reactions are delineated in section 3. Important catalytic applications and their mechanistic significance are discussed in detail in section 4. Selected miscellaneous transformations are briefly discussed in section 5. An astonishing amount of work has been done in this field in recent years, and therefore the focus of this Review is limited to a summary of key developments in the area of bond activation and catalysis by defined ruthenium pincer complexes.

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1. INTRODUCTION Activation of inert chemical bonds by transition metal complexes is an area of utmost importance. Efficient bond activation can provide a leading entry to successful catalytic design with the potential of providing greener synthetic methods for useful products. “Pincer complexes” are composed of “pincer ligands” that are tridentate ligands, which enforce meridional geometry at the metal center upon complexation with metals. Often with planar framework and bulky substituents on the donor atoms, pincer ligands cover much of the coordination sphere around the metal center and thus offer control over vacant coordination sites with enhanced stability of the resulting pincer complexes. One of the major shortcomings of transition metal complexes employed as homogeneous catalysts is their instability at elevated temperatures, which prevents their use in highly endothermic reactions. The possibility of rational design of pincer ligands can enable the generation of superior catalysts for a range of chemical transformations with high selectivity. Pincer ligand frameworks are also amenable to structural and electronic modifications after complexation reactions, providing further opportunities for selective bond activation and catalysis. As a result, “pincer complexes” once considered as a favorite adventure for probing organometallic chemists have become preferred catalysts for various challenging transformations in organic synthesis. As they are becoming important tools in chemical synthesis, many pincer complexes and their precursors are increasingly available commercially, facilitating their wider use and applications. The “chemistry of pincer complexes” emanated from the pioneering reports of Bernard Shaw1−7 in the mid 1970s, and the early development of this enticing field is culminated in excellent reviews8−12 in the early 2000s. Pincer complexes of type A (Scheme 1), particularly chemistry of PCP and NCN

2. SYNTHESIS, REACTIVITIES, AND STRUCTURE OF RUTHENIUM PINCER COMPLEXES 2.1. Synthesis of Ruthenium Pincer Complexes

Ruthenium pincer complexes can be classified into three major classes according to the number of electrons the pincer ligands contribute to the valence electrons of the complexes: (i) neutral L3 type pincer ligands, (ii) monoanionic L2X type pincer ligands, and (iii) dianionic LX2 type pincer ligands. Within these three major classes, the complexes are classified further on the basis of the donor triads. This Review is not intended to provide an exhaustive list of all of the reported ruthenium pincer complexes; rather representative examples of pincer complexes that found interesting catalytic applications and bond activations are presented. 2.1.1. Ruthenium Pincer Complexes with L3 Pincer Ligands. When 2,6-bis(di-tert-butylphosphinomethyl)pyridine (PNP tBu ) 31 and (2-(di-tert-butylphosphinomethyl)-6diethylaminomethyl)pyridine) (PNNtBu) ligands were heated with [RuCl2(PPh3)3] in nitrogen atmosphere, displacement of PPh3 and coordination of N2 ligand resulted in equilibrium mixture of η1-N2 and η2-N2 coordinated complexes of mononuclear 1a, 2a and binuclear 1b, 2b in the ratios of 8:100 and 12:100, respectively. PNPtBu complexes 1a and 1b were reacted with NaBHEt3 to obtain the ruthenium hydrido chloro complex 1 (Scheme 2).32 PNNtBu complexes33 2a and 2b were treated with sodium borohydride, which provided the η2-BH4 coordinated ruthenium hydrido borohydride complex 2.34 One of the most widely used ruthenium precursors for the synthesis of pincer complexes is RuHCl(CO)(PPh3)3, which undergoes PPh3 displacement upon reaction with various pincer ligands to provide ruthenium hydrido chloro carbonyl

Scheme 1. Schematic Representation of Types of Pincer Complexes

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Scheme 2. Synthesis of PNP and PNN Ruthenium Pincer Complexes

Scheme 3. Synthesis of [(L3)RuHCl(CO)] Ruthenium Pincer Complexes by PPh3 Displacement

complexes. Milstein’s group synthesized a series of ruthenium pincer complexes of this type from pyridine-based PNP (3, 4, 9),35−37 PNN (5),35 PONOP (10),38 PNS (13),39 and bipyridine-derived BIPy-PNN ligands (6−8, Scheme 3).40,41 Gusev and Kuriyama reported the PNHN (11)42 and PNHP (12)43 ruthenium pincer complexes with an aliphatic backbone. Recently, Huang and co-workers have reported the 14, 15, and 16 where “CH2” and “CH2NEt2” arms were replaced by “NH”44,45 and oxazoline46 moieties, respectively. Prior to Huang, the aminophosphine PNP pincer ligand of complex 14 was used by Kirchner and co-workers, who reacted it with [RuCl 2 (PPh 3 ) 3 ] to provide the corresponding octahedral complexes [(PNP)RuCl2(PPh3)].47 Schneider and co-workers prepared the ruthenium pincer complex 17 with aliphatic backbone by similar displacement of PPh3 (Scheme 4a)48 and also complex 19, by arene displacement from [RuCl2(p-cymene)]2 upon reaction with ligand PNHP.49 Ruthenium pincer complex 20 derived from PNPtBu ligand with nonclassical hydrogen complexes was prepared under mild hydrogen pressure by Leitner and co-workers (Scheme 4b).50 Recently, Ozawa and co-workers have reported the complexation of 2,6-bis[1-phenyl-2-(2,4,6-tri-tert-butylphenyl)-2phosphaethenyl]pyridine (BPEP-Ph) ligand51 complexed with [Ru3(CO)12] at 80 °C under vacuum in the presence of excess Hünig base to provide the Ru(0) complex 21 (Scheme 4c). The presence of Hünig base prevented the intramolecular CH activation of tBu group and resulted in selective formation of complex 21. Ozerov and co-workers reported the synthesis of pincer complex 22 containing the L3 type PCP ligand derived from the dipyrromethane (Scheme 4d). Double C−H activation at a single methylene unit resulted in Ru−carbene complex 22 with Y-shaped 5-coordination geometry around the ruthenium center.52 Clarke and co-workers reported the synthesis of a PNN pincer complex 23 from the cyclohexanediamine derived PNN ligand, which rapidly underwent complexation with [RuCl2(DMSO)4] when heated under microwave irradiation (Scheme 5a).53 Yu and Zeng prepared the neutral NNN pincer complex 24 by PPh3 displacement (Scheme 5b).54,55 Periana and co-workers obtained the NNN Ru(III) complex 25 (Scheme 5c) by heating a methanol solution of 2,6diimidizoylpyridine and hydrated ruthenium chloride.56 Berry and co-workers reported the synthesis of dinitrogen bridged

dinuclear Ru(0) complexes (Scheme 5d). The labile η2-N2 ligand of the dinuclear complexes 26 and 27 dissociated to provide complexes 26a and 27a, respectively, in arene solvents.57,58 Danopoulos and co-workers reported59 the biscarbene-based CNC ruthenium pincer complex 28. 2,6-[(o-Dialkyl)phenylimidazolylidene]pyridine was obtained by deprotonation of 2,6-[(o-dialkyl)phenylimidazolium]pyridine dibromide with 2 equiv of KN(SiMe3)2 in THF at −10 °C, which further underwent complexation with [RuCl2(PPh3)3] to provide the neutral CNC complex 28. Peris and co-workers prepared the similar ruthenium dibromide biscarbene complex 29 by direct reaction of 2,6-bis(1-n-butylimidazolium-3-yl)pyridine bromide with [(COD)RuCl2]n in refluxing EtOH/Et3N. While triethylamine served as a good base for the deprotonation, ethanol served as a source of the carbonyl ligand upon oxidation to acetaldehyde and decarbonylation. n-Butyl groups were chosen to enhance the solubility of the complex (Scheme 6a).60 Recently, Suárez and co-workers have reported the preparation of biscarbene CNC complexes61 with six-membered chelating rings, which adapted a fac-geometry as a result of flexibility due 12026

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Scheme 4. Synthesis of L3 Type PNP and PCP Pincer Complexes

Scheme 5. Synthesis of L3 Type PNHN and NNN Ruthenium Pincer Complexes

to the extended arms. The bis-NHC carbene derived from the reaction of bis-imidazolium salt and silver oxide was reacted with [RuHCl(CO)(PPh3)3] to provide the complex 30 (Scheme 6b). In contrast, six-membered chelating bisimidazolium CNC ligand with bulky mesityl substituents resulted in the formation of mer-complex 31 when reacted with [RuHCl(CO)(PPh3)3] using 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) as base in the presence of LiBr (Scheme 6c).62 Yu and Zeng reported63 a neutral CNN ruthenium diiodo carbonyl pincer complex 32, which was obtained from the reaction of imidazolium salt with hydrated ruthenium trichloride at high temperature followed by treatment with KI at room temperature (Scheme 7a). Milstein reported the CNN complex 33 (Scheme 7b) by replacing the phosphine arm in PNN complex 6 derived from bipyridine-based pincer ligands;64 a free carbene, formed at lower temperature, was reacted with [RuHCl(CO)(PPh3)3] to obtain the cationic CNN pincer complex 33. Song reported a neutral CNN complex 35 following a similar method (Scheme 7d), which is a modification of the phosphine arm of the pyridine-based PNN

pincer complex 5.65 Similarly, the neutral carbene complex 34 with pyrrolidine amine arm was prepared by Sánchez and coworkers (Scheme 7c).66 Messarle and co-workers reported67 the synthesis of the neutral tridentate SNStBu-derived ruthenium pincer complexes. When 2,6-bis(tert-butylthiomethyl)pyridine (SNStBu) was reacted with [RuCl2(PPh3)3] and [Ru(COD)Cl2(MeCN)2], the complexes [(SNS tBu )RuCl 2 (PPh 3 )] 36 and [(SNS tBu )RuCl2(MeCN)] 37 were obtained, respectively. Complex 37 was isolated as a mixture of two geometrical isomers, 37a and 37b, in which the two chloride ligands occupy the cis and trans positions, respectively (Scheme 8). 2.1.2. Ruthenium Pincer Complexes with L2X Pincer Ligands. Synthesis and catalytic applications of monoanionic pincer complexes of type NCN68 38 and PCPPh 39 (Scheme 9a)69 were explored by the group of van Koten and covered in reviews in early 2000.8,10,11 Here, we review the synthesis of bulky, electron-rich, or electron-poor monoanionic PCP ruthenium pincer complexes developed after 2003 (Scheme 9b−d). The strong Ru−C σ-bond present in PCP ruthenium pincer complexes is preserved during the catalysis. Fogg and co-workers reported the direct synthesis of the electron-rich PCP pincer complex 40 from the reaction of 12027

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Scheme 6. Synthesis of L3 Type CNC Ruthenium Pincer Complexes

Scheme 7. Synthesis of L3 Type CNN Ruthenium Pincer Complexes

Scheme 8. Synthesis of L3 Type SNS Ruthenium Pincer Complexes

PCPcyh with [RuCl2(PPh3)3] in the presence of base (Scheme 9b). The formation of complex 40 was observed even in the absence of base as a result of C−H (sp2) activation at room temperature. The η 2-coordinated intermediate complex [RuCl2(η2-(PCHP)] increases the C−H acidity due to an agostic interaction, followed by deprotonation by base.70 The less basic POCOP and the PCP pincer complexes 41, 42, and 43 were prepared by displacement of PPh3,71 transmetalation,72 and hydrogenation methods,73 respectively, at elevated temperatures (Scheme 9c−e). The dibenzobarrelene-based air-stable PCP pincer complex 44 was recently synthesized by Gelman and co-workers at room temperature (Scheme 9f).74 Baratta and co-workers reported the monoanionic CNN ruthenium pincer complex 45 and 47 derived from 2phenylpyridine derivatives (Scheme 10a).75 Complex 46 was obtained from the reaction of equimolar amounts of the ligand 6-(4′-methylphenyl)-2-pyridylmethylamine and the ruthenium precursor [RuCl2(PPh3)(dppb)] in refluxing 2-propanol in the presence of triethylamine.76 Baratta also developed a series of Ru pincer complexes containing a monoanionic CNN core containing chiral centers 48, 49, and 51 (Scheme 10b,c). Complexes of type [RuCl(CNN)(PP)], 1-(6-arylpyridin-2yl)methanamine,77 and 2-aminomethylbenzo[h]quinoline78 with amine-“NH2” arms are highly effective catalysts for THs

(transfer hydrogenations) of aldehydes and ketones with excellent TOF, TON (in the order of 106 h−1 and 105, respectively), and enantioselectivities. Recently, Baratta and Zhang reported an alternative one-pot synthesis of these CNN ruthenium pincer complexes using the ruthenium precursor 12028

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Scheme 9. Synthesis of L2X Type PCP and POCOP Ruthenium Pincer Complexes

Scheme 10. Synthesis of L2X Type CNN Ruthenium Pincer Complexes

[RuCl(μ-Cl)(η6-p-cymene)]2, HCNN, and diphosphine (PP, including the chiral phosphines) ligands.79 Nishiyama and co-workers prepared several chiral NCN ruthenium pincer complexes based on the bis(oxazolinyl) moiety of “phebox” system, providing C2-symmetric complexes with mer coordination around the ruthenium center, which are suitable catalysts for differentiation of prochiral faces of reactants.80 Representative examples with phenyl substituents are shown in Scheme 11. Complexes with other substituents such as isopropyl and methyl were also reported. When the Phebox-Ph ligand was reacted with ruthenium chloride trihydrate in refluxing ethanol for 24 h in the presence of Zn powder and COD, a dinuclear complex with a bridging ZnCl4 moiety 53 was obtained.81 Mononuclear acetylacetonate (acac)

and acetate ligated complexes 52 and 54 were obtained upon reaction of 53 with Na(acac) and NaOAc, respectively.82 2.1.3. Ruthenium Pincer Complexes with LX2 Pincer Ligands. Ruthenium pincer complexes composed of dianionic pincer ligands are very rare. Tobita and Komuro reported a SiNSi ruthenium pincer complex, in which both silyl donors were covalently bound to the ruthenium center (Scheme 12a). When a solution containing excess of 2,6-bis[(dimethylsilyl)methyl]pyridine and Ru3(CO)12 in hexane was subjected to ultrasonic waves for a few minutes followed by 15 h reflux, complex 55 was formed. Interestingly, thermal reaction of complex 55 in toluene provided a dinuclear complex with a 3center-2-electron Ru−Si−C interaction.83 Hong and co-workers reported an ONO ruthenium pincer complex. Reaction of a dinitrone derived from 2,6-pyridinedicarboxaldehyde with [RuCl2(PPh3)3] in toluene resulted in the Ru(II) pincer complex 56 (Scheme 12b). As established by X-ray structural determination, the ruthenium center in complex 56 is covalently bound to two oxygen atoms, forming six-membered 12029

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5a, and hence the oxidation state of the Ru center remained Ru(II).85 The dearomatization of pincer complexes as a result of deprotonation at the arm upon reaction with a base is general, and observed with other PNP pincer complexes (3−4),86 and bipyridine derived PNN ruthenium pincer complexes 640 and 7−8,41 resulting in the formation of dearomatized stable Ru(II) pincer complexes 3a−8a (Scheme 14). Modified versions of

Scheme 11. Synthesis of Chiral Ruthenium Pincer Complexes with L2X Type NCN Ligands

Scheme 14. Dearomatization of PNP and PNN, PNS and CNN Ru(II) Pincer Complexes upon Deprotonation

Scheme 12. Synthesis of LX2 Type Ruthenium Pincer Complexes with SiNSi and ONO Ligands

chelating rings. This complex also exhibited very good catalytic activities in THs.84 2.2. Deprotonation−Dearomatization Reactions

In an attempt to prepare a Ru(0) complex, Milstein reacted the PNN ruthenium pincer complex with a base (Scheme 13).35 However, rather than loss of hydride ligand, deprotonation occurred at the phosphine methylene arm leading to dearomatization of the pyridine ring, which resulted in the formation of a stable coordinatively unsaturated 16 electroncomplex 5a. In this transformation, the neutral, L3 type PNN pincer ligand in 5 becomes a monoanionic L2X type ligand in

these PNP and PNN complexes 14−16, containing an amine functionality (“NH”) at the arm, also underwent deprotonation−dearomatization to provide the Ru(II) complexes 14a− 16a as demonstrated by Huang and co-workers.44−46 Yu and Zheng reported NNN and CNN Ru pincer complexes 24 and 32 with “NH” functionality present in coordinating heteroaromatics, which also underwent deprotonation; however, despite the deprotonation, the benzimidazole54,55 and triazole63 motifs remain aromatic in complexes 24a and 32a, respectively. In both of these complexes, instead of a central donor atom of a pincer core (i.e., pyridine N), one of the side arm donor “N” becomes an “X” type ligand (overall, L3 to L2X). The PNS

Scheme 13. Discovery of Dearomatization of Pyridine Ring in a PNN Ru(II) Pincer Complex

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framework and forms six-membered chelate rings. When complex 9 was reacted with H2/KOH, a conceptually different reaction from that of pyridine-based pincer complexes occurred, resulting in dearomatization of the central acridine ring as a result of heterolytic activation of dihydrogen. The dearomatization of the central acridine ring was unequivocally established spectroscopically and by a single-crystal X-ray diffraction of the product. Similarly, reaction of complex 9 with D2/KOH provided complex 9a with heterolytic activation of D2 (Scheme 16). DFT calculations of this process suggested the

ruthenium pincer complex 13 also underwent deprotonation to provide a dearomatized unstable intermediate 13a, which underwent further dimerization to form a symmetrical dimeric complex.39 Neutral CNN ruthenium pincer complexes 33−35 were deprotonated at the “NHC” embedded methylene arm, and provided dearomatized complexes 33a−35a, respectively (Scheme 14). 2.3. Metal−Ligand Cooperation (MLC) by Ruthenium Pincer Complexes

Metalloenzymes, such as hydrogenase, can perform chemical transformations via metal−ligand cooperativity, which is also referred to as bifunctional catalysis.87 Such bifunctional transition metal catalysts developed by Noyori efficiently catalyze the hydrogenation of various polar unsaturated substrates upon heterolytic activation of dihydrogen via metal−amine−amide cooperativity.88 In recent years, pincer complexes have been shown to display powerful MLC that provided unprecedented opportunities for homogeneous catalysis. 2.3.1. MLC Based on Aromatization−Dearomatization Process. As described in Scheme 14, the pyridine-based pincer complexes D can undergo deprotonation at the pyridinylmethylene carbon leading to the dearomatization of the pyridine ring. The dearomatized five-coordinate pincer complexes E react stoichiometrically with various substrates (H−X; X = H, C, OH, OR, NH2, NR2) and heterolytically activate polar and nonpolar chemical bonds, in which the proton is accepted by the basic dearomatized “methine carbon” and the X-fragments (also X-type ligands) occupy the empty coordination site on the ruthenium center, leading to the formation of rearomatized, coordinatively saturated pincer complexes F (Scheme 15).25,26 Studies also suggest that H−X

Scheme 16. Long-Range MLC in Acr−PNP Ruthenium Pincer Complexes

involvement of a Ru dihydride intermediate containing a decoordinated, bent acridine ligand (κ2-Acr-PNP) in which the central ring’s C9 center is in close proximity to a hydride ligand followed by hydride migration to C9 through-space. Interestingly, when complex 9 was reacted with ammonia, complex 9b with a dearomatized central acridine ring was obtained. The Xray structure of 9b shows an unusual fac-geometry of the AcrPNP ligand. Apparently, decoordination of central acridine “N” followed by ammonia coordination enforced the bent acridine ring in a favorable position for Ru−H transfer to C9 center. The flexible framework of the AcrPNP ligand enables the formation of both mer (i.e., 9−9a) and fac (9b) PNP complexes (Scheme 16). 2.3.3. MLC by Amine−Amide Interconversion. Schneider and co-workers reported MLC based on reversible amine−amide transformation exhibited by ruthenium pincer complexes with aliphatic PNHP ligands, consisting of a central “NH” donor (Scheme 17, see also Scheme 1).27,49,91,92 Unlike the aryl PNP ligands, in the aliphatic system the “ethylene spacers” underwent β-hydride migration, generating the imide (I) and enamide (H) functionalities in the backbone, which promote heterolytic activation of chemical bonds. MLC based on reversible amine−amide is also assisted by hydrogen bonding from water and alcohols and plays a key role in dehydrogenative coupling of alcohols into esters and dihydrogen, and in hydrogenation of polar bonds.28

Scheme 15. MLC Based on Aromatization−Dearomatization

can add across the dearomatized metal−ligand framework stereoselectively on the same face of the pincer complexes (see below). This new mode of MLC based on the aromatization− dearomatization process of pyridine-based ligands discovered by Milstein provides a new paradigm for bond activation and catalysis by soluble metal complexes, in particular by ruthenium pincer complexes (sections 3 and 4). 2.3.2. Long-Range MLC in Acridine-Derived Pincer Complexes. The acridine-derived PNP ruthenium pincer complex 9 developed by Milstein’s group displays a unique “long-range” MLC.37,89 The single-crystal X-ray structure of 9 shows an unusually long Ru−N bond (2.479 Å),90 and hence we envisaged that N-coordination of the acridine PNP ligand could be hemilabile as this ligand consists of a flexible

2.4. Uncommon Unsaturated Pincer Complexes

One of the characteristic properties of pincer complexes is the ability to stabilize low valent metal complexes with uncommon geometries. As described in the synthesis section, RuII pincer complexes normally exhibit an octahedral geometry. A number 12031

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formation of a 16e− Ru(0) intermediate 58 (Scheme 18), which undergoes proton migration from the phosphine methylene arm93 to regenerate a square pyramidal 5a. This results in a new mode of intramolecular formation of an oxygen−oxygen bond as confirmed by labeling studies leading to stepwise water splitting to H2 and O2 as described in section 3.4.2. On the other hand, the PNP ruthenium nitrosyl complex [(PNPtBu)*Ru(NO)] 59, analogous to 58, is stable in the Ru(0) form (Scheme 18) rather than the dearomatized Ru(II)−H complex, as the nitrosyl ligand is a stronger πacceptor than CO.94 2.4.2. Square-Planar 14e− Ru(II) Pincer Complexes. Square-planar complexes (D4h) with strong-field ligands split the degenerate d-orbitals into three nonbonding orbitals (dxy, dxz, and dyz), weakly antibonding dz2 orbital (as a result of stabilization due to valence s-orbital mixing), and high-lying strongly antibonding dx2−y2 orbital, as predicted by ligand field theory. Thus, an intermediate-spin (S = 1) electronic configuration is expected for the d6 complexes (Figure 1a).

Scheme 17. MLC-Based Amine−Amide Interconversion in Ruthenium Pincer Complexes

of 5-coordinated square-pyramidal 16e− unsaturated ruthenium pincer complexes were also prepared in recent years. The pincer ligand frameworks also have the ability to stabilize fourcoordinate 16e− Ru(0) and 14e− Ru(II) species in unusual square-planar and trigonal pyramidal geometries. Schneider and co-workers described the electronic structure of such unusual pincer complexes in great detail in a recent review.27 Uncommon reactivities of such ruthenium pincer complexes with unusual oxidation states and geometries are concisely considered here. 2.4.1. Square-Planar 16e− Ru(0) Pincer Complexes. Berry and co-workers reported the synthesis of 16e− Ru(0) complexes, which adopt a square-planar geometry (Scheme 5d). The X-ray structure of complex 27 [(NNN)Ru-(μ-N2)Ru(NNN)] clearly revealed the two square-planar ruthenium centers (Scheme 18) with NNN pincer ligands where the ruthenium atoms are bridged by a linear dinitrogen ligand (RuNN = 173.1(4) and 173.6(4) Å) and the two Ru(NNN) planes are perpendicular, interdigitating bulky aryl groups to provide the required steric protection for the 16e− Ru(0) centers. Complex 27 underwent interesting sequential Si−H and Si−Cl bond activations described in section 3.6. In the water splitting reaction promoted by the dearomatized PNN Ru complex 5a (see Scheme 34), the intermediate cisdihydroxo complex 57 presumably undergoes elimination of hydrogen peroxide under photolytic conditions to provide the 16e− Ru(II) complex 5a. This process might proceed via the

Figure 1. Qualitative valence d-orbital splitting of square-planar geometry for d6 complexes with pure σ-donor ligands (a), with one weak π-donor ligand (b), and one strong π-donor ligand (c). Reproduced with permission from ref 48. Copyright 2010 Wiley-VCH.

Valence orbital splitting further lifts the dxz/dyz degeneracy upon introducing a perpendicular single-faced π-donor like an amido ligand. The dxz orbital is further destabilized considerably, if the π-donor is placed along the x-axis, depending on the extent of N−M π-donation (Figure 1b,c). Thus, two electronic configurations with an intermediate-spin state (S = 1) with a singly occupied N−M π-orbital [d(xy, yz, z2)5d(xz)1d(x2−y2)0] (Figure 1b) or a low-spin configuration (S = 0) with vacant N−M π-orbital [d(xy, yz, z2)6d(xz)0d(x2− y2)0] (Figure 1c) are possible. Therefore, the singlet−triplet gap is directly influenced by the N−M π-bond, ultimately favoring a

Scheme 18. 16e− Square-Planar Ru(0) Pincer Complexes as Isolated Complexes and Proposed Intermediates

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Scheme 20. Square-Planar 14e− Ru(II) Pincer Complexes with Singlet Ground State

low-spin over intermediate-spin ground state upon compensating the spin paring energy. In the C−H activation studies of alkyl PCP pincer complexes, based on DFT computational data, Gusev and coworkers have proposed a square-planar 14e− Ru(II) alkyl PCP pincer complex 61 with a triplet ground state as an intermediate (Figure 1a), which is in equilibrium with β- and α-hydrogen elimination products 60 and 62, respectively (Scheme 19).95 Scheme 19. Isolated and Proposed Intermediates of SquarePlanar 14e− Ru(II) Complexes

complexes 69 and 70, which are stabilized by the PSiP pincer ligand, resulting in a trigonal pyramidal geometry devoid of agostic interactions (Scheme 21) as clearly indicated by their solid-state structures.98

Caulton and co-workers have synthesized the four-coordinate Ru(II) pincer complexes 63a−c (Scheme 19) with a disilylamide backbone and unequivocally corroborated their solid-state structures devoid of agostic interactions. As a result, these complexes have an unconventional square-planar coordination geometry with a 14e− triplet ground-state configuration (Figure 1a).96 DFT studies of these molecules indicated that the highest singly occupied molecular orbital (SOMO) of 63a displays a characteristic strong dxz-orbital, which can be attributed to the π-interaction with the disilylamido π-donor (Figure 1b). However, the interaction is too weak to force the spin pairing. Complex 63a exhibits unusual reactivity. When reacted with the azide TMSN3, the chloride ligand is replaced by an azide ligand, leading to the rapid oxidation of Ru(II) to generate [(PNP)RuIVN] by liberating dinitrogen.97 Schneider and co-workers have reported27,48 recently the five-coordinate Ru(II) amino complex 64, which allowed facile access to the square-planar Ru(II) amido 65, enamide 68, and dienamido 66 complexes (Scheme 20). Complex 65 adopts a singlet ground state as a result of increased π-donation from the chelating dialkyl amido ligand, relative to the disilyl amido ligand of complexes 63. Upon treatment with base, complex 64 underwent HCl elimination to generate the square-planar Ru(II) amido complex 65, isolated at lower temperature in over 80% yield (Scheme 20). Complex 65 is diamagnetic. DFT calculations revealed a small singlet−triplet gap. The X-ray structure of 65 showed a short Ru−N bond (1.890(2) Å), in agreement with DFT-optimized structure for the singlet ground state (1.90 Å). The DFT-optimized structure for the triplet ground state showed a longer Ru−N bond (1.99 Å). These structural features indicate that the square-planar complexes with strong amido π-donors are in the singlet ground state; that is, the N−Ru π*-orbital is vacant (Figure 1c) but singly occupied in the triplet state. 2.4.3. Trigonal Pyramidal 14e− Ru(II) Pincer Complexes. Very recently, the groups of Turculet and Tobisch reported the synthesis of four-coordinate, 14-electron Ru(II)

Scheme 21. Trigonal Pyramidal 14-Electron Ru(II) Pincer Complexes

3. BOND ACTIVATION The main modes of bond activation by metal complexes are oxidative addition and heterolytic cleavage, as illustrated in Scheme 22, as well as homolytic cleavage (not discussed here). For example, activation of dihydrogen proceeds via a σ-H2 intermediate, stabilized by back bonding from a filled metal d orbital to the dihydrogen σ* orbital. With a low-valent (typically Ru(0)), electron-rich ruthenium center, increased back-donation leads to H−H bond activation by oxidative addition to provide a Ru-dihydride, concomitant with a formal increase of the metal oxidation state by two. However, with an electrophilic Ru center (such as Ru(II), or when strong π acceptors are bound to the metal), oxidative addition is disfavored and heterolytic activation may take place, in which the coordinated H2 (or HX) can be deprotonated intramolecularly or intermolecularly, with no change in the metal oxidation state, as shown in Scheme 22b. While the proton is 12033

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Scheme 22. Oxidative Addition versus Heterolytic Cleavage of H−H and H−X Bonds

Scheme 24. Heterolytic Activation of Hydrogen by Aromatization−Dearomatization Process

abstracted by an internal site in intramolecular heterolytic splitting, intermolecular activation requires an external base. Such intramolecular heterolytic splitting is also applicable to C−H or other heteroatom−H bond activation as is frequently observed with ruthenium pincer complexes and discussed in this section. 3.1. Activation of the H−H Bond

As shown in Scheme 4b, formation of a dihydride complex such as [(PNPtBu)Ru(H)2(H2)] 20 is a result of dihydrogen activation by oxidative addition due to the electron-rich ruthenium center as discussed above. Gunnnoe and co-workers reported a five-coordinate amido complex (PCP)Ru(CO)(NH2) 71, which heterolytically activates H2, as 71 has the required vacant coordination site for H2 coordination and a basic amido ligand, which abstracts intramolecularly a proton from coordinated H2, followed by dissociation of the formed ammonia (BDERu−NH3 = 12.6 kcal/mol), providing the complex (PCP)RuH(CO) 72 (Scheme 23).99

Figure 2. X-ray structure of complex 5b (50% probability level). Hydrogen atoms (except hydrides) are omitted for clarity. Reproduced with permission from ref 100. Copyright 2011 Nature Publishing Group.

trans-dihydride complexes 3b−5b slowly lose H2 at room temperature to regenerate complexes 3a−5a, respectively, setting the stage for several catalytic processes (see below) including the production of molecular hydrogen from biorenewable sources. As discussed in the MLC section, the acridine pincer complex 9 also heterolytically activates dihydrogen (Scheme 16).89 The amido ruthenium pincer complex 73 is in equilibrium with complexes 74 and 75. Formation of amino trans-dihydride complex 74 results from the reversible heterolysis of dihydrogen (Scheme 25).49,101 The trans-dihydrides of 74, which resonate at δ = −8.00 and δ = −8.52 ppm, are magnetically inequivalent (2JPH = 16.7−24.3 Hz), due to the proximity of one of the hydrides to the backbone amino proton. As observed in heterolysis of hydrogen by Ir pincer complexes,102 DFT studies suggest that proton transfer from ruthenium to the amido nitrogen is facilitated by the presence of water, which forms a hydrogen bond with both amido nitrogen and H2, leading to a six-membered transition state and lowering the barrier for proton transfer.91,92 Complex 73 was found to be an active dehydrogenation catalyst for ammoniaborane and hydrogenation reactions as discussed below. The heterolytic activation of dihydrogen by NH/H2 MLC was reported by Fryzuk and co-workers in 1987 with pincer Ir and Rh complexes.103 Using the pincer complex [RuCl(PPh3)-

Scheme 23. Heterolytic Activation of Hydrogen

The dearomatized pincer complexes 3a−5a developed by Milstein react with molecular hydrogen at room temperature, undergoing rearomatization to provide the trans-dihydride complexes of 3b−5b, respectively, upon heterolysis of dihydrogen (Scheme 24).35,36 In the 1H NMR spectra, the magnetically equivalent trans-dihydrides of 3b and 4b resonate as a triplet at δ = −4.96 ppm (2JPH = 20.0 Hz) and δ = −4.90 ppm (2JPH = 17.0 Hz), respectively, whereas they display a doublet at δ = −4.06 ppm (2JPH = 17.0 Hz) for complex 5b. Further, the structure of the trans-dihydride complex 5b was determined by a single-crystal X-ray analysis (Figure 2).100 The 12034

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Scheme 25. Heterolytic Activation of Hydrogen by Amide−Amine Interconversion

Scheme 26. Intramolecular Activation of sp3 C−H Bonds

(N(SiMe2CH2PPh2)2)], they reported in 1991 that reaction with H2 resulted in a mixture of Ru−H complexes, albeit the reversibility of the reaction was not observed.104 Recently, Koridze and co-workers reported that a metallocene-derived PCP pincer ruthenium complex also activates molecular hydrogen heterolytically.105

Scheme 27. Double C−H Activation Leading to the Formation of a Hydrido Carbene Complex

3.2. Activation of C−H Bonds

While many PCP-type ruthenium pincer complexes were formed as a result of C−H activation8,10,106−110 or even double C−H activation52,111 of the ligand, there are only a few examples of intra- or intermolecular C−H activations by ruthenium pincer complexes, as discussed in this section. C−H activation of arenes is widespread with Ir-pincer PNP and PCP complexes.112,113 However, such sp2 C−H activation by Rupincer complexes is rarely encountered. An example of intramolecular C−H activation in a Ru pincer complex was reported by Fryzuk and co-workers.104 Gunnnoe and co-workers reported that the five-coordinate complexes [(PCP)Ru(CO)(NH2)] 71 and [(PCP)Ru(CO)(CH3)] 76 liberate ammonia and methane, respectively, to generate the cyclometalated PCP ruthenium pincer complex 77 as a result of intramolecular sp3 C−H activation (Scheme 26).99 The conversion rate of the methyl complex 76 to 77 is approximately 5 times faster (Kobs = 3.2(1) × 10−4 s−1 at 50 °C) than the analogous conversion with the amido complex 71 (Kobs = 6.0(3) × 10−5 s−1 at 50 °C). However, attempted intermolecular C−H activation of methane by complex 71 was not successful and led only to intramolecular C−H activation to provide 77. Gusev and co-workers reported a double C−H activation reaction in a pincer complex.114 Caulton’s square-planar Ru(II) pincer complex 63a reacted with 1 equiv of MeLi at −78 °C to afford the hydrido−carbene complex 79 as a result of double C−H activation of a single methyl group (Scheme 27). Apart from the characteristic spectroscopic features, DFT calculations indicate that the Ru−C bond length (2.08 Å) in complex 78 decreases to 1.84 Å in 79, in line with formation of a Ru− carbene. The intermediate complex 78 facilitates the C−H agostic interaction and the observed loss of methane. The hydrido−carbene complex 79 reacts with excess of pyridine, immediately forming the diamagnetic η2-pyridyl complex 80 as a result of ortho sp2 C−H activation.115 Recently, Milstein reported the intramolecular sp3 C−H activation of expanded PNN ruthenium pincer complexes.41 Upon deprotonation of the saturated Ru(II) PNN pincer

complexes (7 and 8), containing alkyl or cycloalkyl groups on one of the methylene arms, the dearomatized pincer complexes 7a and 8a were formed (Scheme 28). Attempted synthesis of 7a also resulted in intramolecular C−H activation and quantitative formation of the cyclometalated 7b after 4 h. Independent synthesis of 7a was possible using the base KHMDS (potassium hexamethyldisilazide) at −35 °C in toluene-d8, although upon workup only 7b was obtained as a single diastereoisomer, implying that 7a is indeed an intermediate that undergoes cyclometalation and concomitant aromatization to provide 7b. The X-ray structure of 7b exhibits a highly distorted octahedron with the PNC donors coordinated in a pseudomeridional manner (Figure 3). The PNN complex 8a, analogous to 7a, was relatively stable due to steric rigidity, and the conversion to cyclometalated aromatized complex 8b occurred slowly over 5 days. Dearomatized pincer complexes, particularly the bipyridine derived [(PNN)Ru(H)(CO)] 6a and its parent complex 6, are involved in the sp3 CH activation/exchange of α- and βpositions of alcohols with D2O, as will be discussed in section 4.3.1. 3.3. Activation of N−H Bonds

As in H2 and C−H activation reactions, MLC of pyridinederived pincer complexes also enables N−H activation of amines and ammonia. As described by Milstein, upon reaction of the dearomatized PNP complex 4a with electron-poor anilines, the unsaturated ligand arm was protonated, and the pyridine ring underwent rearomatization as a result of N−H activation (Scheme 29).116 The saturated amide complexes 82a 12035

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Scheme 28. Intramolecular Activation of sp3 C−H Bond by MLC

dichloroaniline with complex 4a provided equilibrium mixtures of aromatized N−H activated amide complexes 82c and 82d, and the starting 4a, despite the presence of excess of haloanilines. This observation of reversible N−H bond activation at room temperature was unique, and indicated the low barrier for these reactions. For electron-rich amines and ammonia, the amine-coordinated unsaturated complexes of type 81 are thermodynamically favored. Upon reaction of complex 4a with ND3, formation of the deuterated complex 83 was observed after 5 min at room temperature, showing N−D activation (Scheme 30). The 1H NMR spectrum of 83 confirmed that deuteration at the methylene arm is stereospecific as only one of the two CH2 arm protons disappeared. No exchange occurred with vinylic protons, and such high selectivity indicated that the activation process on these types of pincer systems occurs only intramolecularly on one face of the ligand with the coordinated ND3 ligand. This observation indicated that other activation processes could also be stereoselective. The trend observed in the experiment was in agreement with DFT studies carried out on the N−H activation reactions (Figure 4). In the reaction of 2-bromoaniline with 4a, the unbound state (I) and the activated state (III) have similar energies with a connecting barrier of 20 kcal/mol. The N−H activated complex of isopropylamine is 16.8 kcal mol−1 above the unbound state, and experimentally it reacted with complex 4a upon warming to 80 °C, whereas in the case of the amines that underwent irreversible N−H activation at room temperature the calculated activated complexes (III) are energetically below the unbound state (I) as expected; barriers for the exchange between amine coordinated (II) and activated (III) states are accessible at room temperature. PNP Rh(I) pincer complexes also activate N−H bonds by similar MLC.117 N−H bond activation by Pd(II) and Cu(I)

Figure 3. Single-crystal X-ray structure of 7b. Reproduced with permission from ref 41. Copyright 2013 American Chemical Society.

Scheme 29. N−H Activation of Amines by MLC

and 82b were obtained in pure form from the reaction of complex 4a with 4-nitroaniline and 2-chloro-4-nitroaniline, respectively, and their symmetrical structures were evident from the 31P NMR (single signal for each complex) and 1H NMR spectra. However, the reaction of 2-bromoaniline and 3,4Scheme 30. N−D Activation of ND3 by MLC

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Figure 4. (left) Calculated free energies (ΔG298, kcal mol−1) for (I) the unbound starting materials and (II) coordinated and (III) NH-activated amine complexes. (right) Calculated structure of TS(II−III), the transition state for activation of NH3 (H’s on methyl groups are omitted for clarity). Reproduced with permission from ref 116. Copyright 2010 American Chemical Society.

β-hydride elimination mechanism may not be operative in these systems. Alternatively, either dissociation of the alkoxo ligand and further hydride transfer from the anionic alkoxide to the metal center120 or a direct hydrogen transfer from the alcohol to the dearomatized complex, prior to the formation of an alkoxo complex,121 is suggested to be operative to provide the trans-dihydride complex 4b and aldehyde. However, the in situ analysis did not detect the formation of a free aldehyde; rather, an aldehyde adduct 85 was formed (Scheme 31) in which the aldehyde oxygen is connected to Ru (Ru−O) and the aldehyde carbonyl carbon forms a C−C bond with the pincer ligand arm. This unusual C−C coupling was found to be reversible, constituting a new mode of MLC (see section 3.7). 3.4.2. O−H Bond Activation of Water. Upon reaction of the dearomatized PNN ruthenium complex 5a with excess water, O−H activation takes place at room temperature with concomitant aromatization of the pyridine ring, and quantitative formation of the trans-hydrido-hydroxo complex 86 (Scheme 32).122 Similar to alcohol O−H bond activation, this reaction was also reversible, and the complex 5a was quantitatively regenerated from 86 under vacuum or upon heating at 65 °C in benzene. When 5a was treated with 1 equiv of D2O, one deuterium atom was incorporated into the benzylic group to provide 86a. Further, the use of labeled water H217O

complexes of lutidine derived bidentate PN-ligand is reported by van der Vlugt and co-workers.118 3.4. Activation of O−H Bonds

3.4.1. O−H Bond Activation of Alcohols. When the dearomatized complex 4a was reacted with ethanol and benzyl alcohols at −80 °C, the aromatized alkoxo complexes 84a and 84b, respectively, were obtained as a result of O−H activation (Scheme 31).119 Surprisingly, the reactions were reversible even Scheme 31. O−H Bond Activation of Alcohols by the Dearomatized Pincer Complex 4a

Scheme 32. Activation of O−H Bond of Water by Dearomatized Complex 5a at this very low temperature, and a 3-fold excess of alcohols is required to drive the equilibrium toward formation of the aromatized complexes in around 90% yield. The aromatic symmetrical structures of 84a and 84b were unequivocally established spectroscopically. Selective spin saturation transfer (SST) of the methylene protons of the alkoxo ligands of complex 84 resulted in intensity decrease of the methylene protons of free alcohols that were present in excess and clearly confirmed the dynamic equilibrium between 4a and 84a or 84b. Upon warming these reaction mixtures to −30 °C, alcohol dehydrogenation was completed, and both 84a and 84b disappeared. In the absence of a hemilabile arm, the integrity of the PNP complexes 84a and 84b is likely to be retained, and the observed dehydrogenation from the saturated complexes devoid of empty coordination sites indicates that a conventional 12037

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resulted in the formation of 86b, providing direct spectral evidence for the hydroxo ligand coordination to ruthenium, as the 17O NMR spectrum in THF displayed a singlet signal at 32.43 ppm. Coordination of water at the vacant site, that is, trans to the hydride, and further migration of a proton to the dearomatized side arm was the suggested mechanism, which was also indicated by several DFT studies.121,123−126 The reaction of 5a with excess water provided single crystals of 86, and the solid-state structure was unequivocally corroborated by X-ray analysis (Figure 5).

Scheme 34. Consecutive Thermal H2 and Light-Induced O2 Evolution from Water

which was shown by an independent experiment to be an excellent catalyst for H2O2 disproportionation. This work establishes a new approach toward a complete stoichiometric cycle for the generation of H2 and O2 from water promoted by a homogeneous transition metal complex. Extensive DFT studies indicated that the photolytic reductive elimination of H2O2 might occur from a dissociative triplet state via a singlet−triplet crossing.123b In line with all experimental findings, another DFT calculation by Fang showed that a lower energy pathway for triplet O2 formation involves a nonadiabatic two-step process in which concerted hydrogen transfer and dehydration involving two molecules of complex 57 take place (Scheme 35). This O−O bond formation is intramolecular, and occurs along the T1 pathway, as a result of the S1 to T1 intersystem crossing (ISC) being very efficient.123c

Figure 5. Structure of 86. Reproduced with permission from ref 122a. Copyright 2009 AAAS.

Further heating of complex 86 in water at 100 °C resulted in the cis-dihydroxo complex 57 with liberation of hydrogen (Scheme 33). DFT studies carried out by several Scheme 33. Thermal and Photolytic Reaction of Complexes 86 and 57, Respectively

3.5. Activation of B−H Bonds

Upon reaction of the dearomatized PNP ruthenium pincer complex 4a with pinacol and catechol borane, B−H bond cleavage via MLC was observed.127 Because of the Lewis acidic nature of boronic ester derivatives, dehydrogenative addition of the B−H bond to the metal center and unsaturated ligand arm of complex 4a resulted in the formation of the new complexes 87 and 88 in which the boryl motifs are bonded to the benzylic arm of the pincer complexes (Scheme 36). Presumably, the complexes 87 and 88 were formed via the intermediacy of unobserved aromatic trans-dihydride ruthenium pincer complexes 87a and 88a. The mechanism of this C−B bond formation at the benzylic arm rather than formation of Ru−B bond is explained by the DFT calculations performed for the reaction of 4a with catechol borane for which two possible reaction pathways are considered, and the corresponding potential energy surfaces are presented in Figure 6. Complex A that results from the C−B bond formation is located 20 kJ mol−1 below the reactants, whereas B−H bond coordination to the ruthenium center to generate A′ is endergonic by 40 kJ mol−1. As a B−C bond is formed in A, a hydrogen atom bound to boron weakly coordinates to Ru, resulting in elongation of the B−H bond by 0.19 Å relative to the free catechol borane. The B−H bond coordinated to Ru in A′ is elongated by 0.11 Å. Consequently, the barrier for the addition of the B−H bond across the ruthenium and the unsaturated arm in A and A′ to provide B and B′, respectively, is 58 kJ mol−1 lower for A than A′. Thus,

groups121,123−126 on this transformation indicated that H2 release from complex 86 occurs from coupling of the hydride ligand with an acidic proton from the side arm and the resulting dearomatized intermediate reacts with water to provide 57. When complex 57 was irradiated in the 320−450 nm range, O2 liberation with regeneration of complex 86 was observed. Using mixed isotopically labeled 57 17OH/18OH demonstrated unequivocally that the process of O−O bond formation is intramolecular, constituting a fundamentally new mode of O− O bond formation by photolytic coupling of OH ligands. A stepwise cycle in which H2 and O2 are released in consecutive steps was achieved upon combining the above two stoichiometric reactions (Scheme 34). Thermal reaction of complex 86 with water liberates H2 to provide complex 57, which upon subsequent photolysis may generate hydrogen peroxide by reductive elimination of two cis-hydroxo ligands, possibly forming a Ru(0) intermediate 58, which converts to complex 5a by proton migration from the methylene arm to the ruthenium center. The formed hydrogen peroxide decomposed rapidly into O2 and water, perhaps catalyzed by complex 5a, 12038

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Scheme 35. A DFT-Based Mechanism of O2 Formation According to Fang123c

= −21.91 ppm for the intermediate complex [(NNN)RuHCl(CH2CH2)] as a result of Et3Si−H activation.57 Berry and co-workers also reported the activation of Si−Cl bonds.58 When the Ru(0) complex 27 was reacted with tetravalent heterocyclic silanes such as H(Cl)Si(NN) [(Si(NN) = N,N′-bis(neopentyl)-1,2-phenylenedi(amino)silylene)Si-1,2(NCH2tBu)2C6H4] in pentane at room temperature, the ruthenium silylene complex 91 was formed rapidly as a result of sequential Si−H and Si−Cl bond activations (Scheme 38). Upon oxidative addition of the Si−H bond, 1,2-migration of Si−Cl might have followed to provide complex 91 that displays a pseudo octahedral geometry in the single-crystal X-ray structure with hydride and chloride ligands in the trans positions. Successful activation of these two bonds can be attributed to substrate choice of cyclic diaminohydrochlorosilane H(Cl)Si(NN), which has a weak Si−Cl bond and can provide steric protection to the silylene ligated to Ru(II) in complex 91. The silylene ligand reversibly dissociates and was trapped by the more electron-rich Ru(0) complex 27 to provide Ru(0) silylene complex [(NNN)Ru(N2){Si(NN)}].

Scheme 36. B−H Activation by PNP Ruthenium Pincer Complex 4a

although B′ is more stable than B, the formation of B′ under the experimental conditions is excluded. Liberation of H2 from the B provides the dearomatized 88 through the H2intermediate C. The transition state for the conversion of B/ C is higher than expected for a reaction occurring at room temperature. However, as was demonstrated102a already, the involvement of adventitious water could diminish this barrier.

3.7. Activation of CO Bonds and Reversible C−C Bond Formation

Upon dehydrogenation of primary alcohols, the generated aldehyde attacks the dearomatized arm to form the aldehyde adduct of PNP complex 4a. To verify this hypothesis, 4a was reacted independently with acetaldehyde and benzaldehyde at −70 °C, resulting in immediate quantitative formation of adducts 85a and 85b, respectively (Scheme 39). This facile formation of the aldehyde adduct is reversible, and regeneration of the free aldehydes was observed upon warming the reaction mixture to −50 °C. The aldehydes and the dearomatized complex 4a were quantitatively regenerated from their adducts at room temperature.119 This process involves facile activation of CO bond, reversible formation of a Ru−O bond, and a

3.6. Activation of Si−H and Si−Cl Bonds

Berry and co-workers reported that the NNN Ru(II) ethylene pincer complexes 89a and 90a (NNN = 2,6-bis(arylimino)pyridyl) react with excess of triethylsilane in toluene to provide Si−H bond activation, forming the bidentate η6-arene complexes 26a and 27a, respectively, together with Et3SiCl, ethane, and Et4Si (Scheme 37). 1H NMR studies of the reaction mixture of 89a show formation of a Ru−H signal at δ 12039

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Figure 6. Reaction of 4a with catechol borane: Simplified potential energy surface. Gibbs free energies (ΔG) are given in kJ mol−1 at 298 K. Reproduced with permission from ref 127. Copyright 2014 American Chemical Society.

Scheme 37. Activation of Si−H Bond

Scheme 38. Activation of Si−Cl Bond

Scheme 39. Activation of Aldehyde CO Bond and Reversible C−C and Ru−O Bond Formation by 4a reversible C−C bond formation between the aldehyde carbonyl carbon and the dearomatized vinylic carbon of 4a leading to the aromatization−dearomatization of pyridine ring. Recently, Sanford and co-workers extended this adduct formation of carbonyl compounds with the dearomatized PNN complex 5a. In addition to aldehydes (95), adducts of complex 5a were also formed with esters (92 and 93) and a ketone (94) upon CO bond activation (Scheme 40).128 As demonstrated previously by Milstein,119 the adduct formation occurred at the phosphine arm at −50 °C. However, warming the reaction

mixture to room temperature led to the formation of the thermodynamically preferred carbonyl adducts 92, and 93−95, 12040

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Scheme 40. CO Activation and Reversible C−C Bond Formation of PNN Ru Complex 5a with Carbonyl Compounds

Scheme 42. Activation of CO2 by Dearomatized Complex 4a

form, and single-crystal X-ray structure of 96 shows a distorted octahedral geometry around Ru(II) center, which also clearly establishes aromatization of the pyridine ring (Figure 7).

Figure 7. X-ray structure of 96: activated CO2 adduct. Reproduced with permission from ref 131. Copyright 2012 Wiley-VCH.

in which the carbonyl carbons are connected to the amine arm.129 The structures of complexes 92 and 93 were confirmed by single-crystal X-ray analyses. Although these adducts were found to be stable at room temperature, the reactions are generally reversible, and the determined equilibrium constants (in benzene-d6 at room temperature) were found to be sensitive to steric and electronic effects. Apparently, the reaction proceeds via reversible C−C bond formation kinetically at the phosphine arm, and under the reaction conditions, complex 5a with unsaturation at phosphine arm undergoes tautomerization to 5a′ (Scheme 41) that possesses unsaturation at the amine arm, which leads to the thermodynamically preferred activated carbonyl adducts.

DFT calculations of various modes of CO2 adduct formation confirmed that, out of several possibilities, the [1,3]-adduct 96 is the most stable complex (Figure 8). The conventional CO2

Scheme 41. Tautomer of 5a Figure 8. DFT-optimized geometries of compounds 4a, 96−99, and the TS(4a−96). P = PtBu2; tBu groups are omitted for clarity. Reproduced with permission from ref 131. Copyright 2012 WileyVCH.

coordination modes of η1-coordination of oxygen to ruthenium (97), η2-coordination of the CO bond (98), and inverse [1,3]-adduct (99) involving C−O and Ru−C bonds were considered and found to be less stable than 4a, whereas the [1,3]-addition product 96 is more stable than 4a by 7.2 kcal mol−1 in benzene. The located TS(4a−96) involves concerted addition of CO2 to the coordinatively unsaturated complex 4a via the exocyclic methine carbon C1 and the Ru center. In further agreement with experimental observation, DFT studies using polar THF and nonpolar benzene did not provide any significant differences in the relative energies, which is indicative of a concerted mechanism (Table 1).

3.8. Activation of Carbon Dioxide

Generally CO2 can bind with metal centers via π coordination to a CO double bond, σ-bond to the carbon, and often to one of the oxygen atoms.130 When complex 4a reacted with CO2 (1 bar), it displayed an unusual mode of activation that involved reversible C−C and Ru−O bond formation.131 Similar to the activation of carbonyl compounds, CO2 activation is reversible, and adduct 96 loses CO2 under vacuum to regenerate complex 4a, and it also exchanges bound CO2 with labeled free 13CO2 in solution at ambient temperature (Scheme 42). However, the CO2 adduct 96 is stable in the solid 12041

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tautomer 5a′ (Scheme 41). In addition, the reaction of complex 5a with CO2/H2 mixture provided the formate complex 102 in 88% yield in addition to the formation of 101 (Scheme 43).134 The structures of complexes 101 and 102 were unequivocally corroborated by single-crystal X-ray analyses, which show a highly distorted octahedral geometry around ruthenium center of 101, and a relatively less distorted one for 102 (Figure 9a,b). Formation of a Ru formate complex was also observed when the PNS Ru dihydride pincer complex 103 was reacted with CO2, leading to complex 104 (Scheme 44).39

Table 1. Relative Energies [kcal/mol; SMD-PBE0+dv3/ccpV(D+d)Z-PP//DF-PBE+dv2/SDD(d) Level of Theory] complex

THF

benzene

4a TS(4a−96) 96 97 98 99

0.0 8.1 −7.3 12.8 21.2 21.7

0.0 7.5 −7.2 10.8 19.4 22.1

Parallel to the studies of CO2 activation using the PNP ruthenium pincer complex 4a discussed above, Sanford and coworkers reported that the PNN ruthenium pincer complex 5a also undergoes similar CO2 activation.132 Reaction of complex 5a with 1 atm of CO2 at room temperature gave the [1,3]adduct 100 in which CO2 is connected to the phosphine arm of 5a.133 Upon standing in solution overnight or heating at 70 °C for 15 min, complex 100 transformed to the thermodynamically more stable complex 101 in which CO2 is bound to the amine arm carbon (Scheme 43), via the (unobserved) dearomatized

Scheme 44. Activation of CO2 by PNS Pincer Complexes

Scheme 43. Activation of CO2 by Dearomatized Complex 5a

4. CATALYSIS 4.1. Dehydrogenation Reactions

4.1.1. Dehydrogenation of Alkanes. Dehydrogenation of alkanes to alkenes is a difficult transformation in homogeneous catalysis, requiring high temperatures and hence requiring very thermally stable metal complexes. As the mer coordination of pincer ligands provides a good compromise between stability and reactivity, pincer complexes can act as effective catalysts in dehydrogenation of alkanes. Early reports pertained to iridium14,23,135,136 and to less reactive rhodium pincer complexes.137 Recently, Roddick and co-workers reported the

Figure 9. ORTEP diagrams of 101 and 102. Reproduced with permission from refs 133 and 134. Copyright 2012 and 2013 American Chemical Society. 12042

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dehydrogenation of cyclooctane in the presence or absence of a hydrogen acceptor using the PCP pincer ruthenium complex 43, bearing low electron density at the metal center.73 Roddick’s complex is the first efficient ruthenium catalyst for transfer alkane dehydrogenation under thermal conditions. Heating complex 43 with a 1:1 mixture of cyclooctane and tertbutylethylene (acceptor) at 150 and 200 °C provided 180 and 1000 turnovers h−1 of cyclooctene, respectively. Refluxing 2.5 mM solution of complex 43 in cyclooctane provided 10 turnovers of cyclooctene in 1 h (Scheme 45). The modest

Scheme 47. Acceptorless Dehydrogenation of Secondary Alcohols Catalyzed by CNN Ru Pincer Complexes

Scheme 45. Acceptorless Dehydrogenation of Alkanes by PCP Ru Pincer Complex 43

was found to be a more active catalyst in the dehydrogenation of various secondary alcohols into ketones.141 Although good selectivity and efficiency were achieved in the dehydrogenation of secondary alcohols with catalyst 1 and 45/ 50, activation by a catalytic amount of a base was necessary. In an attempt to totally eliminate the base, the electron-rich PNP and PNN type ruthenium(II) hydrido borohydride pincer complexes 105 and 2 were developed. Thus, when secondary alcohols were refluxed with 0.1 mol % of catalysts 105 or 2, dehydrogenation resulted under neutral conditions (Table 2). While the PNP complex 105 exhibited less reactivity, the PNN pincer complex 2 provided superior catalysis.34

catalytic activity of 43 in the dehydrogenation of alkanes was attributed to thermal decomposition. Further catalytic design might result in more active ruthenium pincer complexes for dehydrogenation of alkanes. 4.1.2. Dehydrogenation of Alcohols. Dehydrogenation of alcohols can be carried out using sacrificial hydrogen acceptors or under acceptorless conditions. Although much progress has been achieved in the dehydrogenation in the presence of acceptors, its potential use is limited as it suffers from concomitant production of stoichiometric waste. Robinson has performed pioneering work on acceptorless alcohol dehydrogenation using [Ru(OCOCF 3 ) 2 (CO)(PR 3 ) 2 ]/ CF3COOH.138 Cole-Hamilton139 and Saito140 independently investigated acceptorless dehydrogenation of alcohols in the 1970s and 1980s, respectively. Although devoid of hydrogen acceptors, these early reports required an acid as a hydride ion acceptor. In 2004, effective catalytic acceptorless alcohol dehydrogenation was reported using an electron-rich, bulky ruthenium PNP pincer complex 1.32 Heating of complex 1 (0.4 mol %) with NaOiPr (0.4 mol %) and 2-propanol (1000 equiv) at 83 °C for 24 h provided 265 TON of acetone (Scheme 46). Under similar experimental conditions when the reaction was performed for 70 h with 2 equiv of base and excess of 2propanol (6 mL), 924 TON was attained.

Table 2. Dehydrogenation of Secondary Alcohols under Neutral Conditions

Scheme 46. Acceptorless Dehydrogenation of Secondary Alcohols Catalyzed by 1

R

R1

cat.

time (h)

yield (%)

TON

Ph Ph Ph Me

Me Me Me Me

105 2 2 2

24 24 48 48

27 87 93 90

270 870 930 900

Beller and co-workers also screened various known Ru and Ir pincer complexes for the dehydrogenation of secondary alcohols under acceptorless conditions.142 Although a large excess of base was used, pincer complexes and combinations of pincer ligands and metal precursors have shown impressive TONs and TOFs. Using aliphatic PNHP pincer ligand (PNHP = bis[2-(diisopropylphosphino)ethyl]amine) and ruthenium precursor [RuH2(PPh3)3CO] (which could result in the in situ formation of the pincer complex [(PNHP)Ru(H)2CO] 106), TOFs of 8382 and 1483 h−1 (2 h) for dehydrogenations of isopropyl alcohol and ethanol, respectively, were achieved under mild conditions. Recently, RuH2(CO)(PPh3)3 and Shvo’s catalysts were also shown to catalyze143 the acceptorless dehydrogenation of alcohols under neutral conditions employing harsh reactions conditions of refluxing mesitylene (bp, 165 °C).

Baratta and co-workers reported the ruthenium (as well as osmium) CNN pincer complexes 45 and 50 containing an NH donor that catalyzed the dehydrogenation of secondary alcohols under acceptorless conditions in the presence of base upon heating at 130 °C in tert-butanol (Scheme 47).141 However, the bidentate phosphine complex trans-[RuCl2(dppf)(en)] (dppf = 1,1′-bis(diphenyl-phosphino)ferrocene; en = ethylenediamine) 12043

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As the concept of “hydrogen-economy”144 gets increased acceptance as a result of dwindling fossil fuels sources, the dehydrogenation of alcohols, particularly alcohols derived from biomass, gains importance and has received widespread investigation.145 In this regard, methanol is a prominent renewable resource with 12.6% of hydrogen w/w content. However, liberation of hydrogen from methanol by oxidation is a challenging task and requires harsh reaction conditions. Recently, Beller and co-workers reported the efficient dehydrogenation of methanol to dihydrogen and CO2 (trapped as sodium carbonate) in basic aqueous solution using PNP pincer complexes with aliphatic backbones [(HN(CH 2 CH 2 PPh 2 ) 2 ) and (HN(CH 2 CH 2 P i Pr 2 ) 2 )], Ru− MACHO, [RuHCl(CO)(PNHP)] 12, and [RuHCl(CO)(PNHP)] 107, which provided TONs in excess of 350 000 under mild experimental conditions (Scheme 48).146 When the

Very recently, complex 6 was also reported to catalyze methanol reforming to H2 and CO2.150 A solution of methanol (20 mmol, 1 equiv), KOH (2 equiv), and water (2 mL) with a cosolvent toluene (2 mL) was heated with complex 6 (0.0025 mol %), resulting in the formation of molecular hydrogen in 80% yield over 9 days. GC analysis indicated the presence of only H2 in the gas phase as the CO2 formed was captured as carbonate. The organic layer of this reaction mixture was separated and consecutively used for two further similar reactions, which resulted in H2 production in 82% and 80% yields, respectively. Thus, this catalytic system is robust, remains active over a month, and provided TON of ∼29 000 for methanol reforming. Complex 6 also catalyzed the decomposition of formic acid to H2 and CO2 in triethylamine at room temperature. 4.1.3. Dehydrogenation of Amines. While the dehydrogenation of alcohols is well documented, the dehydrogenation of amines is much less investigated, and the known methods use hydrogen acceptors, excess of base, and high temperatures (160−200 °C).151 Recently, Szymczak and co-workers reported a phthalimide-derived Ru(II) NNN pincer complex 108 that catalyzed the dehydrogenation of primary amines to nitriles, and secondary amines to imines, under oxidant free, acceptorless conditions (Scheme 49).152 When the reaction was

Scheme 48. Homogeneous Aqueous Methanol-Reforming Process

Scheme 49. Dehydrogenation of Amines

dehydrogenation was carried out using the catalyst Ru− MACHO 12 and minimal amount of base (0.1 M of NaOH in a 4:1 MeOH/H2O), liberation of 3:1 ratio of H2:CO2 gases from methanol was attained in 5−6 h, an attractive aqueous methanol-reforming process under homogeneous conditions. The high catalytic activity in the dehydrogenation of methanol is due to the MLC present in these amine PNP Ru complexes 12 and 107. Under basic conditions, the amine complexes undergo deprotonation to provide the amide complexes,27,48,49 which are the actual catalysts and dehydrogenated methanol. It was suggested that upon methanol coordination to the unsaturated amide complexes, the amide ligand undergoes protonation by methanol, whereas the metal accepts a hydride to generate formaldehyde by an outer-sphere mechanism. However, formaldehyde was not detected in solution as it likely undergoes further transformations under the reaction conditions. Regeneration of the catalytically active amide species likely proceeds via a ruthenium trans-dihydride complex. Recent DFT studies on the dehydrogenation of ethanol147 and methanol148 by the amido complex [(PNP)RuH(CO)] (generated from 107) predict that the reaction proceeds via a self-promoted mechanism in which ethanol and methanol or water assist the proton transfer, respectively, from ligated N−H to the metal center, thus facilitating the formation of H2. In an effort to remove the need for base from the aqueous methanol dehydrogenation process, Beller and co-workers recently reported the use of a bicatalytic system containing ruthenium pincer complexes such as [RuH(HBH3)(CO)(PNP)] and various trans-dihydride bidentate phosphine chelated ruthenium complexes, which catalyzed the generation of hydrogen and carbon dioxide gases.149 The mechanism of these transformations was suggested to proceed via formic acid intermediacy.

performed in a closed system, excess of hydrogen acceptor was required to promote the reaction; however, in refluxing toluene in an open system under nitrogen atmosphere, efficient dehydrogenation of amines to nitriles occurred. 4.1.4. Dehydrogenation of Amine-boranes. Primary phosphine-boranes, amine-boranes, and ammonia-borane can undergo dehydrogenative coupling to form oligomers and polymers with liberation of hydrogen. Alkyl and aryl phosphine-boranes liberate approximately 1 equiv of hydrogen153 per monomer, catalyzed by [Rh(μ-Cl)(1,5-COD)]2. 12044

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exhibited higher reactivities (TOF, 10 000 and 27 000 h−1) in the TH of ketones to the corresponding alcohols as compared to the NCN ruthenium pincer complex 38 (TOF, 1100 h−1, Table 3).164 Using the CNC ruthenium complex 28 together with a strong base such as KOtBu, Danopoulos obtained 8800 TON.59 Complex 29 provided the highest TON of 126 000 for the TH of cyclohexanone to cyclohexanol; however, TOF was lower (6300 h−1).60 Baratta and co-workers developed a series of metal complexes163 for TH using 2-propanol, including cyclometalated pincer complexes, which provided fast and robust catalysts. Using complex 45, TOF of 1.5 × 106 h−1 was achieved for the reduction of cyclohexanone to cyclohexanol, which is the highest value reported to date.75 Complex 45 also exhibited similar reactivities in the reduction of other ketones and aldehydes,77a in addition to displaying chemoselectivity in the presence of CC bonds. Baratta and co-workers also reported several complexes containing monodentate oxygen donor ligands like carboxylate, phenoxide, alkoxide, silanolate, and triflate, prepared by replacing the chloride ligand in complex 45. Such complexes were excellent catalysts in the TH of ketones using iso-propanol with NaOiPr. For example, complex 47 containing an acetate ligand exhibited TOF 1.7 × 106 h−1 for TH of cyclohexanone (Table 3, entry 9).77c While the complexes of type 47 containing a dimethyl amino donor (NMe2) showed poor catalytic activities, all of the NH2 pincer complexes with different oxygen-containing ligands like carboxylate, silanolate, and triflate reduced the ketones in basic 2-propanol and provided TOFs in the range of 6 × 105 to 3.8 × 106 h−1. The observed high reactivities of these complexes are attributable to the stabilizing intramolecular hydrogen bond (N···H···O) and faster conversion of Ru−O bond to catalytically active Ru−H/Ru−OiPr intermediates. van Koten and co-workers studied the influence of electronic factors that are imparted on the pincer complexes by varying the substituents on the phosphine donor atoms. Among the various complexes studied, [RuCl(PCPCF3)(PPh3)] 42 that contains pincer ligands with electron-withdrawing substituents such as p-trifluoromethylphenyl displayed the highest catalytic activity, leading to the TOF20 of 35 700 h−1 (when calculated at 20% conversion).72 Similar to that of complex 42, electron-rich PCP ruthenium pincer complexes containing cyclohexyl substituents on the phosphine donors were previously reported by Fogg and co-workers.70 Such a complex, 40, exhibited a TOF50 of 2500 h−1 for the hydrogenation of acetophenone under TH conditions in the presence of KOtBu/H2 additives. The PSiP Ru−silyl pincer complex 109 was also reported to catalyze the hydrosilylation reactions162 under basic conditions. Yu and Zeng have designed CNN63 and NNN55 ruthenium pincer complexes 32 and 32a, respectively, for the TH in the presence of KOiPr as base. Complex 32a, composed of pyrazolyl-imidazolyl-based hemilabile ligand, exhibited higher catalytic activity than complex 32 bearing a CNN carbene ligand (Table 3, entries 2,3). The ruthenium pincer complex 56 derived from an ONO type pyridyl nitrone ligand showed good catalytic activity in terms of yield and TON in the hydrogen transfer reactions, albeit at slow rates.84 The SNStBu Ru pincer complex 37 was used in the TH of acetophenone in 2propanol/KOH at 80 °C, reaching 95% conversion in 90 s with TOF50 of 87 000 h−1; however, the complex decomposed at this point, and no further reaction was observed. The related complex 36 showed only moderate catalytic activity in the same reaction, and 85% conversion occurred after 17 h.67 Although

Because the hydrogen capacity of ammonia-borane is very high (19.6 wt %), it appears to be an attractive candidate for chemical hydrogen-storage applications,154 and thus it was subjected to extensive dehydrogenation studies; a very significant remaining obstacle is accomplishing the reverse hydrogenation reactions. The [(POCOP)IrH2] pincer complex was reported to catalyze the dehydrogenative coupling of ammonia-borane to provide the cyclic pentamer [NH2BH2]5 with liberation of 5 equiv of hydrogen.155 Efficient dehydrogenation of ammonia borane was attained at room temperature upon reaction of the Ru PNP pincer complex 73. Use of 0.1 mol % of 73 provided more than 1 equiv of H2 with TOF 13− 21 S−1 (Scheme 50a), whereas 0.83 equiv of H2 and TON 8300 were obtained with a low loading (0.01 mol %) of catalyst 73.49 Scheme 50. Acceptorless Dehydrogenation of Ammoniaborane and Amine-borane

N-Methylamine-borane was also extensively investigated in the context of dehydrogenation activity as well as because of interest in the resulting polyaminoboranes. Several metal complexes were studied, including the iridium complexes [(POCOPtBu)IrH2] and [N(CH2CH2PiPr2)2IrH(PMe3)], and the ruthenium pincer complex 5a, which provided polymers with very high molecular weights, and the reactions proceeded with liberation of hydrogen (Scheme 50b).156 Unprecedented catalytic activities exhibited by ruthenium complexes 73 and 5a are attributed to MLC. 4.2. Transfer Hydrogenation Reactions

Transfer hydrogenation (TH) reaction attracted the interest of chemists in the last two decades as it offers a simple method for the reduction of various polar bonds under ambient temperature and pressure.157 In particular, TH provides an efficient method for the hydrogenation of ketones. Mono-,158 bi-,159,160 and tridentate161 complexes catalyze the TH reactions, as well as transition metal pincer complexes of rhodium, palladium, platinum,162 and ruthenium.163 Ruthenium pincer complexes effectively catalyze the TH under mild reaction conditions, and have shown superior reactivities163 in comparison with other ruthenium complexes.160 Thermal stability and electronic factors seem to influence the higher reactivity of the pincer complexes in TH. Various pincer complexes developed as catalysts for THs of ketones to the corresponding alcohols, using 2-propanol as the hydrogen source, are shown in Scheme 51. In particular, their reactivity for the hydrogenation of cyclohexanone to cyclohexanol is summarized in Table 3. PCP ruthenium pincer complexes (39a,b) developed by van Koten and co-workers 12045

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Scheme 51. Ruthenium Pincer Complexes Developed for TH Reactions

Table 3. TH of Cyclohexanone to Cyclohexanol Catalyzed by Various Ruthenium Pincer Complexes

a

entry

cat. (mol %)

base (mol %)

temp (°C)

time

1 2 3 4 5 6 7 8 9 10

29 (0.0007) 32 (4)+(0.1 MPa)a 32a (0.05)+(0.1 MPa) 38 (0.1) 39a (0.01) 39b (0.01) 42 (0.1) 45 (0.005) 47 (0.005) 109 (0.2)

KOH (9) KOiPr (0.2) KOiPr (0.2) KOH (2) KOH (2) KOH (2) NaOH (2) NaOH (2) NaOiPr KOtBu (2)

88 82 82 82 82 82 82 82 82 82

20 h 1.5 h 10 s 3.3 h 1.8 h 1.3 h 10 min 2 min 1 min 3h

conv. (%) 100 >98 >98 >98 98 97 99

TOF (h−1)

ref

6300 333 720 000 1100 10 000 27 000 35 700 1.5 × 106 1.7 × 106

60 63 55 164 164 164 72 75 77c 162

MPa = megapascal.

the catalysts developed thus far achieved excellent efficiency for the hydrogen transfer reactions, invariably all of these catalytic systems required basic conditions, and 2−20 mol % of various bases were used in the reactions. Toward achieving neutral reaction conditions, Chen and co-workers reported a PNN-type dearomatized ruthenium pincer complex 16a, which catalyzed

the THs without base under mild neutral reaction condition (40 °C).46 However, the reaction rate was slow, and it took 16 h to provide good yield of products. Thus, the development of catalysts that will provide high TH reaction rate without compromising conversion and yield under neutral conditions remains an interesting goal. 12046

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Scheme 52. Mechanism of THs Catalyzed by Ru Pincer Complexes

4.2.1. Mechanism of THs. Different mechanisms were proposed for TH reactions in which formation of mono and dihydride ruthenium species is invoked. Further, the presence of a high trans-influence ligand such as PPh3 or Cipso trans to a hydride ligand enhances the reactivity of Ru−H bond.88d A higher loading of base, at least 20-fold excess to the catalyst, is required to maintain good conversions. Ruthenium pincer complexes with anionic L2X type ligands, particularly complexes with one Ru−C bond, served as good catalysts for THs. Results established by van Koten, Baratta, and Fogg reveal that the Ru− C σ-bond is preserved throughout the catalysis.70,72,159a,164 Upon reaction with a strong base in 2-propanol, the Ru−halide bond is transformed to catalytically active Ru−H (M) via Ru− OiPr (L) (Scheme 52). Studies by van Koten and co-workers indicate72 that excess of base can shift the equilibrium of a penta-coordinated reactive RuII−H intermediate M toward saturated [(L2X)RuIIH(OiPr)]Na complex N (vide supra). Ketones coordinate to unsaturated Ru−H intermediate M, which could also form from [(L2X)RuIIH(OiPr)]Na (N) upon loss of NaOiPr. Perhaps the reactive Ru−H intermediate is better preserved in the saturated form N, avoiding unwanted reactions, and hence it is imperative to use excess base to obtain good conversions in THs. Reduction of ketones to alkoxide ligands occurs either intra- or intermolecularly. When the intermediate Ru−H complexes possess an empty coordination site, apparently the substrate coordinates to the metal center followed by intramolecular hydride migration to the α-carbon of the ketone (Scheme 52). If the intermediate hydrido− ruthenium complex is saturated, then the ketone undergoes intermolecular insertion into Ru−H bond resulting in the formation of Ru(II)−alkoxide.159a Baratta has also established that ruthenium pincer complexes containing a “NH2” donor stabilize the intermediate Ru(II)−alkoxide species by inter- or intramolecular N···H···O hydrogen bonding.77c The coordinated Ru(II)−alkoxide undergoes protonation by 2-propanol to provide the new alcohol and Ru−OiPr, from which the catalytically active Ru−H is generated. As complexes 39a,b (particularly complex 39b) exhibited very good efficiency in THs, van Koten and co-workers have developed the Ru PCP pincer complex 110 with chiral phosphine donors (Scheme 53). However, complex 110 turned out to be not only less selective but also less reactive as compared to complexes 39a,b (Table 4).165 The (Ph-pybox)based neutral chiral NNN Ru pincer complexes developed by Gimeno and co-workers exhibited very good activity and

Scheme 53. Chiral Ruthenium Pincer Complexes Developed for Asymmetric THs

selectivity for the asymmetric THs (Table 4). Complex 111 provided 92% S-enantiomer of 1-phenylethanol in 5 min.166 The chiral CNN Ru phosphine complex 46, analogous to complex 45, proved to be as highly active as 45, but provided moderate selectivity (ee 71% S).76 A related osmium pincer complex provided excellent enantioselective THs of several phenyl methyl ketones.167 The oxazoline-derived chiral NCN Ru pincer complex 52 provided moderate activity (52:NaOMe, 1:20 mol %) for the asymmetric THs of various aryl ketones.81 Analogous to complex 46, Baratta and co-workers have developed (R, S) Josiphos* bound chiral CNN complexes 48−4977b and 51,77d which provided excellent efficiency and 12047

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Table 4. Asymmetric THs Catalyzed by Chiral Ruthenium Pincer Complexes

entry 1 2 3 4 5 6

cat. (mol %) 46 (0.005) 48 (0.005) 49 (0.005) 51 (0.005) 110 (0.1) 111 (0.2)

base (mol %) i

NaO Pr (2) NaOiPr (2) NaOiPr (2) NaOiPr (2) KOH (2) NaOH (5)

time

temp (°C)

conv. (%)

5 min 10 min 30 min 10 min 17 h 5 min

82 82 82 60 82 82

98 98 98 95 40 96

the best selectivity achieved in enantioselective THs of aryl methyl ketones.

TOF (h−1)

ee (%)

ref

× × × ×

71 S 95 S 95 S 91 R 18 R 92 S

76 77b 77b 77d 165 166

9.3 1.8 9 1.2

105 105 104 105

Scheme 54. H/D Exchange of Arenes and Heteroarenes

4.3. Dehydrogenative Functionalization Reactions

Oxidation of alcohols is an important fundamental process for the production of a range of chemicals for small- and large-scale applications of industrial interest. For the oxidation of alcohols to carboxylic acids, traditional synthetic methods employ catalytic amounts of chromium oxides, ruthenium oxides, and stoichiometric amounts of oxidants such as iodate, chlorite, and oxygen at elevated temperatures resulting in copious waste. In multistep processes, coupling of carboxylic acids or their derivatives such as acid chlorides and anhydrides in the presence of promoters or coupling reagents provides useful products such as esters, acetals, amides, amines, and imines. As these products are important synthetic building blocks in the chemical and pharmaceutical industries, controlling selectivity and precluding the generation of toxic waste in these transformations are imperative challenges. Arising requirements of atom economy and awareness of environmental concerns urge chemists to invent new, greener methods for fundamental reactions to replace traditional reactions that are not atom efficient and produce much waste. Using ruthenium pincer complexes that operate via MLC, a series of new and green catalytic transformations have been developed for the direct conversion of alcohols to functionalized products, which generate no waste, and the only byproducts are hydrogen or water. Such transformations of alcohols catalyzed by ruthenium pincer complexes are described in this section. 4.3.1. Selective Deuteration of Arenes and Alcohols. Deuterated aromatic and heteroaromatic compounds have applications in studies involving drugs and materials and as NMR solvents. Leitner and co-workers reported that the PNP ruthenium pincer complex 20, containing nonclassical hydrides, catalyzes the H/D exchange of arenes and heteroarenes using C6D6 or D2O as the deuterium sources.168,169 This H/D exchange process is selective to the sp2 C−H bonds and sensitive to steric hindrance. Hence, cyclohexane used as a solvent is not involved in the reaction. With toluene as substrate, only aromatic protons were deuterated, while the methyl protons remained unaffected. However, when 2,5dimethylfuran was subjected to the H/D exchange, 92% of sp2 protons were deuterated, and in addition 59% of deuteration also occurred on sp3 protons, perhaps due to precoordination of the substrate via the oxygen atom (Scheme 54). DFT studies suggested that deuterium exchange reactions proceeded via a σbond metathesis mechanism. Periana and co-workers developed the NNN Ru(II) pincer complex 112 by one-electron reduction of [(NNN)RuCl3] 25 in aqueous Zn/KOH solution. Complex 112 underwent reversible deprotonation in strong basic solvents like KOH/

H2O, which facilitated the nucleophilic CH activation (Scheme 55). Complex 112 catalyzed the fast H/D exchange of watersoluble substrates in the basic medium KOD/D2O (3.7 M). The arene-sp2 CH bonds underwent deuterium exchange at 90 °C. Efficient H/D exchange of sp2 and sp3 CH bond occurred at 160 °C in 1 h. However, catalyst decomposition at this higher temperature prevented complete deuteration.56 An efficient method for the selective deuteration of sp3 protons at α- and β-CH2 positions of primary and secondary alcohols using D2O as the deuterium source was developed using the PNN ruthenium pincer complex 6 (Scheme 56). Interestingly, solvents like ethanol and 2-propanol were fully deuterated to become ethanol-d6 and 2-propanol-d8; notably, these deuterated substrates are widely used in NMR as solvents. When longer chain primary alcohols were used, only α- and βCH2 positions were deuterated, as confirmed by 2D NMR.170 Deuterated alcohols are extensively utilized in pharmaceutical and biological studies. Complex 6 undergoes dearomatization under basic experimental conditions, and the dearomatized form of pincer complex 6a acts as the actual catalyst. Upon reaction with D2O, the phosphine methylene arm undergoes H/D exchange to provide HOD. Subsequently, it reacts with the alcohol, generating an intermediate aldehyde and liberating HD/D2. When the aldehyde-bound complex undergoes β-hydride/ deuteride insertion, selective deuteration occurs at the α-carbon 12048

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Scheme 55. H/D Exchange of sp2 and sp3 CH Bonds Catalyzed by NNN Ru(II) Complex 112

oxidants, or oxygen pressure. Direct oxidation of alcohols to carboxylate salts with liberation of H2 using water as a terminal oxidant in the presence of base and a catalytic amount of complex 6 was recently reported by Milstein. Interestingly, under these conditions, water plays the role of both reaction medium and oxygen donor.171 Complex 6 undergoes dearomatization upon reaction with base, and the dearomatized complex 6a generated in situ acts as a catalyst. Various primary alcohols were directly oxidized to carboxylic acid salts in very good yields, posing very good atom economy and holding the potential for large-scale applications (Scheme 57). Notably, even diols were converted to their corresponding Scheme 57. Oxidation of Alcohols to Carboxylates Using Water as a Terminal Oxidant

Scheme 56. Catalytic H/D Exchange at the α,β-Positions of Alcohols

dicarboxylic acids in excellent yields, and only a minor amount of lactone formation was observed. When unsaturated alcohols were used, hydrogenation of the CC bond took place as well using the liberated hydrogen from alcohols. Although the reaction was carried out under basic conditions, no products of aldol condensation were observed, suggesting that the aldehyde intermediates remain coordinated to the metal center and short-lived, if dissociated. Labeling studies unequivocally corroborated the origin of oxygen from water. Overall, the mechanism likely involves alcohol dehydrogenation to form an intermediate aldehyde, addition of water to generate a gem-diol intermediate, and dehydrogenation followed by reaction with base to form a carboxylic acid salt. The proposed detailed catalytic cycle, based on experimental evidence and DFT calculations, suggests that the dearomatized complex 6a, generated in situ, is the actual catalyst (Scheme 58). O−H bond activation leads to the aromatization of complex 6a with a coordinated alkoxo ligand on ruthenium. The subsequent β-hydride elimination mechanism remains unclear at this stage.119 The alkoxo ligated intermediate II could form either from I or directly from 6a. Further hydrogen release and hydride elimination from the alkoxo ligand generates intermediates IV and V, respectively. Further

of alcohols. The lifetime of aldehyde-bound complexes decides the nature of geminal di- or mono-deuteration. When the aldehyde coordinated to the metal center dissociates, keto/enol tautomerism results in H/D exchange at the β-positions. Notably, when the reaction is performed in an open system, the generated hydrogen gas is expelled, and carboxylic acid salts are formed (see section 4.3.2). 4.3.2. Synthesis of Acids from Alcohols Using Water in the Absence of Added Oxidant. Oxidation of alcohols to carboxylic acids normally requires the use of stoichiometric 12049

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with resulting carbonyl derivatives (Scheme 59). In particular, upon dehydrogenation of alcohols by PNN ruthenium pincer

Scheme 58. Proposed Catalytic Cycle for the Oxidation of Alcohols to Carboxylates Using Water

Scheme 59. Ruthenium Pincer Complexes Developed for Dehydrogenative Esterification of Alcohols

nucleophilic attack by water on the coordinated (or free) aldehyde might occur to provide the ketalic intermediate VI. Hydrogen release from the ketal can proceed without involvement of catalyst;172 the generated carboxylic acid is trapped by a stoichiometric amount of base and 6a is regenerated. DFT calculations identified the feasibility of this mechanistic pathway and indicated that hydrogen transfer102,123a,b from the methylene arm to the metal center could be the rate-determining step with a barrier of ∼28.3 kcal mol−1.173 Shortly after publication of this work, Grützmacher also reported a Ru-catalyzed conversion of alcohols to carboxylic acids with water, liberating hydrogen.174 4.3.3. Dehydrogenative Coupling of Alcohols To Form Esters and H2. Esterification is a fundamental and industrially important transformation, and thus development of an efficient green process for the production of esters is highly desirable, as it has an assortment of applications in the production of a range of useful products like fine chemicals, synthetic intermediates, natural products, fragrances, polymers, polyesters, plasticizers, fatty acids, paints, and pharmaceuticals. Environmentally benign methods for the synthesis of esters directly from alcohols with liberation of hydrogen catalyzed by ruthenium pincer complexes have been developed, as described below. 4.3.3.1. Synthesis of Esters from Primary Alcohols. O−H activation of alcohols119 and reversible dihydrogen activation26,35 to form trans-dihydrides by dearomatized pyridinebased pincer complexes indicated the possibility of catalytic dehydrogenation of alcohols and further coupling reactions

complexes, the in situ formed aldehydes react further with alcohols to form hemiacetals, which liberate hydrogen to ultimately provide the self-coupling products of alcohols to esters. Ruthenium pincers complexes developed to catalyze this transformation are shown in Scheme 59. When primary alcohols were reacted with complex 3, in the presence of a catalytic amount of base under reflux conditions, an unusual dehydrogenative coupling to form esters with evolution of H2 was observed.35 Thus, refluxing a hexanol (bp 157 °C) solution containing complex 3 and KOH (0.1 mol % each) under argon in an open system for 24 h resulted in the formation of hexyl hexanoate in 67% yield. The PNN complex 5 containing a hemilabile amine “arm” was a significantly better precatalyst (still in the presence of an equivalent of base) than the corresponding PNP complex 3, leading to 95% (950 turnovers) hexyl hexanoate after 24 h at 115 °C (Scheme 60). The actual catalyst of this reaction is the coordinatively unsaturated dearomatized 16e− complex 5a, formed by deprotonation of 5. As expected, the dearomatized complex 5a catalyzes the dehydrogenative esterification of 1-hexanol under mild and neutral conditions with liberation of hydrogen, forming hexyl hexanoate with excellent efficiency (99% yield, 990 TON). The reaction is quite general; some examples are shown in Scheme 61.35 Formation of trace amounts of aldehydes was also observed in the reaction mixture. The evolved hydrogen gas is efficiently removed under refluxing conditions, pushing the reaction toward completion, while esterification reactions starting with carboxylic acids suffer from generation of 12050

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Scheme 60. Dehydrogenative Coupling of 1-Hexanol To Form Hexyl Hexanoate Catalyzed by PNP and PNN Ru Complexes

Scheme 63. Dehydrogenative Coupling of Alcohols to Esters Catalyzed by 9

alcohol, devoid of β-hydrogens, provided benzyl benzoate in 99.5% yield even under neutral conditions.90 The PNHN ruthenium pincer complex 11 with an aliphatic backbone reported by Gusev and co-workers displayed impressive catalytic activity in the presence of base (KOtBu, 0.5 mol %) for the esterification of simple alcohols such as ethanol and 1-propanol (Table 5). Notably, reactions

Scheme 61. Dehydrogenative Coupling of Alcohols To Form Esters Catalyzed by Dearomatized PNN Ruthenium Pincer Complex 5a

Table 5. Dehydrogenative Coupling of Alcohols To Form Esters Catalyzed by 11

equilibrium mixtures. This catalytic reaction provides a new “green” pathway for the synthesis of esters directly from alcohols. Previous reports of this transformation were less efficient.175,176 Complex 5a catalyzes the reaction between benzaldehyde and benzyl alcohol to yield benzyl benzoate, whereas it failed to form the ester from benzaldehyde alone, indicating that ester formation likely involves hemiacetal intermediacy176 rather than a Tischenko type condensation, at least in the case of aryl methanols (Scheme 62).177

entry

R

T [°C]

time (h)

conv. (%)

1 2 3 4 5

Me Et Pr i-amyl hexyl

78 96 118 131 158

7.5 8 3 2.5 1

30 73 78 92 86

Scheme 62. Formation of Hemiacetal Intermediate in Coupling of Alcohols to Esters proceeded even at temperatures below 100 °C. However, good conversions were achieved at higher temperatures (Table 5, entries 4,5). A dehalogenated osmium-based dimeric pincer complex, analogous to that of 11, was also reported to have comparable reactivity.42 Ethyl acetate is a widely used fine chemical. Thus, the reported conversion of ethanol to ethyl acetate by complex 11 and related osmium dimer complexes42 by Gusev and coworkers elicited interest in the catalytic synthesis of ethyl acetate. Beller and co-workers tested the catalytic activity of several already known pincer complexes for this transformation and found that Takasago’s complex 12 known as Ru−MACHO catalyst is very efficient, and the reaction in the presence of base resulted in very good TON (Table 6).178 Gusev and co-workers also reported a similar finding; among the number of designed pincer complexes, PNHN pincer complex 11 with aliphatic backbone exhibited impressive reactivity179 with 85% conversion of ethanol (Table 6).

The acridine-derived PNP pincer complex 9 in the presence of a catalytic amount of base (1 equiv relative to complex 9, 0.1 mol %) catalyzes the dehydrogenation of alcohols to esters in good yields (Scheme 63). Under neutral conditions, linear alcohols containing β-hydrogen atoms underwent a different reaction and provided acetals as major products (see below). However, mechanistic studies showed that a β-hydrogen is essential for acetal formation; thus, alcohols such as benzyl 12051

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Table 6. Dehydrogenative Coupling of Alcohols To Form Esters Catalyzed by 11 and 12

a

cat. (mol %)

NaOEt (mol %)

time (h)

yield/conv.

TON

11 (0.005) 12 (0.05) 12 (0.005)

1 1.3 0.6

40 6 46

85% conv. 81% yield 77% yield

nra 1620 15 400

Scheme 64. Dehydrogenative Coupling of Alcohols to Esters Catalyzed by 16a and 108

five-coordinate, amido complexes (section 2.3.3), which act as the true catalysts. Upon O−H activation, complex 5a undergoes rearomatization as the proton is accepted at the dearomatized pyridinyl methine arm, whereas in complexes 11 and 12, the amido ligand becomes an amine ligand upon accepting a proton. In the case of the aromatization− dearomatization MLC, the role of a mechanism involving βhydride elimination from the coordinated alkoxo ligand to release aldehyde remains unclear at this stage, and a bifunctional mechanism in which direct outer-sphere transfer of a hydride to Ru and proton to the pincer arm is also possible.119 These two primary steps lead to the formation of saturated trans-ruthenium dihydride intermediate complexes that liberate 1 equiv of dihydrogen (generated from hydride ligand and proton from pincer ligand arm) to regenerate the catalytically active five-coordinate unsaturated complexes. The trans-dihydride configuration is important, due to the relatively weak Ru−H bond and hence the increased hydridic character of the hydride ligand. The intermediate aldehydes (either bound on ruthenium or in solution) undergo nucleophilic attack by the excess alcohols to provide hemiacetal intermediates (Scheme 62), which undergo a similar dehydrogenation process leading to esters and again generating the trans-ruthenium dihydrides that liberate the second equivalent of hydrogen gas and regenerate the catalytically active complexes for further cycles. 4.3.3.2. Synthesis of Esters by Cross-Dehydrogenative Coupling of Primary and Secondary Alcohols. The selfdehydrogenative coupling of alcohols to provide symmetrical esters has become a straightforward reaction, catalyzed by several catalysts. However, the coupling of two different alcohols, primary and secondary alcohols, for the synthesis of unsymmetrical esters is a challenging task. This was accomplished upon reaction of primary alcohols with secondary alcohols. Thus, when equimolar amounts of 1-hexanol and cyclohexanol were refluxed in toluene solution containing complex 6a (1 mol %), cyclohexyl hexanoate was obtained in 79% yield, together with a minimal amount (16%) of hexyl hexanoate resulting from self-coupling of hexanol, and cyclohexanone (12%) from dehydrogenation of cyclohexanol.183 As expected, using a 2.5-fold excess of the secondary alcohol further improved the yield of the cross-esterification product. Thus, refluxing a toluene solution containing cyclohexanol and 1-hexanol in a molar ratio of 2.5/1, respectively, with complex 6a (1 mol %), cyclohexyl hexanoate was obtained in 93% yield (based on 1-hexanol), and cyclohexanone (34%) was also formed. The synthetic and substrate scopes of this

nr = not reported.

The in situ assembled pincer complexes from the metal precursor [Ru(COD)(methylallyl)2] and PNP or PNN pincer ligands (used for complexes 4 and 5, respectively) also catalyzed the direct conversion of alcohol into esters.180 The catalytically active complex (which could be complex 5a, the CO ligand being generated from the intermediate aldehyde) displayed reactivity similar to that of complex 5a. PNP and PNN ruthenium(II) hydrido borohydride complexes [(PNX)RuH(BH4), X = P (105), X = N (2)]34 and PNS ruthenium complexes39 [(PNStBu)RuHCl(CO)] 13, analogues to complex 4, also show catalytic reactivity for the esterification of alcohols. A series of nitrosyl ligated ruthenium pincer complexes isoelectronic to ruthenium carbonyl complexes were prepared by Milstein.94 One such dearomatized PNP complex analogous to 4a, [(PNPtBu)*Ru(NO)], a square-planar complex, also efficiently catalyzed (0.5 mol %) the dehydrogenative coupling of 1-hexanol to hexyl hexanoate in under Ar atmosphere or under air. Gelman and co-workers reported a PCSP3P iridium pincer complex, which catalyzed the conversion of benzyl alcohols to benzyl benzoates, and was suggested to operate via a novel MLC mode.181 Both electron-withdrawing and electrondonating substituents on the aromatic ring are tolerated, and the corresponding esters were obtained in very good yields (88−97%). Following the design of the PNN ruthenium pincer complex 5a, complex 16a containing an “N” analogue of carbon on the dearomatized arm and an imine donor instead of an amine ligand also catalyzed the homocoupling of alcohols to esters (Scheme 64). However, catalytic efficiency was lower as compared to complex 5a, and it required longer reaction time and higher loading of the catalyst.45 (1,3-Bis(6′-methyl-2′pyridylimino)-isoindoline)-derived pincer Ru(II) hydride complex 108 catalyzes the formation of butyl butyrate from nbutanol (1 mol % of 108, 7 h, 99%) under neutral condition with liberation of hydrogen gas.182 In general, several complexes that exhibit MLC catalyze the direct self-coupling of alcohols to provide esters with liberation of 2 equiv of hydrogen gas. The PNN ruthenium pincer complex 5a that operates via aromatization−dearomatization process, and PNN and PNP ruthenium pincer complexes that operate by amine−amide interconversions (11 and 12) are the effective catalysts for this transformation. The unsaturated, dearomatized complex 5a can act as a catalyst under neutral condition, whereas the saturated, amine complexes 11 and 12 require an equivalent amount of base to form the respective 12052

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dehydrogenative cross-esterification process were demonstrated with various cyclic and acyclic secondary alcohols and other primary alcohols (Scheme 65).

Scheme 66. Acylation of Secondary Alcohols Using Esters

Scheme 65. Formation of Esters from Cross-Coupling of Primary and Secondary Alcohols

The mechanism of this reaction is proposed to involve ester coordination (I) followed by insertion of the ester carbonyl to Ru−H to provide the ketalic intermediate II. As II is unsaturated and dearomatized, it readily reacts with alcohols by O−H activation and undergoes aromatization to provide III. The alkoxide exchange is likely to proceed via intramolecular nucleophilic attack, which can provide the cationic intermediate IV. Deprotonation by the alkoxide leads to the formation of the dearomatized V and formation of a primary alcohol. Perhaps βhydride elimination of V produces the cross-coupled product ester and regenerates the catalyst 5a (Scheme 67). The in situ formed primary alcohol undergoes self-coupling to form an ester, which is further consumed for the acylation in a similar catalytic cycle. Thus, upon use of symmetrical esters, both the alkyl and the alkoxo parts of the esters are utilized for the acylation, and hydrogen is the only observed byproduct. The hemilabile amine arm of complex 5a may play a role in the carbonyl insertion step, enabling the isomerization of the transdisposed ester/Ru−H into cis orientation. Indeed, the PNN complex 5a is a better catalyst as compared to the similar but strongly bound PNPi‑Pr, t‑Bu pincer complexes (3a, 4a). 4.3.3.4. Synthesis of Lactones from Diols. The ruthenium hydrido borohydride complex 2 (0.3 mol %) catalyzes the intramolecular dehydrogenative coupling of 1,5- and 1,6-diols to form five- and six-membered lactones with liberation of hydrogen. This lactonization is applicable to diols of primary− primary, as well as primary−secondary alcohols functional groups (Scheme 68).34 Analogous to 2, the PNPtBu ruthenium hydrido borohydride complex 105 also catalyzed this transformation, although less efficiently. The BH3 group is likely removed under the reaction conditions (by complexation with a carbonyl or OH group), providing the trans-dihydride complex, which is the actual catalyst. Notably, the formation of polyesters

4.3.3.3. Acylation of Secondary Alcohols Using Esters, with H2 Liberation. A New Mode of Transesterification. In general, transesterification184 is not an atom-economical transformation. In addition to the desired ester, an equivalent of an alcohol is also produced in the reaction. When complex 5a was reacted with a symmetrical ester and 2 equiv of a secondary alcohol, only formation of the trans-ester and dihydrogen was observed (Scheme 66). When the unsymmetrical ester ethyl butyrate was reacted with 3-pentanol in the presence of 5a (1 mol %) under refluxing toluene, 75% conversion of ethyl butyrate took place to yield 73% of 3-pentyl butyrate. 3-Pentyl acetate, which was expected to be formed from the ethanol intermediate, was observed only in trace amounts, perhaps due to the loss of ethanol under reflux conditions. Likewise, the reaction of methyl hexanoate with cyclohexanol resulted in 42% conversion with the formation of 42% cyclohexyl hexanoate.185 The crux of this unusual coupling reaction is that dehydrogenative coupling of primary alcohols to esters is faster than dehydrogenation of secondary alcohols, which might be due to steric factors. Thus, secondary alcohols predominantly reacted with the ester, and only small amounts of ketones, resulting from the dehydrogenation of excess of secondary alcohols, were observed. 12053

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complex 5a (0.2 mol %, from complex 5, Scheme 13) under vacuum, resulted in polyesters with molecular weights higher than 125 000 g mol−1. Efficient removal of H2 under vacuum helped to drive the reaction and resulted in better performance. Polymerization of 1,10-decanediol resulted in a polymer with a Mn approaching 140 000 g mol−1 and a degree of polymerization over 800 (entry 1, Table 7). The molecular weights of the polymers and the degree of polymerization decreased as the molecular weight and length of monomer decrease, which may be due to the viscosity differences of the molten polymer. The dehydrogenation of 1,5-pentanediol resulted in predominant formation of thermodynamically stable and kinetically favored six-membered δ-valerolactone and 29% of polyester (entry 6). The reaction of 1,4-butanediol with complex 5a provided γ-butyrolactone exclusively. 4.3.4. Synthesis of Acetals from Alcohols. In the dehydrogenative coupling reactions, the intermediate aldehyde reacts with the alcohol to form a hemiacetal intermediate, which undergoes further dehydrogenation to form an ester. However, the intermediate aldehyde could also react with 2 equiv of alcohol to form an acetal. When linear primary alcohols were heated with 0.1 mol % of Acr−PNP ruthenium pincer complex 9, acetals were obtained in very good yields (Scheme 69a). Small amounts of esters were also formed as side products. Analysis of the reaction mixture by GC−MS indicated the intermediacy of enol ethers, which formed by water elimination of the initially formed hemiacetals. The third equivalent of alcohol undergoes addition to the double bond of the enol ether to form an acetal (Scheme 69b). The fact that the alcohol addition mechanism is involved, rather than the traditional acid-catalyzed substitution of the hemiacetal, is further substantiated by the observation that alcohols devoid of β-hydrogen atoms, such as benzyl alcohol, did not produce an acetal, rather forming an ester even under neutral conditions (Scheme 63). Murahashi and co-workers reported the pioneering acetal formation using [RuCl2(PPh3)3] as catalyst, albeit in 8 TON.176 A rhenium complex is also reported to catalyze the reaction to provide 30 TON of acetal.188 Ruthenium sulfate catalyst [Ru(η2-SO4)(PPh3)2(CH3CN)2] also catalyzed the reaction efficiently at lower temperature (110 °C); however, it operates via an acid-catalyzed mechanism.189 4.3.5. Synthesis of Amides. The amide motif is of central importance in biology and chemistry, and its chemical synthesis under neutral conditions is a challenging task.190 Ruthenium pincer complexes derived from pyridine and bipyridine backbones catalyzed the direct formation of secondary and tertiary amides, from amines and alcohols or amines and esters. Interestingly, this catalytic application has also been extended for the synthesis of peptides and polyamides. Green syntheses of these important chemical entities with liberation of hydrogen as the only byproduct are delineated in this section. 4.3.5.1. Synthesis of Amides from Alcohols and Amines. When we reacted the PNN ruthenium pincer catalyst 5a (0.1 mol %) with alcohols and amines in refluxing toluene under argon flow, secondary amides were obtained in excellent yields with liberation of hydrogen gas. This unprecedented intermolecular coupling of alcohols and amines to form amides and H2 is a desirable synthetic method.191 Using this environmentally benign reaction, an assortment of simple alcohols and amines was converted into amides, with high atom economy (Scheme 70). The liberated hydrogen gas shifts the equilibrium toward the completion of the reaction. The reaction mixtures were refluxed under a flow of argon to facilitate the formation

Scheme 67. Proposed Catalytic Cycle for the Transesterification by Acylation of Secondary Alcohols

Scheme 68. Lactones Formation from Diols

was not observed. Ruthenium-catalyzed lactonization of 1,4butanediol to γ-butyrolactone at 205 °C was reported previously.186 4.3.3.5. Synthesis of Polyesters from Diols. Robertson and co-workers applied the dehydrogenative coupling of alcohols for the synthesis of polyesters.187 Conventional polycondensation reactions using carboxylic acid derivatives suffer from drawbacks such as difficulties in obtaining high molecular weight polymers, and challenging removal of byproducts such as H2O, CH3OH, HCl, and salts. The use of the Ru−PNN pincer complex 5a as catalyst in the dehydrogenative coupling of diols resulted in a range of high molecular weights polymers; in addition, the only byproduct, hydrogen gas, was efficiently removed upon performing the reaction under mild vacuum, thus thermodynamically driving the reaction. Reactions of diols (higher than 1,5-pentanediol) catalyzed by the in situ generated 12054

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Table 7. Polymerization of Linear Aliphatic Diols Catalyzed by Complex 5a under Vacuum and Nitrogen Purge,187 Taken from Robertson et al.a

entry

n (diol)

Mn [kg mol−1]b

Mw/Mnb

degree of polymerization

Tm [°C]c

yield (%)

1 2 3 4d 5e 6 7

8 7 6 4 4 3 2

138 91.8 76.6 55.5 29.4 57.7

2.7 3.1 2.3 2.0 1.6 2.9

811 587 538 486 258 576

51 42 40 13 14 −2

78 85 95 70 97 29f 90g

Complex 5a (0.2 mol %) and monomeric diol were heated at 150 °C with a 3 h purge and 5 d under vacuum. bDetermined by gel permeation chromatography (GPC) using polystyrene standard. cDetermined by differential scanning calorimetry (DSC). dNitrogen purge instead of vacuum. e5 h nitrogen purge prior to vacuum to promote oligomerization and minimize loss of monomer. fIsolated yield of polymer. Remaining volatiles in vacuum trap were solvent and lactone. gYield of lactone. a

Scheme 69. Formation of Acetals from Alcohols and Involvement of Enol Ether Intermediates

Scheme 70. Synthesis of Amides from Alcohols and Amines Catalyzed by 5a

of product amides by hydrogen removal. Whereas linear and electron-rich primary amines provided amides in excellent yields, the weakly nucleophilic anilines produced amides in moderate yields. The yields of amides are also adversely affected by the steric hindrance present in amines and alcohols. Amino alcohols also participate in the amidation reactions. When chiral amino alcohols were used, the amide products were obtained with retention of configuration. For example, reaction of (S)-2-amino-3-phenylpropan-1-ol, benzylamine, and 1 mol % of the complex 5a in refluxing toluene provided (S)-2amino-N-benzyl-3-phenylpropanamide in 58% isolated yield (Scheme 71),192 and the specific rotation of the product amide (+16.08) is the same as reported.193 The neutral reaction conditions likely help to prevent racemization. Under these conditions, the reaction is chemoselective to the primary amine functionality. Hence, despite the presence of unprotected secondary amine functionality, the primary amines were acylated selectively. Use of diamines resulted in very good yields of diamides (Scheme 72). The reaction mechanism of this fundamentally new chemical transformation likely involves MLC that operates in complex 5a. Like in the reactions of ester formation catalyzed by 5a, upon formation of an intermediate aldehyde that is either coordinated to the metal or free in solution, nucleophilic attack by the amine can provide a hemiaminal intermediate (Scheme

Scheme 71. Synthesis of Chiral Amides from Amino Alcohols

73), coordinated to Ru or free. Dehydrogenation of the hemiaminal results in the formation of an amide and the ruthenium trans-dihydride 5b, which liberates H2. If nucleophilic attack by the alcohols occurs, it would provide esters via hemiacetal intermediates (Schemes 61 and 62). Complex 5a 12055

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Figure 10. β-Hydride eliminations proceed via inner-sphere mechanism and thus require coordination of alcohol and hemiaminal to the Ru center, the dehydrogenations of which result in aldehyde and amide, respectively, with the concomitant formation of trans-dihydride intermediate 5b. On the other hand, in the outer-sphere BDHT mechanism, the Lewis acidic ruthenium center and Lewis basic unsaturated methine carbon on the phosphine arm of 5a mediate the hydrogen transfer (Scheme 74).126 Along the β-hydride elimination pathway, the transition state (TS) barriers for coordination of alcohol by ring opening of amine arm of 5a to form intermediate I and H2 liberation from 5b to form 5a are 23.1 and 22.5 kcal mol−1, respectively. As the Ru···OH intermediate I is unstable, the proton transfer to the unsaturated methine arm to form II involves a barrier of only 6.5 kcal mol−1. The β-hydride elimination in II to provide the aldehyde and trans-dihydride 5b occurs with a barrier of 14.1 kcal mol−1. Free energy barriers of TSs of alcohol dehydrogenation by 5a to aldehyde and 5b along the BDHT pathway are calculated to be 18.4, 1.0, and 22.5 kcal mol−1, respectively. As the hydrogen transfers occur without metal-alcohol coordination and amine arm opening, the relative TS barrier for the BDHT mechanism is lower than that of β-hydride elimination. However, both dehydrogenation mechanisms result in the formation of same trans-dihydride 5b, and thus liberation of H2 and regeneration of 5a occurs with the same barrier of 22.5 kcal mol−1. The 1 kcal mol−1 barrier of the TS of I′ to II′ (Scheme 74) indicates that double hydrogen transfers occur almost in a concerted manner, rather than successive transfer. Further, the direct coupling of an aldehyde and amine is calculated to have the free energy barrier of 25.4 kcal mol−1. However, when this reaction was considered to be assisted by additional alcohol and amines involving a six-membered TS, the free energy barriers fell to 18.4 (shown in Figure 10a) and 20.1 kcal mol−1, respectively. Dehydrogenation of the hemiaminal by 5a is similar to dehydrogenation of alcohols via both mechanisms. Along the βhydride elimination pathway, the free energy barriers are calculated to be 21.3, 6.5, 15.8, and 22.5 kcal mol−1. Slight variation is due to the thermodynamic stability of the resulting products; dehydrogenation of alcohols generates a reactive aldehyde and is endergonic, whereas hemiaminal dehydrogenation leads to a stable amide and is exergonic. Along the BDHT pathway, free energy barriers for the dehydrogenation of hemiaminal (via III′ to IV′, Scheme 74) to amide and 5b are 18.3, 1.5, and 22.5 kcal mol−1 and are also similar to that of dehydrogenation of alcohols. Thus, for the complete reaction, it was found that both β-hydride elimination and BDHT pathways are accessible under the experimental conditions, the latter favored with a lower reaction profile and energy barriers.121,126 On the basis of the calculations, Lee and coworkers have also suggested that a diethylamine (−NEt2) substituent on the para position of the pyridine ring of 5a would serve as a better catalyst for the conversion of alcohols and amines to amide and dihydrogen.126 The discovery of the catalytic amide formation with liberation of dihydrogen provides the most atom-economical method to make amides directly from amines and alcohols; as such, it elicited much research interest in this direction and diverse catalytic systems were reported,194,195 although generally in significantly lower catalyst turnovers and selectivity. Dong and Guan groups reported that the Ru−MACHO

Scheme 72. Chemoselective Synthesis of Diamides

Scheme 73. Proposed Mechanism of Amide Formation with Liberation of H2; β-Hydride Elimination Pathway

also catalyzes the acylation of amines by esters to provide amides (see below). Several groups have performed detailed DFT calculations on the mechanism of this process catalyzed by 5a, which conclude the involvement of MLC by aromatization and dearomatization process.121,124,126 Wang and co-workers have proposed a bifunctional double hydrogen transfer (BDHT) pathway for the dehydrogenation of alcohols and hemiaminals.121 Lee and co-workers have also carried out DFT calculations for the entire reaction pathways,126 including β-hydride elimination and BDHT pathways of amide formation from 1-pentanol and benzylamine catalyzed by 5a. Potential energy surfaces (PES) of the complete catalytic loop along the β-hydride elimination (a, black) and BDHT (b, green) mechanisms are shown in 12056

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Figure 10. Potential energy surfaces for the complete catalytic formation of amides via β-hydride elimination (a) and BDHT pathway (b). Reproduced with permission from ref 126. Copyright 2013 American Chemical Society. 12057

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intramolecular nucleophilic attack by the amido ligand at the acyl functionality is thought to be a key step. Overall, in one catalytic cycle, two molecules of amide and of H2 are formed. 4.3.5.3. Synthesis of Tertiary Amides. As mentioned before, the pyridine-derived PNN ruthenium pincer complex 5a chemoselectively catalyzes the acylation of primary amines using alcohols. However, using the bipyridine derived PNN ruthenium complexes 6a and 114, tertiary amides were synthesized directly from primary alcohols and secondary amines (Scheme 76).198 While cyclic secondary amines

Scheme 74. Mechanism of Amide Formation via BDHT Pathway

Scheme 76. Synthesis of Tertiary Amides from Secondary Amines and Alcohols catalyst 12 catalyzes the amide formation in the presence of a 15-fold excess of base relative to the catalyst.196 4.3.5.2. Synthesis of Amides from Esters and Amines. Efficient synthesis of amides under neutral conditions was also achieved by the reaction of esters with amines with liberation of H2 when catalyzed by the PNN ruthenium pincer catalyst 5a (Scheme 75).197 When a benzene or toluene solution of Scheme 75. Synthesis of Amides from Esters and Amines Catalyzed by 5a

provided tertiary amides in excellent yields, acyclic secondary amines provided moderate yields. As observed for the acylation of primary amines, the acylation of secondary amines is also sensitive to steric hindrance. Competitive experiments performed in the presence of primary amines indicate that primary amines undergo acylation by alcohols faster than secondary amines, perhaps due to steric factors. The bipyridine derived PNN ruthenium complex 114 with a diphenylphosphine arm also catalyzed the formation of tertiary amides in the presence of a catalytic amount of base. 4.3.5.4. Synthesis of Peptides from β-Amino Alcohols. Peptides are important families of compounds ubiquitous in nature. Short and cyclic peptides have found interesting biological and synthetic applications.199,200 Green and atomeconomical methods for the generation of peptides are highly desirable. As complex 5a catalyzed the amidation of amines by amino alcohols with retention of configuration (Scheme 71), it was expected that use of β-amino alcohols alone would result in linear or cyclic peptides from self-coupling reactions. Thus, when a dioxane solution of (S)-(+)-2-amino-1-propanol and complex 5a (1 mol %) was refluxed under argon flow, a mixture

complex 5a (0.1 mol %) containing amine and ester was refluxed under an argon atmosphere, quantitative conversion of the amine and ester was observed by GC, and the amides were isolated in moderate to excellent yields. Similar to the alcohol acylation process (section 4.3.3.3), both the acyl and the alkoxo parts of symmetrical esters are incorporated in the product. These reactions are possibly initiated by N−H activation of the amine by MLC involving 5a. Ester coordination followed by 12058

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polyamides was further improved (26.6 kDa) by the addition of small amounts of DMSO. The amidation reaction catalyzed by complex 5a is highly selective to primary amines, and this offered an excellent opportunity for the direct synthesis of functional polyamides containing secondary amine groups (such polyamides are potentially useful for gene delivery)203 circumventing tedious protection and deprotection steps. While Guan and co-workers disclosed the preparation of a variety of polyamides, many bearing ether spacers, with Mn in the range of 10−30 kDa, we reported the application of the amidation reaction for the synthesis of a variety of polyamides not bearing ether spacers, under different conditions, using 1,4-dioxane as a solvent. Under these conditions, polyamides from simple diols and diamines were obtained with Mn in the range of 5.3−26.9 kDa. Both the pyridine-derived PNN ruthenium complex 5a and the bipyridine-based PNN complex 6a were used as catalysts. Remarkably, using complex 6a as catalyst, the polyamidation reaction proceeded under solvent-free conditions, and only 0.2 mol % of catalyst was required, representing a “green” reaction. 4.3.6. Synthesis of Amines from Alcohols and Ammonia. The most useful primary amines are also highly reactive, making the selective synthesis of them difficult, particularly from electrophiles such as alkyl halides and ammonia as they can undergo competing alkylation reaction to produce a mixture of products.204 Using the Acr−PNP ruthenium pincer complex 9 (0.1 mol %) as catalyst, selective synthesis of primary amines was achieved directly from alcohols and ammonia (7.5 atm). The reaction proceeded by borrowing hydrogen pathway.37,205 It is likely that the selectivity is a result of steric factors as ammonia could preferably coordinate on the metal center than amines. Small amounts of secondary amines were observed in reactions of aliphatic alcohols. A range of primary alcohols was catalytically converted to the primary amines upon reaction with ammonia (Scheme 79). Impressive selectivity for the primary amines is also attained using water as a reaction medium. Köckritz and co-workers also used 9 as a catalyst for the preparation of diamines from the diols derived

of oligo-alanines containing a small amount of the cyclic dipeptide amounting together to 72% yield was obtained. Similar reactions of amino alcohols bearing larger substituents at the α-position of the amine group provided the corresponding cyclic dipeptides (diketopiperazines) as the only products (Scheme 77) in very good yields, with liberation of H2, as the only byproduct.192 Scheme 77. Catalytic Synthesis of Peptides from Amino Alcohols with Liberation of Hydrogen

4.3.5.5. Synthesis of Polyamides. Direct catalytic synthesis of polyamides from diols and diamines with liberation of hydrogen would avoid the use of activators, would not generate waste, and would provide an atom-economical method for the synthesis of polyamides. Using complex 5a as a catalyst, Guan and co-workers201 as well as Milstein’s group202 have developed such catalytic synthesis of polyamides (Scheme 78). Extensive

Scheme 79. Selective Synthesis of Primary Amines from Alcohols and Ammonia

Scheme 78. Synthesis of Polyamides from Diamines and Diols with Liberation of Hydrogen

optimization studies carried out by Guan and co-workers revealed anisole as a suitable polar solvent for the successful polymerization of diols and diamines, in which the catalyst remained highly active and the number-average molecular weights (Mn) of the polyamides were dramatically increased (3.2 kDa in toluene versus 13.8 kDa in anisole). Mn of the 12059

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from vegetable oils.206 Very recently, the mechanism of this reaction using the PCy2 analogue of 9 (Cy = cyclohexyl) has been studied.207 Efficient synthesis of primary amines from secondary alcohols was reported by Vogt208 and by Beller209 using ruthenium catalysts. 4.3.7. Synthesis of Alcohols from Amines and Water. Interestingly, the Acr−PNP ruthenium catalyst 9 also catalyzes the direct deamination of primary amines to provide primary alcohols and ammonia upon reaction with water; this is the reverse reaction of the formation of primary amines and water from primary alcohols and ammonia described above, which is also catalyzed by the same catalyst, 9.37,210 Although the reaction proceeded in neat water alone, better conversions were achieved using a water/dioxane mixture (1:1 v/v) as this provided better homogeneity. Ammonium carboxylate salts were obtained as side products, the yield of which increased with prolonged reaction time and under anaerobic conditions. While the reactions performed in closed systems provided good selectivity for the formation of primary alcohols, very good yields of primary alcohols were obtained when the reactions were carried out under 5 bar hydrogen pressure. Notably, cycloalkyl amines were also transformed to secondary alcohols (Scheme 80).

Scheme 81. Alkylation of Primary Aryl Amines by Alcohols Catalyzed by the CNN Ru(II) Catalyst 115

Scheme 80. Synthesis of Alcohols from Amines and Water Catalyzed by 9

of primary arylamines was observed even when an excess of alcohols were used. Thus, aryl diamines were selectively mono alkylated on each amine groups, and no overalkylation took place. Interestingly, no alkylation occurred at aliphatic amine groups, and hence amino alcohols were used as alkylating agents for arylamines. During the synthesis of primary amines from primary alcohols and ammonia catalyzed by complex 9, it was found that prolonged reactions provided higher yield of the secondary amine side product, suggesting that 9 catalyzes the self-coupling of primary amines. Indeed, when neat 1-hexylamine was reacted with catalyst 9 in a closed system, dihexylamine was obtained in 86.5% yield (Scheme 82a).37 Recently, complex 9 was also used for the facile conversion of diamines to cyclic secondary amines.210 Upon heating a solution of the diamine in water/ dioxane at 100 °C in the presence of 9, the entropy-driven formation of cyclic secondary amines in very good yields took place. However, with longer diamines, amino alcohols resulting from monodeamination of alcohols were also obtained as major side products (Scheme 82b). 4.3.9. Synthesis of Imines from Primary Amines. Huang and co-workers have prepared the modified PNP and PNN Ru pincer complexes 14a−16a by introducing an amine functionality in the backbone instead of the methylene arms, which converts to an imine group upon dearomatization. Catalytic efficiency of 14a−16a and 5a was tested for the dehydrogenative self-coupling of primary amines to provide

4.3.8. Synthesis of Secondary Amines from Primary Amines. Alcohols were used for the alkylation of amines to obtain higher order amines, particularly for the preparation of secondary amines from primary amines. A number of iridium and ruthenium complexes catalyzed this transformation, which proceeds by alcohol dehydrogenation to the carbonyl compound, followed by reaction with amines to form imines, which are hydrogenated by the hydrogen liberated from ́ alcohols in the first step (borrowing hydrogen).145,211 MartinMatute and co-workers reported that the CNN Ru(II) pincer complex 11576,77c catalyzed the selective synthesis of secondary amines from monoalkylation of aromatic and heteroaromatic amines by primary alcohols (Scheme 81).212 Efficient alkylation of arylamines by alcohols occurred when a toluene solution of a reaction mixture containing 115 (1 mol %) with 1 equiv of KOtBu and molecular sieves was heated for 24 h. The reaction is highly selective, and only monoalkylation 12060

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4.3.10. Synthesis of Lactams from Cyclic Amines Using Water. The Acr−PNP Ru(II) complex 9 catalyzes an unusual reaction, the reaction of cyclic amines with water to form lactams, with evolution of H 2 (Scheme 84). 213

Scheme 82. Self-Coupling of Primary Amines to Secondary Amines Catalyzed by 9

Scheme 84. Synthesis of γ- and δ-Lactams from Cyclic Amines Catalyzed by 9

imines. Imines were obtained in good yields using complexes 14a−16a with a catalyst loading of 1−10 mol % (Scheme 83). Interestingly, as in the oxidation of alcohols to acids, water played the role of oxidant and serves as a source of oxygen atom. Contrary to the known methods, which require stoichiometric oxidants such as iodosobenzene, tBuOOH, RuO2/NaIO4, or O2, complex 9 catalyzed the reaction in water in the presence of a catalytic amount of base with no added oxidant. It is believed that amine dehydrogenation followed by water addition leads to the formation of a hemiaminal intermediate, which undergoes further dehydrogenation to form a lactam. Using cyclic amines, the cyclic hemiaminal intermediates are entropically stabilized against deamination (Scheme 85), which is key to the success of this transformation; a similar reaction with acyclic aliphatic amines resulted in alcohols via a deamination pathway (section 4.3.7; Scheme 80).

Scheme 83. Synthesis of Imines from Amines with Liberation of Ammonia and Hydrogen

Scheme 85. Plausible Mechanism for the Conversion of Alcohols to Amines and Its Reverse Reaction, Primary Amines to Secondary Amines, and Cyclic Amines to Lactams, All Catalyzed by 9

Although no reaction time was reported, 5a also catalyzed this reaction to provide the imine, N-benzylidene-1-phenylmethanamine, in 49% yield.45 On the basis of this observation, it is concluded that replacement of “CH” of a phosphine arm in pincer complexes 4a and 5a with “N” enhanced their reactivities toward amines. Using aniline as a substrate as well as a solvent, unsymmetrical imines were efficiently prepared from other primary amines.

Mechanistically, formation of primary amines, primary alcohols, secondary amines, and lactams catalyzed by complex 9 could be explained as delineated in Scheme 85. Dehydrogenation of an alcohol or amine to the aldehyde and imine, respectively, by catalyst 9 might involve dearomatization of heteroaromatic acridine ring via “long-range” metal−ligand 12061

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cooperation with C9 of the acridine as a cooperative site, as observed in the reaction of complex 9 with ammonia (section 2.3.2; Scheme 16).89 Upon formation of aldehyde or imine intermediates, they undergo nucleophilic attack by ammonia and water, respectively, to generate the common intermediate hemiaminal, from which liberation of water or ammonia facilitates the conversion of alcohol to amine, or amine to alcohol. Nucleophilic attack by the amine on the terminal imine (intramolecular in case of diamines) leads to the formation of a secondary amine. The H2 generated in the dehydrogenation at the outset is used for the hydrogenation of the unsaturated intermediate imine and aldehyde to amine and alcohols by 9 (borrowing hydrogen).145,211 The cyclic imines formed from cyclic amines undergo nucleophilic attack by water to generate a cyclic hemiaminal that undergoes further dehydrogenation to result in a lactam. 4.3.11. Synthesis of Imines from Alcohols and Amines. The PNP complexes 3a and 4a (P = PiPr2 or PtBu2, respectively) catalyze the coupling of alcohols with amines to form imines,36 unlike formation of amides as catalyzed by the PNN complex 5a. In reaction with 3a and 4a, perhaps the intermediate aldehyde dissociates from the metal center leading to formation of a hemiaminal in solution, which undergoes the expected dehydration to form an imine. In the case of the PNN complex, the hemilabile amine “arm” and lower steric bulk around the metal center might allow nucleophilic attack at the aldehyde while still coordinated, followed by dehydrogenation to the amide. The reaction catalyzed by the PNP complex 4a provides an effective method for the synthesis of imines with liberation of hydrogen and water (Scheme 86). An assortment of amines and alcohols containing different functional groups were coupled efficiently to provide imines. Gratifyingly, challenging aliphatic amines were also obtained in good yields.

DFT calculations carried out by Wang and co-workers for the synthesis of imines catalyzed by complex 4a are in line with the observed selectivity.214 The imine formation catalyzed by 4a occurs as depicted in Scheme 87. For the dehydrogenation Scheme 87. Mechanism of Catalytic Imine Formation from Alcohol and Amines

of alcohols by 4a, the β-hydride elimination considered by common wisdom is ruled out as it involves a barrier of 41.3 kcal mol−1 due to stronger coordination of phosphine arms with ruthenium center. Alternatively, a BDHT mechanism was calculated involving stepwise transfer of a proton to the unsaturated methine of the phosphine arm (I) and a hydride to the ruthenium center, generating an aldehyde and the transdihydride intermediate 4b. The barrier for formation of the hydrogen bridged intermediate complex I is calculated to be 26.6 kcal mol−1 (Figure 11). Formation of the trans-dihydride 4b and aldehyde from 4a and n-butanol is thermodynamically favored by 1.3 kcal mol−1. The coupling of the aldehyde with the amine to form the hemiaminal is thermodynamically uphill by 8.3 kcal mol−1, and is assisted by an additional alcohol and/ or water molecule (forms in situ in the reaction) via a sixmembered TS with barrier of 24.2 and 22.2 kcal mol−1, respectively. Thus, water facilitates the coupling reaction more effectively than alcohol as shown in Figure 11. Similarly, the barrier of the H2O mediated hemiaminal dehydration to form an imine is lower by 3 kcal than that of alcohol-mediated hemiaminal dehydration. The DFT calculations also found that the thermodynamically favorable amide (15.3 kcal mol−1) and ester (13.5 kcal mol−1) formations are kinetically less favorable than that of imine formation. H2 liberation from 4b to regenerate 4a is endergonic by 5.4 kcal mol−1 with a barrier of 23.9 kcal mol−1, indicating the nonspontaneous reactions; however, under reflux conditions, hydrogen gas is continuously removed from the solution, which drives the equilibrium toward 4a and imine. As a result of steric effects, the barrier for hydrogen transfer from the trans-dihydride complex 4b to imine is calculated to be 46.8 kcal mol−1 (relative to imine and 4b), which is 22.9 kcal mol−1 higher than H2 liberation from 4b. This provides an explanation for the absence of hydrogenated products (secondary amines) in the reaction mixture.

Scheme 86. Synthesis of Imines from Alcohols and Amines Catalyzed by 4a

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Figure 11. Catalytic formation of imines from alcohols and amines via BDHT pathway. Reproduced with permission from ref 214. Copyright 2012 Wiley-VCH.

The phosphaalkene-based PNP Ru pincer complex 21,51 and a dibenzobarrelene-based PCP Ru pincer complex 44,74 which operate by MLC, also catalyzed this imine formation from alcohols and amines. However, complex 21 requires a 10-fold excess of CsOH relative to the catalyst, and with complex 44, 2 mol % of catalyst load and higher reaction temperature were required. The formation of N-benzylidene-1-phenylmethanamine from benzyl alcohol and benzyl amine catalyzed by complexes 21, 44, and 4a are compared in Scheme 88.

A Ru−carbene complex215 and an OsPOP [POP: 4,6bis(diisopropylphosphino)dibenzofuran] complex216 were also later reported to catalyze this transformation. Very recently, a cationic CoPNP pincer complex was shown to catalyze the dehydrogenative coupling of primary amines and alcohols efficiently to form imines.217 Interestingly, Schomaker and co-workers found that the PNN Ru pincer complex 5a catalyzes the α,β-unsaturated imine formation from allylic alcohols and primary amines (Scheme 89).218 The intermediate vinyl hemiaminal formed preferentially underwent dehydration to generate α,β-unsaturated imine products, in preference to dehydrogenation to the α,βunsaturated amides. 4.3.12. Synthesis of Heteroaromatics from Amino Alcohols. De novo synthesis of heteroaromatics such as pyrroles, pyridines, quinolines, and pyrazines from simple starting materials remains challenging despite the existence of advanced synthetic methods for these compounds. Development of such simple and atom-economical routes to these heteroaromatics would be highly attractive as these compounds display a myriad of applications.219 Ruthenium pincer complexes emerged as excellent catalysts for the construction of these heteroaromatic compounds directly from amino alcohols. 4.3.12.1. Pyrroles from β-Amino Alcohols and Secondary Alcohols. As PNP and PNN ruthenium pincer complexes catalyze the acceptorless dehydrogenation of various alcohols, amines, and amino alcohols, it was envisaged that reacting βamino alcohols with secondary alcohols in the presence of base, catalyzed by the ruthenium pincer complex 6, might lead to selective construction of C−C and C−N bonds to form pyrroles. Indeed, when a toluene solution containing equimolar amounts of β-amino alcohols and secondary alcohols, together

Scheme 88. Synthesis of Benzylidene-1-phenylmethanamine from Benzyl Alcohol and Benzylamine Catalyzed by Different Ruthenium Pincer Complexes

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Scheme 89. Synthesis of α,β-Unsaturated Imine from Allylic Alcohols and Primary Amines

reaction of β-amino alcohols and secondary alcohols in the presence of base to form pyrroles, it was expected that employing γ-amino alcohols under similar conditions would provide pyridines and quinolines. As anticipated, reaction of γamino alcohols with 2 equiv of secondary alcohols and 2 equiv of base, catalyzed by 6, produced pyridines and quinolines in very good yields (Scheme 91).224

with 0.5 equiv of base and a catalytic amount of the bipyridinederived PNN complex 6 (0.5 mol %), was refluxed under argon flow, pyrroles were obtained in excellent yields (Scheme 90).220 Scheme 90. Synthesis of Pyrroles from β-Amino Alcohols and Secondary Alcohols

Scheme 91. Synthesis of Pyridines and Quinolines from γAmino Alcohols Catalyzed by 6

A PNP iridium pincer catalyst221 developed by Michlik and Kempe and a bidentate “PN” ligated ruthenium complex developed by Saito and co-workers222 also catalyzed this transformation efficiently. Dehydrogenation of diols in the presence of alkylamines and ketones, catalyzed by diphosphine ruthenium complexes, leading to the formation of N-alkyl pyrroles, was reported by the groups of Crabtree194j and Beller.223 4.3.12.2. Pyridines and Quinolines from γ-Amino Alcohols. As the bipyridine-derived PNN complex 6 catalyzed the

Mechanistically, pyrrole, pyridine, and quinoline formation catalyzed by 6a (formed in situ by deprotonation of 6 with base) begins with dehydrogenation of the secondary alcohols to form ketones, which undergo coupling with amino alcohols to provide imines. Further dehydrogenation of the primary alcohol functionality gives imino aldehyde intermediates, which upon 12064

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4.4. Hydrogenation/Hydrogenolysis Reactions

reaction with base generates a carbanion that attacks the aldehyde intramolecularly to construct five- or six-membered rings. Subsequent dehydration and aromatization provides the pyrroles, pyridines, and quinolines as described in Scheme 92.

Reduction of aldehydes, ketones, esters, and amides are important transformations, which are traditionally carried out using stoichiometric amounts of reducing agents, such as lithium aluminum hydride, leading to copious toxic waste production. Catalytic methods for the hydrogenation of aldehydes and ketones by molecular hydrogen using heterogeneous catalysts under very high pressure and temperatures are known. As described by Ikariya and co-workers in 2011,226 homogeneous transition metal complexes capable of catalyzing hydrogenation of aldehydes and ketones using hydrogen were found in the last few decades; hydrogenation of carboxylic acid derivatives such as esters and amides is a challenge, and only a few methods have been developed thus far. However, the hydrogenation of carbonic acid derivatives remained a tantalizing task (Scheme 94). Recent development of

Scheme 92. Proposed Mechanism for the Formation of Pyrroles, Pyridines, and Quinolines from Amino Alcohols Catalyzed by PNN Ruthenium Complex 6

Scheme 94. Challenge Levels in Catalytic Hydrogenationa

Ir-catalyzed formation of pyridines from γ-amino alcohols and primary alcohols was reported by Kempe at the same time.225 4.3.12.3. Pyrazines from β-Amino Alcohols. The dearomatized PNP pincer complex 4a catalyzes the transformation of β-amino alcohols in toluene or neat under vigorous reflux conditions (oil bath temperature 165 °C) to pyrazines in moderate yields (Scheme 93). Apparently, the initially formed

a

Reproduced with permission from ref 226. Copyright 2011 American Chemical Society.

ruthenium pincer complexes, in particular complexes capable of acting in concert with metal center, that is, exhibit MLC, provided much-required breakthroughs for the hydrogenation of these unsaturated functionalities under mild conditions using dihydrogen,28 which are summarized in this section as categorized by the challenge level described in Scheme 94. 4.4.1. Hydrogenation of Aldehydes and Ketones. Hydrogenation of carbonyl compounds using dihydrogen, carried out predominantly using transition metal complexes of rhodium, iridium, and ruthenium, constitute an important transformation in industrial organic processes.227 Noyori and co-workers developed diphosphine and diamine coordinated ruthenium complexes that operate via metal−ligand bifunctional mechanism involving 18-electron ruthenium hydride amino complex and 16-electron amido complex, which provided excellent reactivity and selectivity in the hydrogenation of carbonyl compounds.88a,228 Clarke and co-workers reported a pincer complex derived from a PNHN ligand composed of amine containing chiral aliphatic backbone 23, which catalyze the chemoselective hydrogenation of aldehydes, not affecting alkenes.53,229 Thus, heating complex 23/KOBut (0.5/1 mol %), cocatalyst DMAP (4-(dimethylamino)pyridine, 1.5 mol %), with cinnamaldehyde provided 76% yield (87% conversion) of cinnamyl alcohol using 39.5 atm hydrogen pressure (Scheme 95a). Complex 23 also hydrogenates bulkier ketones under similar conditions at 50 °C and provides S-alcohols with 90% selectivities (Scheme 95b).

Scheme 93. Synthesis of Pyrazines from β-Amino Alcohols Catalyzed by 4a

cyclic diimine intermediates undergo further dehydrogenation to provide the aromatic pyrazines. Reactions carried out under aerobic conditions or under argon provide similar results, indicating that dehydrogenation of the cyclic diimine is not influenced by oxygen.192 12065

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Scheme 95. Selective Hydrogenation of Cinnamaldehyde to Cinnamyl Alcohol and Prochiral Ketone to S-Alcohol

Scheme 97. Enantioselective Hydrogenation of Ketones Catalyzed by NCN Ruthenium Pincer Complexes

of aryl methyl ketones was attained in 30 min, which provided enantioselective S-alcohols with 90% ee and above. When ethyl phenylketone was subjected to the hydrogenation by 48 under these conditions, the corresponding S-alcohol with 90% ee was obtained (Scheme 98).

The benzoquinoline derived CNN ruthenium pincer complex 50 efficiently catalyzed the hydrogenation of ketones under mild pressure in methanol solution or methanol/ethanol mixture in the presence of a strong base (Scheme 96).78b An Os complex similar to that of 50 provided better performance for the hydrogenation of ketones.

Scheme 98. Enantioselective Hydrogenation of Aryl Methyl Ketones Catalyzed by Chiral CNN Ruthenium Pincer Complexes

Scheme 96. Efficient Hydrogenation of Ketones Catalyzed by CNN Ruthenium Pincer Complex 50

4.4.2. Hydrogenation of Carboxylic Acid Derivatives. 4.4.2.1. Hydrogenation of Esters, Formates, Lactones, and Polyesters. Hydrogenation of esters to alcohols is an industrially important transformation as many alcohols, for example, fatty alcohols, are commercially produced from the hydrogenation of fatty esters.230 In industry, this process is carried out under heterogeneous conditions using catalysts such as copper chromite at high pressure (200−300 atm) and temperature (200−300 °C).231 Soluble transitions metal complexes reported to catalyze the ester hydrogenation were few, and they required a large amount of additives and were limited to the hydrogenation of activated esters.232−235 The development of well-defined catalysts for ester hydrogenation was initiated by the disclosure of pyridine derived RuPNN catalyst 5a.86 The other ruthenium pincer complexes developed for this transformation are shown in Scheme 99. For the first time, complex 5a catalyzed the hydrogenolysis of esters at mild conditions of 5 atm of H2 pressure and 115 °C, devoid of base and additives. Sparing sterically hindered esters,

Nishiyama and co-workers have reported the chiral NCN ruthenium pincer complexes 52 (R = Ph) and 52a (R = iPr) based on bis(oxazolinyl)phenyl moiety, which catalyze the enantioselective hydrogenation of ketones to S-alcohols in very good yields and up to 90% ee (Scheme 97). Selective formation of alcohols with S-absolute configuration might be the result of apical metal hydride attack on the Re-face of ketones.80a The diphosphine ligand dppb in complex 45 (Scheme 10) was replaced by (S,R)-Josiphos* (Josiphos: 1-[1(dicyclohexylphosphano)ethyl]-2-(diarylphosphano)ferrocene) to get chiral complexes that are effective catalysts for the asymmetric hydrogenation of ketones. Baratta and co-workers developed CNN ruthenium pincer complexes [(CNN)RuCl(Josiphos)] 45a and 48, which catalyze the highly efficient enantioselective hydrogenation of aryl methyl ketones under mild conditions.76,77b Using 5 atm of hydrogen pressure, and minimal catalyst loading (0.1−0.2 mol % of 48), hydrogenation 12066

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Scheme 99. Selected Ruthenium Pincer Complexes Developed for the Hydrogenation of Esters to Alcohols

requires 59 atm of hydrogen pressure, 150 °C heating, and a strong base (LiBHEt3 or KOBut) to hydrogenate o-phthalate (Scheme 100).

both activated and unactivated esters were efficiently hydrogenated to the alcohols (Table 8).86 The PNN Ru pincer complex 23 catalyzes the hydrogenation of esters.53,229 However, it is catalytically less active and

Scheme 100. Hydrogenation of Dimethyl Phthalate Catalyzed by 23

Table 8. Mild Hydrogenation of Esters to Alcohols Catalyzed by the PNN Pincer Complex 5a

The dearomatized PNPiPr ruthenium complex 3a, similar to that of PNN ruthenium pincer complex 5a, showed less efficiency in hydrogenation of esters, due to the lack of a hemilabile amine arm.86 However, Kuriyama and co-workers reported that the Ru−MACHO catalyst 12 catalyzes the hydrogenolysis of esters very efficiently in basic methanol solution at 50 atm of hydrogen pressure (Table 9).43,236 Enticingly, the Ru−MACHO catalyst 12 was further optimized for the industrial production of (R)-1,2-propanediol and 2-(L-menthoxy)ethanol as described in Scheme 101.43,236 Previously, asymmetric hydrogenation and longer synthetic routes were required for 1,2-propanediol production.237 2-(LMenthoxy)ethanol was produced on the basis of LiAlH4 reductions, generating huge aluminate waste.238 Optimization studies showed that elevated temperatures have a negative impact on optical purity in the process for (R)-1,2-propanediol. However, a large-scale reaction near room temperature provided very good yield and optical purity of 99.2% ee, successfully offsetting the existing process. After hydrogenation of menthyl methoxyacetate using catalyst 12, 2-(L-menthoxy)ethanol (87%, 1740 TON) was obtained from distillation of reaction mixture without the need for tedious exothermic workup. Ikariya and co-workers utilized catalyst 12 for the selective hydrogenation of α-fluorinated esters to obtain the corresponding fluorinated alcohols in very good yields (Scheme 102) with wide substrate scope. When the reactions were performed under milder conditions (99 96 89 89 >99 85

>99 >99 96 88 89 >99 nr

Reaction carried out under neat condition. nr = not reported.

dioxane solution of complex 5a (0.04 mol %) and dimethyl carbonate under 40 atm pressure of hydrogen provided quantitative conversion and yield in 3.5 h. When the reaction was carried out at 60 atm of hydrogen, the hydrogenation was completed in 1 h. Hydrogenation could also be carried out at lower temperature (110 °C) and pressure (10 atm) using 6a (0.1 mol %) as a catalyst, leading to 96% conversion and yield after 48 h. Use of higher pressure resulted in 89% conversion after 14 h. Further, catalyst 6a efficiently hydrogenates dimethyl carbonate even under neat conditions and only 10 atm to provide quantitative conversion with complete selectivity to methanol.100 Gusev and co-workers reported that complex 117 also catalyzes the hydrogenation of dimethyl carbonate.42 The impressive development in the area of homogeneous catalysis made it possible to hydrogenate dialkyl carbonates, which were previously used as solvents in hydrogenation reactions.261 Ding and co-workers used the Kuriyama’s PNHP ruthenium catalyst 12 for the catalytic hydrogenation of cyclic carbonates to methanol and diols. At 50 atm pressure of hydrogen and 140 °C, methanol and ethylene glycols were formed in almost quantitative yields (Scheme 105).262

The bridged bipyridine-based PNN ruthenium(II) catalyst 8a also hydrogenates amides to amines and alcohols, but only in moderate efficiency (25−65%), perhaps due to cyclometalation to form 8b, which is detrimental to the catalysis.41 Recently, a DFT calculation on classical C−O cleavage versus newly reported C−N bond breaking in the amide hydrogenation reaction was reported by Cantillo.125 Recently, nonpincer type Ru complexes for catalytic amide hydrogenation to alcohols and amines were reported.217,257 4.4.3. Hydrogenation of Carbonic Acid Derivatives. Hydrogenation of carbonic acid derivatives, including organic carbonates, carbamates, and urea, is considered to be the most difficult of all carbonyl compounds (Scheme 94), due to the less electrophilic carbonyl group of these compounds, and the hydrogenation of these families of compounds was accomplished only very recently by Milstein’s group using ruthenium pincer complexes (Scheme 94).100 4.4.3.1. Hydrogenation of Organic Carbonates. Industrial production of methanol involves hydrogenation of CO at high temperatures (250−300 °C) and high pressures using heterogeneous catalysts.258 Efficient hydrogenation of CO2 into methanol under mild conditions remains highly desirable. Dimethyl carbonate is produced by direct reaction of CO2 with 2 equiv of methanol in the presence of dehydrating agents,259 or from oxidative carbonylation of methanol.260

Scheme 105. Hydrogenation of Cyclic Carbonates to Methanol and Glycols

Polycarbonates were also hydrogenated under mild conditions by Robertson.252 Both catalysts 5a and 6a efficiently catalyzed the hydrogenative depolymerization of polypropylene carbonate (PPC) and polyethylene carbonate (PEC) to provide propylene glycol/methanol and ethylene glycol/methanol, respectively (Table 15). The reaction mechanism for the PNN ruthenium pincer complex 5a catalyzed hydrogenation of dimethyl carbonate to 12071

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and from the ligand arm (PyCH2P, protonic hydrogen) to carbonyl oxygen via TS3 and TS3′ with regeneration of 5a. In the third step, the in situ formed hemiketal and hemiacetal undergo decomposition upon reaction with 5a, which undergo aromatization upon O−H activation to form the intermediates II and II′, respectively. In II and II′, the methoxy group abstracts a proton from the PyCH2P arm to provide the intermediates III or III′ and methyl formate or formaldehyde, respectively, with concurrent release of the first and second methanol molecules. While the second step is thermodynamically uphill, the third step is thermodynamically downhill from the hemiketal and hemiacetal to methyl formate and formaldehyde, respectively, together with the release of methanol. Further, hydrogenation of methyl formate to methanol and formaldehyde is both kinetically and thermodynamically more favorable than hydrogenation of dimethyl carbonate to methyl formate and methanol (Figure 12b,c). Decomposition of the hemiacetal intermediate to provide the second methanol molecule and formaldehyde proceeds via TS4′, II′, TS5′, and III′. Calculations also indicate that the first and second stages occur separately. Overall the second stage is kinetically more favorable despite being thermodynamically more uphill.264 The direct formation of II and II′ from I and I′ via TS6 and TS6′, respectively, involves barriers of 30.8 and 27.3 kcal mol−1, which are higher than those of the stepwise pathway, implying that such a pathway is less favorable. Hydrogenation of formaldehyde formed in stage ii occurs in stage iii to deliver the third molecule of methanol from dimethyl carbonate. The reaction mechanism is shown in Figure 13a. The first step, hydrogen activation, is the same as that of the initial two stages i and ii. The second step, hydrogen transfer, proceeds successively along the intermediates 5b → TS7 → IV → TS8 → 5a + MeOH. Relative to 5b and formaldehyde, the barriers for this hydrogen transfer step are 7.7 (TS7) and 7.2 kcal mol−1 (TS8, Figure 13b), much lower than those in stages i and ii (Figure 12b,c). The initial two stages are endergonic by 1.6 and 5.8 kcal mol−1, respectively, whereas the hydrogenation of formaldehyde is exergonic by 9.7 kcal mol−1 (Figure 13b) and provides the thermodynamic driving force for stages i and ii and for the complete conversion of dimethyl carbonate to three molecules of methanol.264 Recently, Hasanayn and co-workers proposed that metathesis of Ru−H of 5b and C−OMe of dimethyl carbonate occurs via “ion-pair” formation and rearrangement, based on DFT studies.265 4.4.3.2. Hydrogenation of Carbamates to Methanol and Amines. Catalytic hydrogenation of carbamates in general serves as a deprotection method to obtain amines as a result of C−O bond cleavage with liberation of CO2 and alkanes. However, analogous to ester and amide hydrogenolysis reactions catalyzed by Milstein’s ruthenium pincer complexes, complex 6a catalyzes the hydrogenation of methyl carbamates to methanol (rather than CO2) and amines (Scheme 106). Hydrogenolysis of benzyl morpholine-4-carboxylate catalyzed by 6a (1 mol %) under mild hydrogen pressures and experimental conditions provides morpholine, benzyl alcohol, and methanol in very good yields.100 4.4.3.3. Hydrogenation of Urea Derivatives to Amines and Alcohols. Like formate, carbonate, and carbamate, urea is also derived from carbon dioxide, and its hydrogenation to methanol could provide indirect hydrogenation of CO2. However, similar to other carbonyl derivatives, the resonance effect makes the carbonyl group of urea derivatives the least

Table 15. Catalytic Hydrogenation of Polycarbonates

methanol was investigated by different groups using DFT.263−265 Yang carried out the DFT calculations along the proposed pathway, which involves direct transfer of hydride ligand to the carbonyl carbon to form the hydrido alkoxo complexes and cleavage of alkoxide C−O bond by MLC.263 Concurrent breaking of C−O bond in CH3OCH2O− and methylene proton transfer from the ligand phosphine arm (PyCH2P) to the dissociated CH3O− group (in the hydrogenation of methyl formate) was found to be the ratedetermining step in complete hydrogenation of dimethyl carbonate to three molecules of methanol by 5a. Wang and co-workers264 found that the low energy pathways in hydrogenation of dimethyl carbonate catalyzed by 5a involve three stages, (i) hydrogenation of dimethyl carbonate to methyl formate and methanol, (ii) hydrogenation of methyl formate to formaldehyde and methanol, and (iii) formaldehyde hydrogenation to methanol. The anticipated BDHT pathway based on alcohol dehydrogenation121,126 was found to be more favorable. The first two stages proceed via a similar mechanism (Figure 12a) involving three steps, hydrogen activation, hydrogen transfer resulting in hemiketal (R1 = OMe, stage i) or hemiacetal (R1 = H, stage ii), and the catalyzed decomposition of hemiketal or hemiacetal intermediates to methyl formate and formaldehyde, respectively, along with formation of methanol. The first step of heterolytic dihydrogen activation by 5a to provide trans-dihydride ruthenium complex 5b (Scheme 24) is the same for all three stages. The calculated barrier for hydrogen activation is 25.6 kcal mol−1 (TS1). The computed free energy profiles for the formation of first methanol (R1 = OMe, stage i) and second methanol (R1 = H, stage ii) molecules are shown in Figure 12b and c, respectively. In the second step, complex 5b transfers the hydrogen atoms to the carbonyl carbon of dimethyl carbonate or methyl formate. This step is the reverse process of alcohol dehydrogenation in which the BDHT mechanism is more favorable than β-hydride elimination (Figure 10b).121,126 Similarly, in the BDHT pathway (again found to be preferred over carbonyl insertion into Ru−H bond), complex 5b reacts with dimethyl carbonate or methyl formate to provide the hemiketal or hemiacetal, and this second step is endergonic by 11.3 and 4.4 kcal mol−1, respectively. Hydrogen transfer occurs sequentially from ruthenium center (hydride ligand) to the carbonyl carbon 12072

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Figure 12. (a) Proposed mechanism of the catalytic hydrogenation of dimethyl carbonate to methyl formate (R1 = OMe) and formaldehyde (R1 = H) and two molecules of methanol, as calculated by DFT in two stages. (b) R1 = OMe. (c) R1 = H. Free-energy profiles of stages i and ii, respectively. Reproduced with permission from ref 264. Copyright 2012 American Chemical Society. 12073

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Figure 13. (a) Proposed mechanism of the catalytic hydrogenation of formaldehyde to methanol in stage iii. (b) Free-energy profile corresponding to stage iii. Reproduced with permission from ref 264. Copyright 2012 American Chemical Society.

hydrogenation of urea derivatives to methanol and amines was achieved by Milstein for the first time using catalyst 6a (2 mol %) at 13.6 atm of hydrogen pressure. The products were obtained in good yields after 72 h (Scheme 107).266 4.4.4. Hydrogenation of Carbon Dioxide to Methanol and Formates. 4.4.4.1. Hydrogenation of Carbon Dioxide to Methanol. The efficient transformation of CO2 to a carbonneutral fuel is an attractive prospect. Hence, the development of catalytic methods for the direct hydrogenation of CO2 to methanol under homogeneous and mild conditions remains an attractive goal. While catalytic routes for the conversion of CO2 to formic acid and methyl formate were known for a long time, the hydrogenation of methyl formate to methanol under mild conditions was unknown, until reported by Milstein’s group in 2011 (Table 12).100 Combining these catalytic processes in one pot, CO2 was hydrogenated to MeOH by Sanford and Huff to obtain 2.5 turnovers of methanol (Scheme 108). Further, separation of catalysts within the reactor provided a TON of 21.267 Recently, Leitner, Klankermayer, and co-workers reported the direct hydrogenation of CO2 to methanol catalyzed by a single Ru(II) complex [(triphos)Ru-

Scheme 106. Hydrogenation of Carbamates to Amines and Methanol

electrophilic and thus makes it the most challenging family of carbonyl compounds for hydrogenation (Scheme 94). Catalytic 12074

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Use of a large excess of base and prolonged heating at elevated temperature provided good TONs (Table 16).

Scheme 107. Hydrogenation of Urea Derivatives to Amines and Methanol

Table 16. Hydrogenation of CO2 to Potassium Formate Catalyzed by 5a

temp (°C) 120 120 200 200

base (equiv) K2CO3 K2CO3 K2CO3 K2CO3

(1200) (100 000) (100 000) (100 000)

time (h)

TON

4 24 4 48

1100 1400 9000 23 000

The H2 and CO2 activation by PNP ruthenium complex 4a resulted in the formation of 4b and 96 (Schemes 24 and 42, respectively).36,131 Pidko and co-workers studied the hydrogenation of CO2 by 4b and 96 using dihydrogen in the presence of organic base such as triethylamine or DBU (1,8diazabicyclo[5.4.0]undec-7-ene).273 The CO2 activated adduct 96 has a negative impact on the catalysis, which could be surmounted by the addition of water. When subjected to catalysis, 96 provided a TOF of 14 500 h−1 for the formation of 2HCOOH·DBU. The reaction involves the induction period at the outset indicating the transition of complex 96 to the catalytically active species. However, when the trans-dihydrido ruthenium PNP complex 4b is used as catalyst in the presence of DBU, highly efficient formation of formate adduct was observed with TOF 21 500 h−1. Very recently, Pidko and coworkers found that complex 4b act as a unique catalyst and provides the lowest-energy reaction pathway,273b without involving MLC for the hydrogenation of CO2 to formate (Scheme 109). The reaction proceeds via CO2 activation by Ru−H, leading to the formation of polarized complex II. Dissociation of formate anion from II provides a fivecoordinated Ru monohydride complex, which activates dihydrogen assisted by the formate anion (III). The initial CO2 activation is the rate-determining step with an activation energy of 24 kJ/mol.

Scheme 108. Direct Hydrogenation of CO2 to Methanol

Scheme 109. Hydrogenation of CO2 to Formate Catalyzed by the Ru trans-Dihydride Complex 4b (trimethylenemethane)2] in the presence of organic acids, such as methanesulfonic acid or bis(trifluoromethane)sulfonimide (HNTf2), that provides up to 221 TON.268 4.4.4.2. Hydrogenation of Carbon Dioxide to Formates. The hydrogenation of CO2 to formate salts catalyzed by a highly active Ir(III) pincer complex,269 a Fe(II) pincer complex,270 and a Ru(II) amide complex was also reported.271 Although several other soluble catalysts were reported to catalyze this transformation, Nozaki’s pincer complex (PNPiPr)IrH3 is the most active catalyst.272 Subsequent to the reports on CO2 hydrogenation to methanol and activation of CO2,133 Sanford and Huff also reported very recently the hydrogenation of carbon dioxide to formate salt using PNN Ru complex 5a.134 The reaction of complex 5a with H2/CO2 mixture provided the formate complex 97 (section 3.8, Scheme 43). When complex 97 was treated with a strong base, deprotonation of the ligand at the phosphine arm took place to quantitatively regenerate complex 5a together with formation of potassium formate. Heating complex 5a with a mixture of CO2 and H2 at higher pressure together with excess base resulted in the formate salt. 12075

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Table 17. Reversible Hydrogenation of CO2 4 (1.42 μmol)

4 (1.42 μmol)

[BH]+ [HCOO]− ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ CO2 + H 2

CO2 + H 2 ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ [BH]+ [HCOO]−

DMF/base

entry 1 2 3 4 a

base NEt3 NEt3 Nhex3 DBU

T (°C) 65 90 90 90

−1

TOF (h ) 46 495 257 000 256 000 93 100

DMF/base

TON

entry

P (bar) H2:CO2

base

T (°C)

TOF (h−1)

AAR

5 6 7 8

20:20 20:20 2.5:2.5 2.5:2.5

NEt3 DBU DBU DBU

65 65 90 65

34 000 360 000 60 000 7900

0.26 1.6 1.18 1

a

nd 326 500 706 500 310 000

nd = no data.

4.4.4.3. Reversible Hydrogenation of Carbon Dioxide to Formates. Reversible catalytic hydrogenation of CO2 is interesting with regard to hydrogen storage. Very recently, Pidko and co-workers studied the dehydrogenation of formic acid (Table 17, entries 1−4) as well as hydrogenation of formates (Table 17, entries 5−8) using PNP Ru pincer complex 4 as the catalyst in the presence of nitrogen-based organic bases.274 Using catalyst 4 together with triethylamine, TOF 257 000 h−1 is obtained for the dehydrogenation of formic acid (Table 17). Only equimolar amounts of H2 and CO2 formed without any formation of CO. When 0.35 μmol of 4 was used, a TON of 1 063 000 was reached. Effective dehydrogenation was also observed with other nonvolatile and non-nucleophilic organic bases, trihexylamine and DBU, respectively. Although the strength of the base had no influence on the rate of hydrogenation of formate salts, a substantial effect was observed on the final acid-to-amine (AAR) ratio. While a low yield was obtained with triethylamine (entry 5), excellent yields were obtained when DBU was used as a base (entries 6−8). With 0.178 μmol of 4 and a H2/CO2 molar ratio of 3:1 (Ptotal = 40 bar) at 120 °C, TOF 1 100 000 h−1 was attained for the hydrogenation of formates. The trans-dihydride Ru complex 4b formed from 4 (via 4a) is the actual catalyst, which provided the highest rates of dehydrogenation and hydrogenation of formates reported to date. The hydrogenation cycle proceeds as described in Scheme 109 in reverse. 4.4.5. Hydrogenation of Nitriles to Amines. Leitner and co-workers reported the hydrogenation of nitriles to primary amines catalyzed by the PNP pincer complex 20, containing nonclassical hydrides.275 High pressure was not necessary for the hydrogenation of nitriles. However, good selectivity for the primary amines was achieved at 75 atm of hydrogen. Both aromatic and aliphatic nitriles were hydrogenated to primary amines (Scheme 110). Although several catalytic systems were reported to catalyze the hydrogenation of nitriles to amines, they suffer from the need of a large amount of base (ca. 10 mol %).276 Despite the use of a high pressure of hydrogen, 20 catalyzed the reaction under neutral conditions. Sabo-Etienne and co-workers reported a ruthenium nonclassical hydrogen complex [RuH2(H2)2(PCyp3)3] that catalyzes the hydrogenation of benzonitrile under mild conditions.277 Upon hydrogenation, the initially formed primary imine can undergo further hydrogenation to provide a primary amine. On the other hand, the primary imine can undergo nucleophilic attack on the electron-deficient imine carbon by the product primary amine to provide an intermediate gem-diamine, which eliminates ammonia to form a secondary imine, the hydrogenation of which could provide a secondary amine. Both secondary imines and secondary amines were formed as side products. Addition of water enhanced both the selectivity and the reaction rate. This might be due to hydrolysis of the imine intermediate to provide a primary amine and aldehyde under

Scheme 110. Hydrogenation of Nitriles to Primary Amines Catalyzed by the PNP Ruthenium Pincer Complex 20

the experimental conditions. The in situ generated aldehyde can react with ammonia to form a terminal imine, which could undergo hydrogenation to a primary amine, enhancing the selectivity and rate of the reactions (Scheme 111). DFT Scheme 111. Proposed Mechanism for the Hydrogenation of Nitriles to Primary and Secondary Amines

calculations of the reaction mechanism indicated that initial loss of a nonclassical dihydrogen ligand and subsequent geometrical change creates a vacant coordinating site trans to the pyridine backbone for the coordination of nitriles. Further stepwise intramolecular migrations of the hydride ligands from ruthenium to CN multiple bonds lead to the formation of primary amines. Dissociation of amines from the metal center and further coordination of nitrile closes the catalytic cycle. 4.4.6. Hydrogenation of Nitriles to Imines. As discussed in Scheme 111, when nitrile hydrogenation was performed 12076

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4.4.7. Hydrogenation of Imines to Amines. Recently, a CNC ruthenium complex 30 with a pyridine backbone and facgeometry was reported to catalyze the hydrogenation of imines to amines.61 In general, quantitative conversions were obtained with most of the imines, and only electron-withdrawing substituents like fluorine diminished the conversion (Scheme 114). In the presence of base, methylene arm deprotonation led

under mild pressure of hydrogen in the presence of catalyst 6a, secondary imines products were obtained via a gem-diamine intermediate followed by ammonia elimination (Scheme 112). When the reactions were carried out under mild hydrogen pressure (3.9 atm), hydrogenation of neither primary imine intermediates nor secondary imines occurs.278 Scheme 112. Hydrogenation of Nitriles to Imines under Mild Conditions

Scheme 114. Hydrogenation of Imines to Amines under Mild Conditions

Further, nitriles can also be hydrogenated in the presence of added primary amines to obtain unsymmetrical imines. Various aryl and alkyl nitriles reductively couple with primary amines by catalyst 6a (Scheme 113). Higher loading of catalyst (0.6−0.8 mol %, vide supra) and longer reaction times (15−72 h) were required. Unlike the hydrogenation of nitriles by 20, the PNN complex 6a is proposed to split hydrogen by an MLC mechanism.278 Scheme 113. Synthesis of Imines from Nitriles and Primary Amines Catalyzed by 6a

to dearomatization of the pyridine ring to provide a neutral CNC Ru(II) species, which catalyzed the hydrogenation of imines to amine under mild reaction conditions. 4.4.8. Hydrogenation of Azide to Ammonia. Catalytic hydrogenation of dinitrogen to ammonia under mild conditions is a highly desirable goal.279 Schneider and co-workers have demonstrated that nitrido complexes could be employed as models toward hydrogenation of dinitrogen.280 However, terminal nitrido complexes are in general inert toward hydrogenation. Contrarily, the terminal nitrido complex 119 generated from the PNP pincer complex 118 underwent hydrogenation at the mild conditions of 0.98 atm H2 and 50 °C to liberate ammonia and form a polyhydride ruthenium complex I (Scheme 115). The MLC between “Ru-amide” in complex 119 is responsible for the initial, rate-determining heterolytic hydrogen splitting. Further, stepwise proton transfer reactions to the nitrido ligand generate imido, amido, and then ammonia, which dissociate from the metal center. Protonolysis of the polyhydride complex II regenerated the dichloro complex 118, which upon further reactions with the azide liberate ammonia in an efficient catalytic cycle. The proposed mechanistic cycle is in agreement with a quantum chemical study. 12077

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Scheme 115. Hydrogenation of Azide to Ammonia

Scheme 116. Selective Hydroboration of Terminal Alkynes to Z-Vinylboronates

5. MISCELLANEOUS USAGES 5.1. Hydroboration of Terminal Alkynes

Vinylboron reagents are widely used in organic synthesis, as they are stable organometallic reagents, which undergo a number of synthetically useful transformations including the metal-catalyzed C−C bond formations.281 While hydroboration of terminal alkynes results in only E-vinylboronates,282 the Zvinylboronates were prepared in two steps.283 The first transhydroboration reaction catalyzed by [(M(COD)Cl)2]/PCy3 (M = Rh, Ir) is not selective, and a considerable amount of cis-hydroboration products also forms.284 Leitner and coworkers disclosed that the nonclassical ruthenium hydride pincer complex 20 catalyzed the chemo-, regio-, and stereoselective unconventional trans-hydroboration of terminal alkynes with pinacolborane to provide Z-vinylboronates with very good stereoselectivity.285 An assortment of Z-vinylboronates were prepared in very good yields with good functional group tolerance, and the TON up to 970 (Scheme 116) was attained. Reaction of 20 with pinacolborane resulted in immediate formation of 120 with H2 evolution. NMR studies of the reaction mixture indicated that 120 is the only phosphine species present after completion of the reaction, and when tested independently, 120 also exhibited similar catalytic efficiency for the Z-selective hydroboration of terminal alkynes. An experiment with labeled 1-deuterio-2-phenylacetylene confirmed that the terminal deuterium atom is quantitatively transferred to the internal vinyl carbon, trans to the boron atom, and established that this transformation is an unconventional trans-hydroboration. On the basis of these observations, a catalytic cycle was proposed (Scheme 117), which involves η2alkyne coordination to Ru upon liberation of dihydrogen from 120. The η2-ligated alkyne undergoes isomerization as a result of 1,2-hydrogen migration to generate the η1-vinylidene intermediate II, and further C−B bond formation occurs as a result of intramolecular coupling of vinylidene and pinacolborate ligands. The resulting vacant coordination site is occupied by a pinacolborane, leading to σ-bond metathesis to release Zvinylboronates and generate pinacolborate ligated intermediate V with a vacant site for the incoming alkynes, setting the stage for another cycle.

5.2. Asymmetric Alkynylation of Aldehydes

The chiral NCN ruthenium pincer complexes 53 and 54, composed of bis(oxazolinyl)phenyl ligands developed by Nishiyama and co-workers, catalyze the enantioselective direct alkynylation of aldehydes (Table 18). The dimeric complex 53 provides higher yield and stereoselectivity.82 5.3. Conjugate Addition of Alkynes to α,β-Unsaturated Carbonyl Compounds

Using the chiral NCN ruthenium catalyst 54, Nishiyama and co-workers have developed the direct conjugate additions of alkynes to α,β-unsaturated carbonyl compounds.286 The NCN ruthenium pincer complex 54 (1−5 mol %) catalyzes the reaction of a range of terminal alkynes with various α,βunsaturated ketones, esters, and amides, leading to the corresponding β-alkynyl carbonyl compounds in very good yields (Scheme 118). Similar rhodium and iridium pincer complexes were much less effective catalysts in this transformation. Complex 54 also catalyzes the conjugate addition of phenyl acetylene with vinylphosphonate to provide alkynyl phosphonate, a synthetically useful precursor. The reaction of 12078

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Scheme 117. Proposed Catalytic Cycle for the Z-Selective Hydroboration of Terminal Alkynes

Scheme 118. Conjugate Addition of Alkynes with α,βUnsaturated Carbonyl Compounds

Table 18. Enantioselective Alkynylation of Aldehydes

R1

time (h)

yield (%)

ee (%)

4-CF3C6H4 4-BrC6H4 4-NO2C6H4 4-MeC6H4 4-MeOC6H4 3-BrC6H4 2-BrC6H4 1-naphthyl 2-naphthyl

48 48 24 96 96 48 48 48 48

94 93 88 70 42 95 95 86 82

90 93 89 95 95 94 77 94 95

119). The presence of the base NaOAc shifts the equilibrium toward the formation of I. The α,β-unsaturated carbonyl compound coordinates trans to the benzene ring in I, leading to nucleophilic attack by the acetylide ligand at the electrophilic βposition of the unsaturated carbonyl compound to generate intermediate III. Protonation of intermediate III releases the product and regenerates 54. 5.4. Decarbonylation of Acetone and Carbonate

Ozerov and co-workers reported a square-pyramidal PNP ruthenium dihydrogen complex 121 (Scheme 120). However, the initial attempt to prepare complex 121 from the corresponding PNHP ligand in the presence of a base (K2CO3) in iso-propanol resulted in direct formation of complex 124. When labeled K213CO3 was used, 124:124* (possessing labeled 13CO) formed in the ratio of 1:3, indicating that both the carbonate base and the secondary alcohol underwent decarbonylation under the reaction conditions. When complex 121 was reacted with 4 equiv of acetone in fluorobenzene, complex 124 was obtained in 95% yield. Methane formation was observed by 1H NMR. Hence, it was proposed that reaction of 121 with acetone results in C−C cleavage to generate the intermediate 122 with methyl and acetyl ligands. Following reductive elimination of methane and methyl migration from the acetonyl intermediate, 123 is

phenyl acetylene with 3-penten-2-one catalyzed by 54 (5 mol %) resulted in asymmetric conjugate addition to form the corresponding β-alkynyl substituted compound with 82% ee. Catalytic conjugate addition of alkynes to α,β-unsaturated carbonyl compounds was proposed to begin with a reversible heterolytic C−H activation of the terminal alkyne by 54, generating a η1-alkyne intermediate I and acetic acid (Scheme 12079

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Scheme 119. Proposed Mechanism for Conjugate Addition of Alkynes with α,β-Unsaturated Carbonyls

Scheme 121. Reduction of Hydrazine to Ammonia by Dinuclear PNP Ruthenium Complex

6. CONCLUSIONS AND OUTLOOK It is clear that ruthenium pincer complexes possess a plethora of important and enticing catalytic reactivities, which can explain their popularity and ever-increasing applications.289 Most of this interest centers on their ability to engage in MLC; that is, both the metal and the ligand act in concert during bond activation and bond formation. The possibility of modulating their electronic properties by rational design of pincer ligands with suitable donor triads, the nature of backbone (aliphatic, aromatic, and varied heteroatom frameworks, etc.), appropriate substituents, and size of the metallic rings (five to sixmembered) provide both electronic and steric balance. Moreover, on the basis of the nature of the ancillary neutral (L) and anionic (X)-type ligands, further opportunities for catalyst design and modulation are possible. While moderating all of these options, one has to remember that it is the strong mer-coordination of pincer ligands and planarity around the metal center that provide a good compromise between stability and reactivity, which make the pincer complexes distinct from other homogeneous catalysts. The selected representation of synthesis, structure, various bond activations, and catalytic processes represents the progress in the area of ruthenium pincer complexes in the last 10 years and provides further insight for future catalyst design. Out of the many facets of this field, one key development is that it uncovered a range of green, catalytic hitherto unknown dehydrogenative transformations for the synthesis of products of industrial significance from simple feedstocks, with liberation of hydrogen gas as the only byproduct and providing new methodology for efficient production of hydrogen from biorenewable resources such as simple alcohols. On the other hand, it also offers catalytic platforms for the unprecedented hydrogenation of strong polar bonds under mild conditions. Hydrogenation of esters using ruthenium pincer complexes has been already applied on the industrial scale. Isolated intermediates involved in catalytic reactions and DFT studies provide much mechanistic insight, and further in-depth investigation in this direction is anticipated. Starting with benzenoid or aliphatic backbone with aryl phosphine or amine donors on the arms, the pincer ligand framework has been expanded to an assortment of heteroaromatic or aliphatic backbones with heteroatom donors with

Scheme 120. Decarbonylation of Acetone by a Nonclassical Dihydrogen PNP Ruthenium Pincer Complex 121

formed, which reacts with H2 liberated from 121 to result in 124 and methane. When the independently synthesized complex 123 was reacted with H2, complete conversion to 124 and methane took place, substantiating the proposed mechanism. Overall, the PNP ruthenium pincer dihydrogen complex converts acetone into two molecules of methane and to the carbonyl complex 124 (Scheme 120).287 5.5. Reduction of Hydrazine to Ammonia

Arnold and Rozenel treated Schneider’s dimeric ruthenium complex 18 (Scheme 4)49 with 2 equiv of AgBF4 in nitrogen atmosphere to obtain the dinitrogen ligated dinuclear ruthenium pincer complex 125 with bridging chlorides. Upon reaction with 1 equiv of hydrazine, both nitrogen ligands on complex 125 were displaced by a hydrazine ligand to provide 126 (Scheme 121). However, when 125 was reacted with excess of hydrazine, ammonia and the hydrazine-bound monometallic complex 127 were formed as a result of disproportionation of hydrazine. Studies indicate that complex 126 promotes the ammonia formation from hydrazine.288 12080

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electron-rich or electron-poor phosphines. While pincer ligands bearing the same donors on both pincer arms are normally easy to prepare, unsymmetrical donors are increasingly designed as they offer enhanced reactivity while ensuring the stability and selectivity of the reactions. Introduction of carbene donors provided highly stable ruthenium pincer catalysts for several reactions, particularly THs. Enantioselective reactions (such as TH) using pincer ruthenium catalysts were also reported. Such parallel development of chiral catalytic entities for other transformations can be expected. As many useful ruthenium pincer complexes and their prerequisite pincer ligands and metal salts are commercially available, they are well on their way to displacing conventional reactions involving toxic, waste-generating reagents and additives. Although these ruthenium pincer complexes are generally viewed as air- and moisture-sensitive catalysts, there are many discrete reactions performed under air without loss of much activity; in addition, they can readily be generated in situ from air-stable precursors; further, recently developed air-stable SNHS ruthenium pincer complexes with outstanding catalytic efficiency are indicative of further potential development of benchtop catalysts. Efficient and controlled release of hydrogen from simple alcohols and other substrates using pincer catalysts is also promising with regard to alternative energy issues.

interests include the design and catalytic applications of pincer complexes for atom-economical processes.

David Milstein is the Israel Matz Professor of Chemistry and the Director of the Kimmel Center of Molecular Design at the Weizmann Institute of Science in Israel. He received his Ph.D. degree at the Hebrew University in 1976 with Prof. Blum and performed postdoctoral research at Colorado State University, where together with his advisor, John Stille, he discovered the Stille Reaction. In 1979 he joined DuPont Company’s CR&D department, and in 1986 he moved to the Weizmann Institute, where he headed the Department of Organic Chemistry from 1996−2005. His research interests include fundamental organometallic chemistry, particularly the activation of strong bonds, and the design of environmentally benign processes catalyzed by transition metal complexes. His awards include the Kolthoff Prize (2002), the Israel Chemical Society Prize (2006), the ACS National Award in Organometallic Chemistry (2007), the RSC Sir Geoffrey Wilkinson Award (2010), the Humboldt Senior Award (2011), and the Israel Prize (2012, Israel’s highest honor). He was also awarded several lectureships and visiting professorships. He is a member of the Israel National Academy of Sciences and Humanities, and the German National Academy of Sciences-Leopoldina.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

ACKNOWLEDGMENTS We thank all of our outstanding co-workers and collaborators, whose names appear in the cited references, for their valuable contributions. This research was supported by the European Research Council under the FP7 framework (ERC No 246837) and by the Israel Science Foundation. C.G. thanks DST-SERB (SR/S1/OC-16/2012 and SR/S2/RJN-64/2010), NISER Bhubaneswar, and he is a Ramanujan Fellow. D.M. is the holder of the Israel Matz Professorial Chair of Organic Chemistry. Chidambaram Gunanathan completed his bachelor studies in chemistry (1997) at RKM Vivekananda College, University of Madras, and Master studies in organic chemistry (1999) at the Department of Organic Chemistry, University of Madras, Chennai. He carried out his Doctoral studies in the group of Prof. S. Muthusamy at Central Salt and Marine Chemicals Research Institute (CSMCRI), and in 2005 he obtained his Ph.D. degree in chemistry. Thereafter, he joined in the groups of Prof. David Milstein and Prof. Hadassa Degani at the Weizmann Institute of Science, Israel, for his postdoctoral stint, where he was also a Dean of Faculty Postdoctoral Fellow. After spending two years as an Alexander von Humboldt Research Fellow in the group of Prof. Walter Leitner at RWTH Aachen University, Germany, he joined as an Assistant Professor at NISER, Bhubaneswar, in 2011. He has been promoted to Reader F in 2013. He is also a recipient of Ramanujan Fellowship from DST-SERB, New Delhi. His research

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DOI: 10.1021/cr5002782 Chem. Rev. 2014, 114, 12024−12087