Asymmetric Transfer Hydrogenation with a Bifunctional Iron (II

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Asymmetric Transfer Hydrogenation with a Bifunctional Iron(II) Hydride: Experiment Meets Computation Lorena De Luca, Alessandro Passera, and Antonio Mezzetti J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12506 • Publication Date (Web): 09 Jan 2019 Downloaded from http://pubs.acs.org on January 10, 2019

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Journal of the American Chemical Society

Asymmetric Transfer Hydrogenation with a Bifunctional Iron(II) Hydride: Experiment Meets Computation Lorena De Luca, Alessandro Passera, and Antonio Mezzetti* Dept. of Chemistry and Applied Biosciences, ETH Zurich, Switzerland ABSTRACT: Hydride cis-β-[FeH(CNCEt3)(1)]BF4 (5) (1 is a chiral N2P2 macrocycle) is the catalytically active species in the asymmetric transfer hydrogenation of ketones formed upon reaction of [Fe(CNCEt3)2(1)](BF4)2 (3) with base. Stoichiometric reactions show that hydride 5 is formed by H-elimination from the 2-propoxo complex [Fe(OiPr)(CNCEt3)(1)]BF4 (8a) and inserts the C=O bond of acetophenone to give the diastereoisomeric alcoholato complexes [Fe(OCH(Me)Ph)(CNCEt3)(1)]BF4 (10R and 10S). Complexes 5, 8a, and 10 were characterized by NMR spectroscopy, and their structures were calculated by DFT. The DFT study supports a bifunctional mechanism with the alkoxo complexes 8a and 10 as resting species. The stereochemical model reproduces the high enantioselectivity with acetophenone, which results from the combination of the rigid macrocyclic scaffold with the bulky, yet conformationally flexible isonitrile.

INTRODUCTION 1,2

Since Noyori's pioneering work, the asymmetric transfer hydrogenation (ATH) of polar double bonds has become the benchmark method for the synthesis of chiral alcohols as single enantiomers on a small scale.3 The corresponding catalysts are stabilized by soft ligands (phosphine2 or η6-arene1) and contain at least one hard NH donor that directs and activates the ketone toward hydride attack. The H–M–N–H moiety is the token of the bifunctional mechanism, that has been studied experimentally4 and by calculation,5 mostly for ruthenium. The recent trend of replacing precious metals with cheaper and less toxic base-metal catalysts has appointed iron as a viable alternative to ruthenium for ATH.6 Morris' group has pioneered the field of iron(II) catalysis with tetradentate PNNP ligands that attain enzyme-like activity.7 Gao has introduced N4P2 macrocycles in connection with Fe(0) precursors,8 whereas our group has shown that N2P2 macrocyclic ligands (1) form stable, diamagnetic complexes (such as 2 and 3 in Scheme 1) that catalyze the ATH of a broad scope of ketones with excellent enantioselectivity.9 Despite the successful applications, the understanding of the mechanism for ATH with iron catalysts is still rudimental. The elusive nature of the catalytically active species has hampered the experimental studies of these systems, whose mechanistic understanding heavily relies on calculation.10 A major issue of ATH is the ubiquitous presence of base that is required to form the hydride complex as the active species with most ATH catalysts.11 Interestingly, this is the case also for most Fe(II),12 Ru(II),13 and Mn(I)14 hydrogenation catalysts operating under H2 pressure. Notable exceptions are the BH4adduct [RuH(η1-BH4)(1,2-diamine)(binap)]15 and the achiral iron(II) catalyst [FeH(η2-BH4)(PNP)].16 Basic conditions are incompatible with molecules that contain base-labile stereocenters, which easily racemize in basic media, such as αhydroxyketones.17 Hence, much effort has been directed to develop base-free hydrogenation catalysts,18 but only a few are chiral.19 Therefore, we decided to exploit our (NH)2P2 macro-

cyclic ligands to prepare a iron hydride that, possessing the H– Fe–N–H motif, would be active without the addition of base according to the bifunctional mechanism.4,5 As previously reported, the hydride complex [FeH(CNCEt3)(1)]BF4 (5, Chart 1) catalyzes the base-free ATH of ketones with the same enantioselectivity (up to 99% ee)20 obtained in the base-activated catalytic system formed by the bis(isonitrile) complex 3 and NaOtBu.9a Also, hydride 5 the first example of highly enantioselective catalyst for the hydrogenation of benzil to benzoin (up to 95% ee).20-22 (BF4)2

H H (S) N (S)

P

(S)

N

H

N

Ph P

(S)

P

Ph

Fe

L Ph

P

BF4

C Et3C N

4

Fe P Ph

BF4

H

N Ph P

L

2 (L = MeCN) Ph 3 (L = CNCEt3)

(SP,SP,SC,SC)-1 H

N H

N N H Br

Ph P C Et3C N

5

Fe P

N H H

Ph

Chart 1. The N2P2 macrocycle 1 and its iron(II) complexes. As [FeH(CNCEt3)(1)]BF4 (5) is a rare example of iron(II) hydride that can be formed as a single species in solution and used as such in the ATH of polar double bonds, it also offers the opportunity of lending experimental support to the mechanistic features of an iron(II) ATH catalyst. Thus, we identified and characterized by NMR spectroscopy the diastereoisomeric 1-phenylethanolato and the 2-propoxo complexes, which, in the case of Fe(II) catalysts based on macrocycle 1, are the resting species of the transfer hydrogenation reaction. The unobservable reaction intermediates and transition states (TS)

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were calculated by DFT to give the overall mechanistic picture described below.

RESULTS AND DISCUSSION [FeBr(CNCEt3)(1)]BF4 (4). The bench-stable bromoisonitrile complex 4 is a convenient synthon for hydride 5. We have previously reported20 that [Fe(MeCN)2(1)](BF4)2 (2) reacts with CNCEt3 (1 equiv) and an excess of KBr in dichloromethane (50 °C, 16 h) to give the bromoisonitrile complex trans-[FeBr(CNCEt3)(1)]BF4 (trans-4) as an orange solid after precipitation with hexane. We find now that, upon changing to acetone as solvent, cis-β-[FeBr(CNCEt3)(1)]BF4 (cis-β-4) is formed instead, which was isolated as a red solid in 85% yield after evaporation of the solvent and recrystallization from THF/Et2O (Scheme 1). H

H

(BF4)2

N N H Fe N N P

KBr (excess) acetone

Ph

of 5 in solution by 2D NMR spectroscopy using the metrical parameters of [Fe(CNR)2(1)](BF4)2 (R = adamantyl)9a as a guide to assign the signals and NOE contacts. For the NMR spectroscopic study, hydride 5 was prepared in THF-d8 by treating 4 with NaBHEt3 (1 M solution in toluene-d8).24 A 15N1 H HSQC experiment revealed the 1H NMR signals of the amine protons (δ 6.08 and 1.12) of 5. The more deshielded N– H proton at δ 6.08 shows an NOE contact to the hydride ligand and identifies the H–N–Fe–H motif that is deemed responsible for the hydrogen transfer (Figures 1 and S15). The 1H NOESY experiment also revealed weak NOE contacts between two H atoms of the CH2–P groups (δ 1.95 and 2.10) and the methylene groups of the isonitrile ligand at δ 1.40. This combined information strongly supports a trans P–Fe–H arrangement. Accordingly, there are no NOE contacts between the hydride and the methylene protons of the 1,3-propanediyl P–P bridge.

BF4

N

CNCEt3 (1 equiv)

Ph P

Ph P

6.08 N H

Fe

C Et3C N P

Br

N(2)

Ph P(2) H 2.10 H C N C H 2.62 H CH2 2.37 H 1.40 1.95 H

Scheme 1: Preparation of cis-β-[FeBr(CNCEt3)(1)]BF4 (cis-β4). The 31P{1H} NMR spectrum (THF-d8) shows an AX system at δ 66.1 and 50.1 (2JP,P’ = 55.7 Hz), which suggests that the phosphines are trans to bromide and amine, respectively. The effect of solvent (and of traces of water)23 suggests that bromoisonitrile complex 4 is formed stepwise via a dicationic acetonitrile/isonitrile complex that rapidly reacts with bromide to give 4. As cis-β-4 is formed in higher purity than trans-4, we used it as starting material for the following studies. [FeH(CNCEt3)(1)]BF4 (5). Analogously to trans-4, cis-β-4 reacts with NaBHEt3 (1 equiv) in THF to give the previously reported hydride complex cis-β-[FeH(CNCEt3)(1)]BF4 (5) (Scheme 2) (see Supporting Information for details).20 +

N Ph P C

Et3C N

cis-β-4

Fe P

N H Br H

Ph +

H N

Br

H N

Ph

L

THF

+

Ph P Et3C N

C

Fe P

O

H

R

Ph

6

OH Ph

(R)

trans-4 (L = CNCEt3)

Fe

H

H

1.12

H H 3.99

–5.45

P(1)

H

8.32

In this configuration, the dihedral angle between the acidic and hydridic H atoms is close to the ideal value of 0° required for the bifunctional mechanism4,5 (DFT calculations give a value of –8°, see below). Hydride 5 in the ATH of Ketones. The hydride complex 5 catalyzes the transfer hydrogenation of acetophenone (6a) and other ketones (6b-6d, Chart 2) from 2-propanol without addition of a base. The reaction conditions used were the same as with [Fe(CNR)2(1)](BF4)2 (3), with the sole exception that no base was added.

N H

P

N(1)

Figure 1. Major NOE contacts in hydride 5. In red the H-N-Fe-H motif involved in the H2 transfer.

N

5

Fe P

NaBHEt3 (1 equiv)

+

H

–1.30

Ph cis-β-4

2

H

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3 (0.1 mol%), NaOtBu (1 mol%) or 5 (0.1 mol%), base-free 50 °C, 0.2 M, iPrOH

OH MeO

7a

Scheme 2: Convergent synthesis of 5 from trans-4 and cis-β-4.

(R)

7b

F3C

CF3

OH R (R)-7

OH

OH

(R)

(R)

7c

7d

Chart 2. Comparison of 3/base and 5 in the ATH of 6a-6d. We originally suggested a trans H–Fe–N arrangement in 5 on the basis of similar 2JP,C values in the 13CNCEt3 derivative. As DFT calculations indicated that the hydride ligand is trans to phosphine instead (see below), we determined the structure

Since our previous communication,20 we have discovered that the catalytic activity (but not the enantioselectivity) critically depends on the concentration of the NaBHEt3 solution in toluene used to generate hydride 5 in situ and on the presence

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of traces of water in the 2-propanol used for the ATH reaction. Therefore, in the present study, the commercial NaBHEt3 solution in toluene was titrated25 before each catalytic run, and each substrate was tested with 5 and 3/base in parallel runs using the same batch of 2-propanol distilled over CaH2. Under such strictly controlled conditions, hydride 5 and the bis(isonitrile) complex 3 gave not only the same enantioselectivity (as observed previously),20 but also the same activity with acetophenone (6a) and other selected ketones (6b-6d, Table 1). Table 1. ATH of Ketones 6a-6d to 7a-7d Catalyzed by 3 and 5.a entry 1

substrate. 6a

cat. 5 b

TOF

Yield

ee

(min–1)

(%)

(%)

70

93

98

65

93

98

2

6a

3

3

6b

5

75

92

97

4

6b

3b

70

92

97

5

6c

5

65

99

99

65

99

99

90

77 c

66

75

c

67

6

6c

3

7

6d

5

8

6d

3

b

b

77

(a) Reaction conditions: Substrate (2.5 mmol), catalyst (2.5 µmol, 0.1 mol%), 2-propanol, T = 50 °C. TOF are at 5 min. Conversion and enantiomeric excess were determined by GC (see Supporting Information for details). Yields are at 30 min unless otherwise stated. (b) NaOtBu (0.25 mmol, 1 mol%) was added. (c) Yield at 15 min.

The TOF and ee values in Table 1 show that hydride 5 (under base-free conditions) and 3/NaOtBu give essentially the same catalytic performance,26 which suggests that the catalytically active species in both systems is hydride 5. To verify this hypothesis, we studied the activation of the bis(isonitrile) complex 3 with NaOtBu in 2-propanol by 31P NMR spectroscopy. Base Activation of [Fe(CNCEt3)2(1)](BF4)2. To study the activation process, a 2-propanol solution of bis(isonitrile) complex 3 was treated with sodium 2-propoxide (prepared by adding the equivalent amount of NaH to 2-propanol), and the resulting solution was analyzed by 31P NMR spectroscopy (see Supporting Information). After addition of NaOiPr (1 equiv) at room temperature, 3 was partially converted to a small amount of hydride 5 (3%) and a new species (21%, AX system at δ 62.6 and 59.0, 2JP,P = 51.2 Hz), which we assign to the 2-propoxo complex [Fe(OiPr)(CNCEt3)(1)]BF4 (8a) (Scheme 3, Table S1). Additionally, a small amount (7%) of the isonitrile carbene complex [Fe(C(OiPr)NHCEt3)(CNCEt3)(1)](BF4)2 (9) (31P NMR AX system at δ 51.6 and 36.5, 2JP,P' = 31.2 Hz) was formed by nucleophilic attack of the excess 2-propoxide to coordinated isonitrile (see below). Raising the temperature to 50 °C shifts the equilibria in Scheme 3 from bis(isonitrile) complex 3 toward hydride 5 (Figure 2 bottom). Interestingly, the concentration of 2-propoxo complex 8a remains almost constant. After adding a second equivalent of NaOiPr, most 3 is still unreacted at room temperature (61%), whereas 10 equiv of base give the 2-propoxo derivative 8a as the major product even at room temperature (49%). After raising the temperature to 50 °C as in catalysis, most 3 (87%) has been converted to

8a (42%) and 5 (19%) (and carbene 9, 26%). This observation is consistent with preliminary catalytic tests indicating that the bis(isonitrile) complex 3 requires a tenfold excess of base give optimum catalytic activity.9b

Figure 2. 31P{1H} NMR spectra (at 50 °C) of the reaction solution of 3 and NaOiPr. At all base concentrations, the reactions between the bis(isonitrile) complex 3, the 2-propoxo complex 8a, and hydride 5 are fast and completely reversible on the NMR timescale, whereas the formation of carbene 9 is slow and irreversible (Scheme 3). Even at 50 °C, hydride 5 is never the major species, but its formation is favored at higher temperature, as expected on the basis of entropy considerations. (BF4)2

H N Ph P

N H

Fe

C R N 3

C N R

P

– CNEt3 – NaBF4

Ph

(c) NaOiPr

N Ph P

R

N

C 8

N H

Fe

O

P

H

Ph

(b)

(R = CEt3)

iPrOH

BF4

H (a) NaOiPr iPrOH

BF4

H H

(BF4)2

N Ph P

C R N 9

N H Fe i C O Pr NHR P Ph

N Ph P

C R N 5

N H

Fe

H

P Ph +

O

Scheme 3: Reactivity of precatalyst 3 with NaOiPr in iPrOH. The occurrence of isonitrile dissociation with 3 as precatalyst is also consistent with the decrease in rate for the reduction of acetophenone that is observed in the presence of excess isonitrile.9g Notably, this is not the case when hydride 5 is used as catalyst (See Supporting Information). To support the occurrence the equilibria a and b in Scheme 3 and the formulation of 8a as a 2-propoxide complex, an excess of acetone was added to the reaction solution containing 3 and



NaOiPr (10 equiv) at room temperature. Thereupon, the signals of hydride 5 disappeared both at room temperature and at 50 °C, and 8a was the only species detected (beside carbene 9, Table S1, entries 10, 11). After one night at room temperature, the isonitrile carbene species 9 was the only species present in solution (Table S1, entry 12). Carbene 9 did not react with acetophenone (added in excess to this solution, Table S1, entry 13), indicating that it is inactive in the ATH of ketones and hence an off-cycle species. To support the formulation of 9 as an isonitrile carbene complex, the 13C-labeled [Fe(13CNCEt3)2(1)](BF4)2 was treated with NaOiPr (10 equiv) in 2-propanol-d8. After 72 h, the 13C NMR spectrum showed multiplets at δ 218.6 and 171.1, which we assign to the carbene and isonitrile ligands, respectively (see Supporting Information). The above results show that the activation of 3 occurs via reversible dissociation of isonitrile and requires an excess of base to shift the equilibrium a in Scheme 3 toward the 2-propoxo complex 8a. As free isonitrile inhibits the reaction, we envisaged an alternative route to the 2-propoxide complex 8a. Reaction of [FeBr(CNCEt3)(1)]BF4 (4) with NaOiPr. The bromoisonitrile complex 4 reacts quantitatively with sodium 2-propoxide (1 equiv) in iPrOH at 25 °C to give the 2-propoxo complex 8a (80%) and hydride 5 (10%). Additionally, a small, but detectable amount of bis(isonitrile) complex 3 (10%) is formed, whose concentration remains constant (Table S2). Notably, in the absence of free isonitrile, a stoichiometric amount of base fully converts the bromoisonitrile complex 4 to 8a and to the catalytically active species, hydride 5.

Figure 3. 31P{1H} NMR spectra of the reaction solution of [FeBr(CNCEt3)(1)]BF4 (4) and NaOiPr (1 equiv). Upon heating at 50 °C, the equilibrium between the 2propoxo complex 8a and hydride 5 shifts toward the latter (29%, Figure 3 top and Table S2, entry 2). The conversion of 8 to 5 is fully reversible with temperature as observed for the analogous reaction of 3 with sodium 2-propoxide (Scheme 3 b). The addition of an excess of acetone to the sample shifted the equilibrium completely to the 2-propoxo complex 8a, and hydride 5 was not formed even at 50 °C. Characterization of 8a. The 2-propoxo complex 8a was prepared from 4 as described above and precipitated with pentane from 2-propanol at –78 °C. Although the resulting orange solid decomposed upon filtration and drying either under vacuum or in a stream of argon, careful removal of the superna-

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tant with a syringe and addition of acetone-d6 (or THF-d8) to the wet solid gave solutions of 8a in reasonable purity, which was studied by NMR spectroscopy (see Supporting Information). An NOE contact between the amine pointing to the back of the molecule (δ 1.77) and the ortho phenyl proton on the phosphine trans to alkoxide (δ 7.39) indicates that the macrocyclic ligand is bent in cis-β configuration in 8a (Figure S69). All efforts devoted to identify the protons of the 2propoxo ligand were unsuccessful, probably because of rapid exchange with the acetone solvent. Accordingly, the 1H signals are broad even at –15 °C (Figure S65). [Fe(OPh)(CNCEt3)(1)]BF4 (8b). To suppress hydride elimination and support the formulation of 8a, we prepared the phenolato analogue [Fe(OPh)(CNCEt3)(1)]BF4 (8b) by treating the bromoisonitrile complex 4 with sodium phenoxide (1 equiv) in anhydrous THF-d8. The phenoxide complex 8b gives a 31P NMR AX system at δ 64.4 and 51.2 (2JP,P = 50.7 Hz). An NOE contact between the terminal methyl groups of the isonitrile (δ 0.68) and the ortho proton of phenolate (δ 6.14) indicates that these ligands are mutually cis (Figure S70). Additional NOE contacts between the ortho protons of the phenolate (δ 6.14), the amine proton at δ 4.06, and the benzylic proton pointing to the front of the molecule (δ 5.22) show unambiguously that the phenolato ligand is trans to P (Figure S78). [Fe(OH)(CNCEt3)(1)]BF4 (8c). Finally, to identify minor impurities detected in a number of experiments (see below), we prepared the hydroxo derivative 8c by treating bromoisonitrile complex 4 with an excess of sodium hydroxide (100 equiv) in THF-d8. In view of the excess of NaOH required to force this heterogeneous reaction, extensive decomposition was observed, as indicated by the signal of free macrocycle 1 (23%) and of bis(isonitrile) complex 3 (50%) in the 31P spectrum of the reaction solution. A 31P AX system at δ 61.9 and 59.5 (2JP,P = 48.5 Hz) can be assigned to the hydroxo complex 8c (27%) based on its correlation (by 31P-1H HMBC) to a 1H NMR singlet at δ –3.13, which is the fingerprint of the Fe–OH moiety (Figure S96). According to DFT calculations (Table S16), the hydroxo complex 8c is more stable than the 2propoxide analogue 8a (by 3.2 kcal mol–1), which explains the partial catalyst deactivation in presence of water (see above). Insertion of Acetone into the Fe–H Bond. Additionally to the H-elimination from the 2-propoxo complex 8a to give acetone and 5, we also studied the inverse reaction (Scheme 3b). A THF-d8 solution of hydride 5 (prepared from 4 and NaBHEt3) was diluted with iPrOH, and acetone (2.5 equiv) was added. The 31P NMR spectrum of the resulting solution indicated that 5 had been quantitatively converted to the 2propoxo complex 8a (70%). Minor products were bromoisonitrile complex 4 (5%) (apparently from NaBr formed in the synthesis of 5) and an unidentified species (25%) featuring an AX system at δ 61.1 and 55.0 (2JP,P = 45.9 Hz) that is in chemical exchange with 8a (Figure S102, Supporting Information). As the latter species was never observed in pure 2-propanol, we assume that it is irrelevant to catalysis.27 Insertion of Acetophenone in the Fe–H Bond. Acetophenone (2 equiv) was added to hydride 5 (prepared in anhydrous THF-d8 from 4 and NaBHEt3 (1 equiv)). The 31P NMR spectrum of the reaction solution showed, along with the signals of unreacted 5 and 4, new broad signals in the δ 65–52 region. At –40 °C, the signals of hydride 5 disappeared, and the new signals sharpened up to two AX systems (δ 61.7 and 53.1, 2JP,P’ =


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46.6 Hz, 48%; δ 60.2 and 56.3, 2JP,P’ = 46.6 Hz, 22% (Figure S106), which we assign to the diastereomeric 1-phenylethanolato complexes [Fe(OCH(Me)Ph)(CNCEt3)(1)]BF4, (10R and 10S, Scheme 4).28 Complexes 10R and 10S are present in a 2.2:1 ratio, which is in good agreement with the value expected from their energies as calculated by DFT (2.6:1 at 25 °C, see Table S19). The formulation of complexes 10 is supported also by HRMS (see Supporting Information). +

H

+

H

(b) O

N Ph P

Fe

C R N 5

P

N Ph P R

N

N H

C

P

N H Me (R) O Ph

10R Ph + H

H

Ph

+

N Ph P

(a) NaBHEt3 THF-d8

Fe

R

N

(c) ONa

a

iPrOH

b

H C(4)

N(2) C(3)

C(1) C(2)

10S Ph P(2)

C(5)

H

Me N

P(1)

Fe

H H

C(6) Et

aa

Reaction of 4 with (rac)-Sodium 1-Phenylethanolate. The 1-phenylethanolato complexes 10 were also prepared from [FeBr(CNCEt3)(1)](BF4) (4) and sodium (rac)-1-phenylethanolate (1 equiv) in THF (Scheme 4c). The 31P NMR spectrum of the reaction solution at 25 °C showed ca. 50% conversion of 4 to a mixture of hydride 5 (52%) and of 10R and 10S (48%), which give broad signals in the δ 65-52 region. Upon cooling to –40 °C, the 31P NMR signals of hydride 5 disappeared, and those of the diastereomeric 1-phenylethanolato complexes sharpened up and gained in intensity (10R: δ 61.7 and 52.6 2JP,P’ = 46.6 Hz, 41%; 10S: δ 60.3 and 56.1, 2JP,P’ = 46.6 Hz, 31%) (Figure S93). An additional AX system (δ 62.8 and 59.7, 2JP,P’ = 50.3 Hz) is assigned to the hydroxo complex [Fe(OH)(CNCEt3)(1)]BF4 (8c) (28%), whose amount is constant in the temperature range in which it gives individual signals (–40 and 0 °C). The elimination/insertion equilibrium between 5 and 10 (Scheme 4b) is fully reversible with temperature (Table S3). The 1-phenylethanolato complexes 10 release 1-phenylethanol in the presence of 2-propanol and regenerate the 2propoxo complex 8a, which is in equilibrium with hydride 5 (see Supporting Information, p. S63).29

H Me Et

g –a

C(8)

H H

Me Me H

N

g+g+ Et

The absolute configuration of the 1-phenylethanolato ligand in 10R and 10S was assigned by adding enantiopure (R)-1phenylethanol (35 equiv) to the above mixture of 10R and 10S at –80 °C. After heating at –20 °C, the 31P NMR signals of 10S at δ 60.2 and 56.3 had disappeared, and those of 10R at δ 61.7 and 53.1 had gained in intensity. Additionally, some hydroxo complex 8c was formed (60%), possibly from traces of water in the enantiopure alcohol. No epimerization was observed at –20 °C during 16 h, which indicates that the elimination of acetophenone is slow at this temperature. After keeping the reaction solution at room temperature for 5 days, extensive epimerization was observed (10R:10S = 1.2:1, Figure S110).

Me

H

Me N

H

C(7) H

10R + 10S (1:1)

Scheme 4. Synthesis of 10 from 5 and from 4.

H

H

N(1)

quant., 2.2:1 ratio at –40 °C

rac

[FeBr(CNCEt3)(1)]+ (4)

C

N H Me Fe (S) O P Ph

DFT Structure of Hydride 5. To complement the above experimental study, DFT calculations were performed both on the observed species and on unobservable transient intermediates (B3LYP–GD3/cc-pVDZ/Fe:SDD/IEF-PCM(2-propanol), see Computational Details). Hydride 5 was modeled starting from the X-ray structure of Δ-cis-β-[Fe(CNR)2(1)](BF4)2 (R = 1-adamantyl)9f,30 by substituting the isonitrile ligand trans to P for hydride. To check whether this structure is the most stable, the alternative cis-β(H trans to N, 5’) and trans-5 structures were calculated, too (see below). However, the first issue to be considered was the conformation of the highly flexible CEt3 unit (Figure 4a). To keep calculation as close as possible to experiment, we decided to tackle the CEt3 conformational issue exhaustively rather than using a simplified model.

H

H

H Me Me

N

g –g+ Et

H

Figure 4. CEt3 unit of the isonitrile ligand (a) and conformations of the 3-pentyl unit (b). The conformation of the CEt3 unit is described by three torsion angles involving the ethyl groups and the H–Fe–C(2)– C(3) moiety. The CEt3 conformation in hydride Δ-cis-β-5 was optimized by scanning the C(1)–C(2)–C(x)–C(x+1) torsion angles (x = 3, 5, 7) by 120° and H–Fe–C(2)–C(3) by 60°. The resulting 54 unique starting CEt3 conformations converged to 34 minima (Figure S115). The five most stable thereof are sketched in Figure 5. H

A3 (0)

B3 (0.2)

A2 (1.0)

B2 (1.1)

C2 (2.3)

Figure 5. CEt3 conformers (view along the Fe–CN vector, hydride in red, dots are out-of-plane CH3). Relative Gibbs free energies are in kcal mol–1. Multiple pentane interferences31 dictate the relative stability within the CEt3 unit (Figure 4b). The most stable conformers A3 and B3 feature three anti-gauche interactions (g±a) and no unfavorable g±g± interactions. The less stable conformers A2 and B2 (Figure 5) feature one g±g± interaction, and two such interactions are present in C2. Despite their higher energy, also A2, B2 and C2 were used for the study of the reaction intermediates and transition states because they do not place a CH3 group close to the incoming acetophenone or 2-propanol. Then, the cis-β-(H trans to N, 5’) and trans-5 structures (Figure 7) were studied starting from the A3 conformation of the CEt3 group. As Δ-cis-β-5’ is close in energy to Δ-cis-β-5, its structure was optimized also with the other four CEt3 conformations in Figure 5, which were always energetically unfavorable (Table S7).



a) H– transfer

H

N Fe

H

Me

H

Fe

Me

+

H

N

O

H

9.2

Ph

O (S)

TS11R

H Fe 12S

5.5

5.5

Me Ph

N

16

Fe

8.2

14

N

6.4

Fe

H

TS16

N

10.1

Fe

TS11S

Ph N

H

b2) H+ transfer via amido

O

hydrogen bond

Page 6 of 29 O

H Me Me

O

H H

Me Me

b1) H+ shunt

N Ph P N H Fe H C N P R

12R

Ph

H

N

5

O (R)

H

Fe

15

2.5 Ph Me

13S

H O

N

1.3

(S)

Fe

H

Me Ph

1.8

0

N Fe

H H

O 17

Me Me N

11S –1.8 11R

N

–2.8

Fe H

O

H

13R

N

–2.2

Fe

H O (R)

H

Ph Me

Me Ph

5

1.4 H

Fe H

1.0 O Me Me

c) H– regeneration

Figure 6. Computed reaction pathway for the transfer hydrogenation of acetophenone (6a) catalyzed by hydride 5. Relative Gibbs free energies are in kcal mol–1. Inverting the stereochemistry at nitrogen (> 10 kcal mol–1) or changing the helicity from Δ to Λ (> 30 kcal mol–1) destabilizes the complex significantly (> 10 kcal mol–1) (Table S6). H

H

BF4

N Ph P

Et3C N

C

BF4

N Ph P

Fe N H H P

H

Fe

P Δ-cis-β-5' Ph 1.5 kcal mol–1

Δ-cis-β-5 Ph 0 kcal mol–1

N H C N CEt3

BF4 H N

H

H N

Fe P

Ph

L

P

Ph

conformers of each intermediate interconvert on the ps time scale32 under Curtin-Hammett conditions.33 The energy profile for all five conformers is given in Table S8.34 For the following discussion, we divide the reaction profile (Figure 6) into three parts: a) hydride transfer from hydride 5 to acetophenone; b) proton transfer from 2-propanol to 1phenyletoxide; c) hydride transfer from 2-propoxide to restore hydride 5. Hydride Transfer (a). The starting point is hydride 5 (Figure S117). Acetophenone approaches with either enantioface to give the catalyst-substrate adducts 11R and 11S, in which a N–H···O hydrogen bond (1.98 Å in 11R) directs and activates the carbonyl group of 6a.4,5 These adducts evolve to TS11R and TS11S, in which hydride transfer occurs (Figure 8, Fe–H = 1.68, C–H = 1.54 Å in TS11R).

trans-5 (L = CNCEt3) 10.5 kcal mol–1

Figure 7. Isomers of hydride 5 and relative Gibbs free energies. As the trans isomer of hydride 5 is much higher in energy than both other isomers, its participation in the catalytic cycle can be ruled out. Instead, Δ-cis-β-5 (H trans to N) is close in energy to Δ-cis-β-5 (H trans to P), but its H–Fe–N–H dihedral angle is about 90° and hence does not fulfill the requirements of the bifunctional mechanism.4 Thus, only the experimentally observed Δ-cis-β-5 (H trans to P) was considered for the study of the reaction mechanism, as it is both stable and features an N–H group in the correct position to H-bond to acetophenone, which decreases the activation barrier (H–Fe–N–H ≈ 0°). Reaction Profile. The catalytic cycle was studied with hydride 5 in the Δ-cis-β configuration (with H trans to P) and the five CEt3 conformations in Figure 5. For each intermediate and TS, these conformations are close in energy (≤ 3.7 kcal mol–1, Table S8), and IRC (Intrinsic Reaction Coordinate) calculations indicate that no conformational rearrangement occurs between the TS and the corresponding minima. Therefore, the reaction profile in Figure 6 connects the most stable intermediates to the lowest TSs, in the assumption that the different

Figure 8. Transition states TS11R and TS11S (A2 CEt3 conformations). The hydride transfer to acetophenone (11→TS11) is the enantiodetermining step because it is not influenced by the relative energies of the weak adducts 11, which interconvert via 5 and hence react under Curtin-Hammett conditions.33 Also, as generally observed for related systems,10a,12e,35 the subsequent proton transfer is barrierless and not kinetically relevant (see below). Therefore, the enantioselectivity is uniquely determined by the Boltzmann distribution among the conformers of the diastereoisomeric TSs involved in hydride transfer (TS11R


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and TS11S). Taking into account the five most stable conformers gives an ee value of 99.6% (Table S10), which is in good agreement with the experimental value (98% ee).36 Figure 8 shows that the bulky, yet conformationally flexible CEt3 substituent on the isonitrile ligand is pivotal to enantiodiscrimination. In the favored Si attack (TS11R), acetophenone (6a) places the small methyl group toward the bulky CEt3 group of the isonitrile ligand and the phenyl in the less sterically hindered P–Fe–N quadrant. Instead, the Re approach of 6a causes the phenyl ring to clash with the CEt3 group, which destabilizes TS11S. Accordingly, the isonitrile ligand in TS11S is distorted from linearity (Fe–N(3)–C(1)= 175° vs. 179° in TS11R).37 Also, it is important to note that the CEt3 group is flexible and adapts its conformation to the specific situation in each transition state (A2 conformation in TS11R, C2 in TS16, see below). Therefore, the combination of the rigid cis-β framework offered by macrocycle 1 with the bulky, yet conformationally soft isonitrile ligand is the key to high enantioselectivity. The hydride transfer produces the five-coordinate species 12R and 12S (Figure S117), in which the newly formed 1phenylethanolate is H-bonded to N–H. Combining this finding with that from the NMR spectroscopic experiments, we conclude that the N–H-bonded 1-phenylethanolato adduct 12 is in equilibrium with the experimentally observed Fe-bound 1phenylethanolato complex 10, which is hence an off-cycle species (see below). Analogously, the two coordination forms (N–H···OMe and Fe–OMe) of the methoxide complex [FeH(OMe)(CO)(PNP)] are connected by a barrierless equilibrium (0.3 kcal mol–1).38 Proton Transfer (b). After 12, the reaction mechanism can follow (at least) two different pathways. The section of the reaction profile joining 12 and 16 formally involves proton transfer from 2-propanol to the newly formed 1-phenylethanolate. In a protic environment such as 2-propanol, H+ transfer can occur via several mechanisms and is conceivably fast. In pathway b1 of Figure 6, which we dub proton shunt, the 1phenylethanolato adduct 12 is converted to 16 in a single step. Although we were not able to locate the corresponding transition state, an analogous, barrierless step has been found for [RuH[(p-TsNCH(Ph)CH(Ph)NH2)(η6-mesitylene)].5a Alternatively, in pathway b2) (grey in Figure 6), the 1phenylethanolato ligand of 12 deprotonates the N–H group and the resulting 1-phenylethanol forms an O–H···N hydrogen bond (1.82 Å in 13R) to the N atom of the Fe-amido species 13 (Figure S117). We were unable to locate the TS for the proton transfer, but analogous processes have been found to be barrierless for other iron(II)12e,35b and ruthenium(II)35a complexes. The release of 1-phenylethanol from 13 gives the amido complex 14 (Figure S117), in which the Fe–N bond is significantly shorter than in hydride 5 (1.88 Å and 2.07 Å, respectively). Next, the inverse proton transfer sequence from 2-propanol generates intermediates 15 and 16 (Figure S117). The latter is a 16-electron iron(II) complex featuring a H-bonded 2propoxide ion (Figure 9). Albeit relatively high, the energy of amido complex 14 is lower than that of 16, which is the connection point between the two sections of the H+ transfer mechanisms. In addition, all the processes in b2) are barrierless. Therefore, pathways b1) and b2) cannot be distinguished unambiguously (see below).

Figure 9: Fe-bonded 2-propoxide Δ-cis-β-8a and NH-bonded 2-propoxide Δ-cis-β-16. Black dashed lines depict the N–H···O hydrogen bond. The CEt3 conformations are B2 and C2 in 8a and 16, respectively. Hydride Regeneration (c). The H-elimination from 2propoxide in adduct 16 regenerates the Fe–H moiety. The weak adduct 17 (Figure S117) releases acetone and restores the starting hydride 5, closing the catalytic cycle. As TS16 has the highest energy in the profile, the H-elimination from 2propoxide with regeneration of the Fe–H bond is the kinetically relevant step of the catalytic cycle. With B3LYP–GD3, the energy difference between the most stable TS16 and TS11 is 4.6 kcal mol–1.39 The Gibbs free energy (ΔG°) of the overall reaction (6a + 2-PrOH → 7a + acetone) is 1.0 kcal mol–1, in agreement with a thermoneutral equilibrium reaction.40 Alkoxo Complexes 8a and 10. Additionally to the undetectable intermediates discussed above, the 2-propoxo (8a) and (R)- and (S)-1-phenylethanolato (10R/10S) complexes (Figures 9 and S132) observed by NMR spectroscopy were studied by DFT as possible resting species of the catalytic cycle. Analogously to hydride 5, the alkoxo complexes 8a and 10 can exist in principle as Δ-cis-β, Δ-cis-β’, and trans isomers with the alkoxo ligand instead of hydride (Figure 7).41 In agreement with experiment, the most stable structure is Δ-cisβ (O trans to P) both for 8a and for 10. For 8a, isomers Δ-cisβ-8a’ (O trans to N) and trans-8a are higher in energy by 5.7 and 11.5 kcal mol–1, respectively (Table S13). Being sixcoordinate 18-electron species, both Fe–OR complexes 8a and 10 are more stable than the 16-electron adducts 16 and 12 (17.2 and 15.1 kcal mol–1, respectively). Similarly, the energy difference between the Fe–OR and N– H···OR forms is 15.6 kcal mol–1 in [FeH(OMe)(CO)(PNP)].38 The geometry of the alkoxide ligand differs significantly in the Fe–OR and N–H···OR binding isomers.42 Catalytic Cycle and Resting Species. The results of the above experimental and computational studies of the asymmetric transfer hydrogenation of polar double bonds with (NH)2P2 macrocyclic Fe(II) complexes are combined in the catalytic cycle in Scheme 5, which also considers the alkoxo complexes 8a and 10 as resting species. Its key features are the formation of hydride [FeH(CNCEt3)(1)]BF4 (5) by H-elimination from 2-propoxide (c and d) and the insertion of acetophenone into the Fe–H bond (a) via a bifunctional mechanism.4,5 The N–H group syn to hydride orientates and activates the ketone via a hydrogen bond with the oxygen atom of the carbonyl moiety, as previously reported both for iron(II)7h,i and for ruthenium(II).5



+

H N

O Ph

H O

+ N

N Ph

P

Et3CNC

Fe P

N H OiPr

Ph 8a (–9.0) observed by NMR spectroscopy

d)

H

Fe 16 (8.2)

b2), no barrier

OH

Me Me Me Ph

H

P

Me O Ph 6a

N H

Fe

Et3CNC

c), ΔG‡ = 1.9

H

P

a), ΔG‡ = 5.5

H

Ph Me

H

Ph 5 (0) (R)

Page 8 of 29

O

(R)

O

b1), no barrier N P

Fe

Et3CNC

P

N

Fe 12 (2.5)

e)

Ph

P

Et3CNC

Fe P Ph

+

b2), no barrier

N Me Ph

(R)

OH H 7a

14 (6.4)

+

H

H N

OH 7a

N H Me O C Ph (R) H

10R (–12.6) observed by NMR spectroscopy

Scheme 5: Catalytic cycle for the transfer hydrogenation (shunt pathway in blue). Energies (in parentheses) are in kcal mol–1. The H–/H+ transfer occurs in a stepwise fashion as calculated for other iron(II) catalysts.10b,12d,e The hydride transfer is enantiodetermining, whereas the proton transfer is barrierless12d,e,35 and does not affect the enantioselectivity. The energy difference of the two diasterometic TSs of the chiral hydride 5 with the acetophenone gives a calculated enantioselectivity of 99.6% ee, which is in good agreement with the experimental value (98% ee). After hydride transfer, the catalytic cycle branches in two indistinguishable routes,5a as the 1-phenylethanolato adduct 12 can undergo exchange with the 2-propanol solvent to give 16 (b1) or form the amido species 14 (b2). In the first pathway (“shunt”, Scheme 5, b1), we assume that proton transfer is assisted by 2-propanol and is barrierless, as found for [RuH(pTsNCH(Ph)CH(Ph)NH2)(η6-mesitylene).5a Amido complexes have been assumed as on-cycle species in AH and ATH reactions catalyzed by iron(II)7c,f-i,10a,b,16b and ruthenium(II).13 In the present case, however, the formation of the relatively unstable amido species 14 can be avoided if the shunt pathway (b1) is operative. However, amido complex14 might be the entry point of the catalytic cycle with the bis(isonitrile) complex 3/NaOtBu in 2-propanol. In fact, the base probably deprotonates one amine moiety of the macrocycle and triggers the decoordination of one isonitrile. The resulting five-coordinate complex 14 reacts then with 2-propanol to form hydride 5. Additionally to proton transfer via b1) or b2), adduct 12 can also decay to the 1-phenylethanolato complex 10 (e) as offcycle species (Scheme 8). As the corresponding TS was not located, we assume that this step is barrierless as for iron(II) complexes.38 Accordingly, the NMR spectroscopic study shows that 10 is in fast equilibrium with hydride 5. The DFT calculations indicate that the 1-phenylethanolato complex 10 is more stable than hydride 5 by 12.6 kcal mol–1, in qualitative agreement with the NMR spectroscopic study.

propoxo (8a) complex, albeit less stable than its 1-phenylethanolato analogue (10), was prepared and fully characterized by NMR spectroscopy in aprotic solvents as described above despite its tendency to undergo β-hydride elimination. Hydrogen elimination from the 2-propoxo complex 8a gives the hydride complex 5 and closes the catalytic cycle. This step is calculated to be turnover determining. Thus, the enantiodetermining (H– transfer) and turnover-determining (hydride regeneration) steps do not coincide, as observed for other iron(II) PNNP.10b,43 However, it is reasonable to assume that the equilibrium is pushed towards the products by the large excess of 2-propanol used as solvent. Therefore, the 1phenylethanolato intermediate 12 is rapidly scavenged by 2propanol, which is present in large excess, and high enantioselectivity is achieved. Alcoholato Complexes and Catalyst Activity. DFT calculations have suggested that 2-propoxo and 1-phenylethanolato complexes are resting species in other iron(II)-catalyzed hydrogenation reactions,7h,10a-c,10e-f,16a,38 but their characterization has been severely hampered by their low stability and by the formation of complex mixtures.7h,38 For instance, an iron(II) PNNP’ bromo carbonyl complex reacts with base in iPrOH to give a putative 2-propoxo complex, but its formulation remains speculative.7h In contrast, hydride elimination from alkoxide to give the corresponding hydride has been studied thoroughly with ruthenium.44 Thus, 2-propanolato complexes of ruthenium are known to eliminate acetone and give the corresponding hydride complexes, which were shown competent for the catalytic transfer hydrogenation of ketones.44a,b Ruthenium analogues of the 1-phenylethanolato complexes 10 have been observed in the mechanistic studies for the AH of ketones either by CO insertion of acetophenone in the Ru–H bond of trans[Ru(H)2(R-binap)((R,R)-dpen)],44e or by reaction of the amido complex trans-[Ru(H)(R-binap)(tmen)] with acetophenone.44f

Both the shunt (b1) and amido (b2) branches converge to the NH-bonded 2-propoxo adduct 16, which is less stable than its 1-phenylethanolato analogue 12 by 5.7 kcal mol–1 (Scheme 5). However, the formation of 16 is driven by the excess of 2propanol present as solvent. Analogously, the Fe-bonded 2-

In this study, we have characterized in solution the 2propoxo complex 8a and the 1-phenylethanolato analogue 10, and shown that they are in fast equilibrium with hydride 5. Also, 10 has been experimentally found to release 1-phenylethanol upon treatment with 2-propanol and form the 2-


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propoxo analogue 8a, which is less stable than 10 by DFT. This identifies the 1-phenylethanoato complex 10R (–12.6 kcal mol–1 with respect to hydride 5) as the most stable intermediate or resting state of the catalytic cycle, and hence as the TOF-determining intermediate (TDI).45 Overall, the DFT study indicates that the energetic span is 22.7 kcal mol–1, as results from the energy difference between the TDI and the highest transition state TS16 (–12.6 and 10.1 kcal mol–1, respectively.45 It should be noted that, however, the major species during catalysis is the 2-propoxo complex 8a, whose formation is driven by the presence of 2-propanol as solvent. The reaction profile complemented with the off-cycle species (Scheme 5) fully agrees with the experimental observations in stoichiometric and catalytic reactions. In 2-propanol at room temperature, the 2-propoxo complex 8a is the major resting species (80%), and temperature above 25 °C are needed to convert it to the on-cycle hydride 5, whose concentration increases to 29% at 50 °C. Therefore, a possible strategy to enhance the catalytic activity might be the selectively destabilization of the alcoholato complexes 8a and 10, which can be considered as the next challenge.

real frequencies for minima, one imaginary frequency for transition states), and IRC calculations were carried out on the calculated transition states in order to confirm their correct identification. Computed harmonic frequencies were used to calculate the thermal contribution to Gibbs free energy at 298 K.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and compound characterization (PDF) DFT coordinates of intermediates and transition states (xyz)

AUTHOR INFORMATION Corresponding Author *[email protected]

ORCID Lorena De Luca: 0000-0002-4094-4175 Alessandro Passera: 0000-0003-1995-0666 Antonio Mezzetti: 0000-0002-1824-7760

CONCLUSION

Notes

To the best of our knowledge, this is the first study on the iron(II) catalyzed ATH of ketones that combines the experimental observation of on- and off-cycle species with a DFT study of the entire reaction profile and resting species on a real catalytic system (rather than a simplified model). Herein, we show that the role of base in the asymmetric transfer hydrogenation of ketones catalyzed by dicationic N2P2 macrocyclic complexes is to form the corresponding hydride complex, which is the active catalyst both after activation with base and under base-free conditions. Furthermore, we have identified and characterized by NMR spectroscopy the 2-propoxo and 1phenylethanolato complexes as resting species of the catalytic cycle. The DFT calculations suggest that the stability of the alkoxo complexes gives a significant contribution to the energetic span of the catalytic cycle. The combination of the welldefined and rigid geometry of macrocycle 1 with the bulky, yet conformationally flexible CEt3 substituent on the isonitrile ligand accounts for the large energy difference between the enantiodetermining transition states for hydride transfer derives, and hence for the excellent enantioselectivity obtained with the N2P2 macrocyclic catalysts. Overall, the present study brings the mechanistic understanding of the iron catalyzed ATH of ketones at the same level achieved for ruthenium catalysts.

The authors declare no competing financial interests.

ACKNOWLEDGMENTS Financial support from ETH Zürich is gratefully acknowledged (ETH Grants ETH-0914-2 to LDL and ETH-3617-1 to AP). We thank Dr. René Verel and Dr. Alex Lauber for their support with the NMR spectroscopic studies.

ABBREVIATIONS DFT, Density Functional Theory.

REFERENCES 1

2

COMPUTATIONA L DETAILS All DFT calculations were performed with the Gaussian09 program package (Revision D.01) (see Supporting Information). The structures of all minima and transition states were fully optimized using the hybrid density functional B3LYP46 with Grimme’s D3 empirical correction (GD3)47 for dispersion (PBE0–GD348 and ωB97X–D49 for specific molecules) with the ultrafine pruned (99,590) grid. The SDD basis set with the associated Stuttgart-Dresden ECP10MDF pseudo potential50 was used for Fe and the cc-pVDZ basis set51 for C, H, N, O, and P. All the structures were optimized in 2propanol using the implicit solvation model IEF-PCM.52 Stationary points were characterized by vibrational analysis (only

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Journal of the American Chemical Society Hydrogenation of Simple Ketones und Base-Free Conditions. J. Am. Chem. Soc. 2002, 124, 6508. (a) Langer, R.; Iron, M. A.; Konstantinovski, L.; Diskin-Posner, Y.; Leitus, G.; Ben-David, Y.; Milstein, D. Iron Borohydride Pincer Complexes for the Efficient Hydrogenation of Ketones under Mild, BaseFree Conditions: Synthesis and Mechanistic Insight. Chem. Eur. J. 2012, 18, 7196. (b) Schneck, F.; Assmann, M.; Balmer, M.; Harms, K.; Langer, R. Selective Hydrogenation of Amides to Amines and Alcohols Catalyzed by Improved Pincer Complexes. Organometallics 2016, 35, 1931. (a) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikariya, T. A Practical Stereoselective Synthesis of Chiral Hydrobenzoins via Asymmetric Transfer Hydrogenation of Benzils. Org. Lett. 1999, 1119. (b) Zhang, H.; Feng, D.; Sheng, H.; Ma, X.; Wan, J.; Tang, Q. Asymmetric transfer hydrogenation of unsymmetrical benzils. RSC Advances 2014 4, 6417. (a) Burling, S.; Whittlesey, M. K.; Williams, J. M. J. Direct and Transfer Hydrogenation of Ketones and Imines with a Ruthenium NHeterocyclic Carbene Complex. Adv, Synth. Catal. 2005, 347, 591. (b) Clarke, Z. E.; Maragh, P. T.; Dasgupta, T. P.; Gusev, D. G.; Lough, A. J.; Abdur-Rashid, K. A Family of Active Iridium Catalysts for Transfer Hydrogenation of Ketones. Organometallics 2006, 25, 4113. (c) Corberán, R.; Peris, E. An Unusual Example of Base-Free Catalyzed Reduction of C=O and C=NR bonds by Transfer Hydrogenation and Some Useful Implications. Organometallics 2008, 27, 1954. (d) Carrion, M. C.; Sepulveda, F.; Jalon, F. A.; Manzano, B. R.; Rodríguez, A. M. Base-Free Transfer Hydrogenation of Ketones Using Arene Ruthenium(II) Complexes. Organometallics, 2009, 28, 3822. (e) Landwehr, A.; Dudle, B.; Fox, T.; Blacque, O.; Berke, H. Bifunctional Rhenium Complexes for the Catalytic Transfer-Hydrogenation Reactions of Ketones and Imines. Chem. Eur. J. 2012, 18, 5701. (f) Kumar, M.; DePasquale, J.; White, N. J.; Zeller, M.; Papish, E. T. Ruthenium Complexes of Triazole-Based Scorpionate Ligands Transfer Hydrogen to Substrates under Base-Free Conditions. Organometallics, 2013, 32, 2135. (g) Clapham, S. E.; Zimmer-De Iuliis, M.; Mack, K.; Prokopchuck, D. E.; Morris, R. H. Alcohol-assisted base-free hydrogenation of acetophenone catalyzed by OsH(NHCMe2CMe2NH2)(PPh3)2. Can. J. Chem. 2014, 92, 731. (h) Ruff, A.; Kirby, C.; Chan, B. C.; O’Connor, A. R. Base-Free Transfer Hydrogenation of Ketones Using Cp*Ir(pyridinesulfonamide)Cl Precatalysts. Organometallics, 2016, 35, 327. (i) Sommer, M. G.; Marinova, M.; Krafft, M. J.; Urankar, D.; Schweinfurth, D.; Bubrin, M.; Sarkar, B. Ruthenium Azocarboxamide Half-Sandwich Complexes: Influence of the Coordination Mode on the Electronic Structure and Activity in Base-Free Transfer Hydrogenation Catalysts. Organometallics, 2016, 35, 2840, and reference 8 therein. (j) Alvarez-Rodríguez, L.; Cabeza, J. A.; Fernandez-Colinas, J. M.; Garcia-Alvarez, P.; Polo, D. Amidinatogermylene Metal Complexes as Homogeneous Catalysts in Alcoholic Media. Organometallics, 2016, 35, 2516. (a) Guo, R. W.; Chen, X. H.; Elpelt, C.; Song, D. T.; Morris, R. H. Applications of Ruthenium Hydride Borohydride Complexes Containing Phosphinite and Diamine Ligands to Asymmetric Catalytic Reactions. Org. Lett. 2005, 7, 1757. (b) Dong, Z. R.; Li, Y. Y.; Chen, J. S.; Li, B. Z.; Xing, Y.; Gao, J. X. Highly Efficient Iridium Catalyst for Asymmetric Transfer Hydrogenation of Aromatic Ketones under Base-Free Conditions. Org. Lett. 2005, 7, 1043. (c) Soltani, A.; Ariger, M. A.; Vázquez-Villa, H.; Carreira, E. M. Transfer Hydrogenation in Water: Enantioselective, Catalytic Reduction of α-Cyano and α-Nitro Substituted Acetophenones. Org. Lett, 2010, 12, 2893. (d) Ariger, M. A.; Carreira, E. M. pH-Independent Transfer Hydrogenation in Water: Catalytic, Enantioselective Reduction of β-Keto Esters. Org. Lett, 2012, 14, 4522. (a) De Luca, L.; Mezzetti, A. Base-Free Asymmetric Transfer Hydrogenation of 1,2-Di- and Monoketones Catalyzed by a (NH)2P2Macrocyclic Iron(II) Hydride. Angew. Chem. Int. Ed. 2017, 56, 11949. (b) De Luca, L.; Mezzetti, A. Base-free Asymmetric Transfer Hydrogenation of 1,2 Di- and Monoketones Catalyzed by a Chiral Iron(II) Hydride. Chimia 2018, 72, 233.

21 Ohgo has pioneered the asymmetric hydrogenation of benzil to benzoin (62% ee) with a cobalt catalyst: (a) Ohgo, Y.; Takeuchi, S.; Natori, Y.; Yoshimura, J. Asymmetric Reactions. X. Asymmetric Hydrogenation Catalyzed by Bis(dimethylglyoximato)cobalt(II)-Chiral Cocatalyst (Amino Alcohol) System. J. Bull. Chem. Soc. Jpn. 1981, 54, 2124. (b) Ohgo, Y.; Tashiro, Y.; Takeuchi, S. Asymmetric Hydrogenation Catalyzed by Bis(disubstituted glyoximato)cobalt(II)(L)-Chiral Cocatalyst System. Effect of Structural Variation of Ligands and Hydrogen Pressure. Bull. Chem. Soc. Jpn. 1987, 60, 1549. 22 (a) The ATH of arylalkyl 1,2-diketones such as 1-phenyl-1,2-propanedione gives enantiopure a-hydroxy ketones with up to 99% ee: (b) Koike, T.; Murata, K.; Ikariya, T. Stereoselective Synthesis of Optically Active α-Hydroxy Ketones and anti-1,2-Diols via Asymmetric Transfer Hydrogenation of Unsymmetrically Substituted 1,2-Diketones. Org. Lett. 2000, 2, 3833. 23 (a) In CH2Cl2 dried over molecular sieves, a conspicuous amount of bis(isonitrile) complex 3 is formed along with trans-4 and other unidentified products. Instead, cis-β-4 is the only product in wet CH2Cl2, which we attribute to the higher bromide concentration in the reaction solution: (b) Burfield, D. R.; Lee, K. H.; Smithers, R. H. Desiccant Efficiency in Solvent Drying. A Reappraisal by Application of a Novel Method for Solvent Water Assay. J. Org. Chem. 1977, 42, 3060. 24 Prepared by adding deuterated toluene (1 mL) to commercial NaBHEt3 in THF (1 mL) and removing the THF in vacuum at –50 °C. 25 Brown, H. C.; Krishnamurthy, S.; Hubbard, J. L. Addition Compounds of Alkali Metal Hydrides. 15. Steric Effects in the Reaction of Representative Trialkylboranes with Lithium and Sodium Hydrides to Form the Corresponding Trialkylborohydrides. J. Am. Chem. Soc. 1978, 100, 3343. 26 The TOFs at 5 min observed for 6d are slightly different possibly because the reaction reaches equilibrium after 15 min (instead of 30 min as for the other substrates), which may cause larger measuring errors. 27 When the reaction of 5 with acetone is carried out in THF solution, this species is the major product, and no trace of 8a is observed. Together with the chemical exchange, this suggests that the unknown species results from the dimerization of 8a in THF, which is less polar than 2-propanol. Attempts of determining its hydrodynamic radius by 31 P NMR DOSY experiments between –40 and 0 °C failed because of the unfavorable ratio between diffusion rate and relaxation times, and the signals were too broad at higher temperatures. 28 Some bromoisontrile complex 4 (10%, form the preparation of 5) was also present (see Supporting Information for details). Additionally, an unknown species gives an AX system (δ 63.7 and 53.9, 2JP,P’ = 50.1 Hz, 20%) whose form and intensity remain unaltered at any temperature and is hence not involved in equilibria with other complexes. 29 Interestingly, also the hydroxo complex 8c, which is formed as impurity along with 10, reacts with iPrOH to give 8a and hydride 5. If the reaction is carried out in THF, the tentatively assigned dimeric species of 8a is formed upon addition of an excess of 2-propanol, which further supports our assignment (see footnote 27 above). 30 The helicity of this complex was erroneously assigned as Λ in a previous paper (see reference 9f). We correct it here to D based on the oriented skew lines convention (Figure S10). 31 Stereochemistry of Organic Compounds; Eliel, E. L., Wilen, S. H., Eds.: Wiley, New York, 1994, p. 603. 32 Zheng, J. R.; Kwak, K. W.; Xie, J.; Fayer, M. D. Ultrafast carboncarbon-single-bond rotational isomerization in room-temperature solution. Science 2006, 313, 1951. 33 Seeman, J. I. Effect of Conformational Change on Reactivity in Organic Chemistry. Evaluations, Applications, and Extensions of Curtin– Hammett/Winstein–Holness Kinetics. Chem. Rev. 1983, 83, 83. 34 The energies for all species along the reaction profile were calculated both for the singlet and for the triplet state. In all case, the single state is more stable than the corresponding triplet (see Table S9). 35 (a) Li, L. F.; Pan, Y. H.; Lei, M. The enantioselectivity in asymmetric ketone hydrogenation catalyzed by RuH2(diphosphine)(diamine) complexes: insights from a 3D-QSSR and DFT study. Catal. Sci. Technol. 2016, 6, 4450. (b) Sonnenberg, J. F.; Wan, K. Y.; Sues, P. E.; Mor-



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ris, R. H. Ketone Asymmetric Hydrogenation Catalyzed by P-NH-P’ Pincer Iron Catalysts: An Experimental and Computational Study. ACS Catal. 2017, 7, 316. The optimization of TS11R and TS11S with PBE0–GD3 and ωB97X–D give the same enantioselectivity (99.6%, Tables S11 and S12), which indicates a good precision of the DFT method. The analysis of the CEt3 conformation throughout the reaction profile shows that the isonitrile CEt3 group has the A2 conformation in all intermediates and TSs featuring the favored Re attack and leading to the (S)-alcohol, whereas minima and TSs connected to the (R)-alcohol have different conformations (A3, A2, B2, C2) (see Figures 6 and 7 and Table S8). Gorgas, N.; Stöger, B.; Veiros, L. F.; Kirchner, K. Highly Efficient and Selective Hydrogenation of Aldehydes: A Well-Defined Fe(II) Catalyst Exhibits Noble-Metal Activity. ACS Catal. 2016, 6, 2664. PBE0–GD3 and ωB97X–D give 3.6 and 3.9 kcal mol–1, respectively. ΔG° is 0.6 and 0.1 kcal mol–1 with PBE0–GD3 and ωB97X–D, respectively. For the three isomers, the RNC–Fe–O–C dihedral angle was scanned by 60° (6 conformers) with the conformation A3 of the CEt3 unit for the three isomers. The same approach was used to calculate the 1phenylethanolato complex 10 (see Supporting Information). The off-cycle complex 8a has a Fe–O distance of 1.98 Å and an unperturbed 2-propoxide ligand. In the on-cycle adduct 16, the 2-propoxide forms a very strong hydrogen bond to N–H (the H···O distance is 1.43 Å) and features a longer C–H bond than 8a (1.21 and 1.11 Å, respectively) due to a Fe···H interaction (1.94 Å) that is not present in 8a Consequently, the C–O bond has partial double bond character in 16 (1.34 Å, vs. 1.40 Å in 8a). (a) In contrast, hydride transfer to acetophenone is turnoverdetermining in ruthenium(II) transfer hydrogenation catalysts: (b) Bacchi, A.; Balordi, M.; Cammi, R.; Elviri, L.; Pelizzi, C.; Picchioni, F.; Verdolino, V.; Goubitz, K.; Peschar, R.; Pelagatti, P. Mechanistic Insights into Acetophenone Transfer Hydrogenation Catalyzed by Half‐ Sandwich Ruthenium(II) Complexes Containing 2‐(Diphenylphosphanyl)aniline – A Combined Experimental and Theoretical Study. Eur. J. Inorg. Chem. 2008, 28, 4462. (a) Baratta, W.; Chelucci, G.; Gladiali, S.; Siega, K.; Toniutti, M.; Zanette, M.; Zangrando, E.; Rigo, P. Ruthenium(II) Terdentate CNN Complexes: Superlative Catalysts for the Hydrogen-Transfer Reduction of Ketones by Reversible Insertion of a Carbonyl Group into the Ru–H Bond. Angew. Chem. Int. Ed. 2005, 44, 6214. (b) Baratta, W.; Bosco, M.; Chelucci, G.; Del Zotto, A.; Siega, K.; Toniutti, M.; Zangrando, E.; Rigo, P. Terdentate RuX(CNN)(PP) (X = Cl, H, OR) Complexes: Synthesis, Properties, and Catalytic Activity in Fast

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Transfer Hydrogenation. Organometallics, 2006, 25, 4611. (c) Nolan, S. P.; Belderrain, T. R.; Grubbs R. H. Convenient Synthesis of Ruthenium(II) Dihydride Phosphine Complexes Ru(H)2(PP)2 and Ru(H)2(PR3)x (x = 3 and 4). Organometallics 1997, 16, 5569. (d) Esteruelas M. A.; Sola. E.; Oro L. A.; Werner H.; Meyer U. MHCl(CO)(PiPr3)2 (M= Ru, Os) complexes as catalyst precursors for the reduction of unsaturated substrates. J. Mol. Catal. 1988, 45, 1. (e) Hamilton, R. J.; Bergens, S. H. Direct Observations of the Metal−Ligand Bifunctional Addition Step in an Enantioselective Ketone Hydrogenation. J. Am. Chem. Soc. 2008, 130, 11979. (f) Abdur-Rashid, K.; Clapham, S. E.; Hadzovic, A. Harvey, J. N.; Lough, A. J.; Morris, R. H. Mechanism of the Hydrogenation of Ketones Catalyzed by transDihydrido(diamine)ruthenium(II) Complexes. J. Am. Chem. Soc. 2002, 124, 15104. Kozuch, S.; Shaik, S. How to Conceptualize Catalytic Cycles? The Energetic Span Model. Acc. Chem. Res. 2011, 44, 101. Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994, 98, 11623. Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104. Adamo, C.; Barone, V. Toward reliable density functional methods without adjustable parameters: The PBE0 model. J. Chem. Phys. 1999, 110, 6158. (a) Chai, J. D.; Head-Gordon, M. Systematic optimization of longrange corrected hybrid density functionals. J. Chem. Phys. 2008, 128, 1. (b) Chai, J. D.; Head-Gordon, M. Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections. Phys. Chem. Chem. Phys. 2008, 10, 6615. (a) Dolg, M.; Wedig, U., Stoll, H.; Preuss, H. Energy‐adjusted ab initio pseudopotentials for the first row transition elements. J. Chem. Phys. 1987, 86, 866. (b) Martin, J. M. L.; Sundermann, A. Correlation consistent valence basis sets for use with the Stuttgart–Dresden–Bonn relativistic effective core potentials: The atoms Ga–Kr and In–Xe. J. Chem. Phys. 2001, 114, 3408. Dunning, T. H. Jr. Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen. J. Chem. Phys. 1989, 90, 1007. (a) Tomasi, J.; Mennucci, B.; Cammi, R. Quantum Mechanical Continuum Solvation Models. Chem. Rev. 2005, 105, 2999. (b) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. New developments in the polarizable continuum model for quantum mechanical and classical calculations on molecules in solution. J. Chem. Phys. 2002, 117, 43.

Table of Contents (TOC)


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Asymmetric Transfer Hydrogenation with a Bifunctional Iron (II

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