Structural, kinetic, and DFT studies of the transfer hydrogenation of ketones mediated by (pyrazole)pyridine iron(II) and nickel(II) complexes

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Structural, kinetic, and DFT studies of the transfer hydrogenation

of ketones mediated by (pyrazole)pyridine iron(II) and nickel(II)

complexes†,‡

Received 00th January 20xx,

Accepted 00th January 20xx

Makhosazane N. Magubane,^aGeorge S. Nyamato,^aStephen O. Ojwach,*^,aand Orde Q. Munro*^,b

DOI: 10.1039/x0xx00000x

A series of iron(II) and nickel(II) complexes chelated by 2-pyrazolyl(methyl)pyridine (L1), 2,6-bis(pyrazolylmethyl)pyridine

(L2), and 2,6-bis(pyrazolyl)pyridine (L3) ligands have been investigated as transfer hydrogenation (TH) catalysts for a range

of ketones. Nine chelates in total were studied: [Ni(L1)Br₂] (1), [Ni(L1)Cl₂] (2), [Fe(L1)Br₂] (3), [Ni(L2)Br₂] (4), [Ni(L2)Br₂] (5),

[Fe(L2)Cl₂] (6), [Ni(L3)Br₂] (7), [Ni(L3)Br₂] (8), and [Fe(L3)Cl₂] (9). Attempted crystallization of complexes 4 and 6 afforded

stable six-coordinate cationic species 4a and 6a with a 2:1 ligand:metal (L:M) stoichiometry, as opposed to the

monochelates that function as precursors to catalytic species for TH reactions. Crystallization of 7⋅4H₂O and 8⋅2H₂O, in

contrast, afforded tri- and bis(aqua) salts of L3 chelated to Ni(II) in a 1:1 L:M stoichiometry, respectively. Complexes 1-9

formed active catalysts for TH of a range of ketones in 2-propanol at 82 °C. Both the nature of the metal ion and ligand

moiety had a discernible impact on the catalytic activities of the complexes, with nickel(II) chelate 5 affording the most

active catalyst (k_obs, 4.3 × 10^–5s^–1) when the inductive phase lag was appropriately modelled in the kinetics. Iron(II)

complex 3 formed the most active TH catalyst without a significant inductive phase lag in the kinetics. DFT and solid angle

calculations were used to rationalize the kinetic data: both steric shielding of the metal ion and electronic effects

correlating with the metal–ligand distances appear to be significant factors underpinning the reactivity of 1–9. Catalysts

derived from 1 and 9 exhibit a distinct preference for aryl ketone substrates, suggesting the possible involvement of π-type

catalyst⋅⋅⋅substrate adducts in their catalytic cycles. A catalytic cycle involving only 4 steps (after induction) with stable

DFT-simulated structures is proposed which accounts for the experimental data for the system.

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complex (TH) or stereoselectively using a chiral catalyst, in

which case it is referred to as asymmetric transfer

hydrogenation (ATH). To date, the most common metal

Introduction

Transfer hydrogenation (TH) of ketones is one of the most

widely used processes for the reduction of ketones to alcohols

due to its high selectivity.¹Hydrogenation reactions are mostly

applied in industry for the synthesis of fine chemicals, in the

pharmaceutical industry for the synthesis of certain alcohol

compounds, in the synthesis of agrochemicals, as well as the

production of fragrances and flavours.^2-4This process is usually

catalysed by homogeneous transition-metal complexes in the

presence of a base and an alcohol (typically 2-propanol) as the

source of hydrogen. The reaction may be catalysed non-

stereoselectively (Scheme 1) with an achiral transition metal

complexes that have been investigated and found to be active

catalysts for the reduction of ketones are ruthenium based.⁵

Notably, several Ru(II) complexes are active TH catalysts for

ketones,⁶including complexes of the planar tridentate NNN-

donor ligands 2-[6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]-

1H-benzimidazole⁷and 2,6-bis(3,5-dimethylpyrazol-1-yl)pyrid-

9

ine.^8,Ruthenium, however, is expensive and therefore not

economically suitable for industrial applications. It is also

environmentally unfriendly and is toxic in its ionic form.¹⁰The

development of iron¹¹and nickel¹²catalysts for the transfer

hydrogenation of ketones potentially offers some advantages

over the ruthenium catalysts. For instance, both nickel and

iron are relatively cheap, more abundant, and environmentally

benign compared with ruthenium.¹³Current efforts in the field

recognize these attributes and Meyer et al.¹⁴have reported

that iron(II) compounds of ethylenediamine-derived diimino-

diphosphine ligands form effective catalysts in the transfer

hydrogenation of ketones. Homogeneous Ni(0) carbene

complexes,¹⁵Ni(0)-based nanoparticles,^{16, 17}and even NiBr₂in

a binary NaOH-iPrOH mixture¹⁸are evidently also potentially

useful catalysts for the TH of ketones. Recently, chiral Ni(II)

complexes chelated by PNO-donor ligands have been used as

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catalysis in the ATH of a series of aromatic ketones using 2- significance to the mechanism of catalyst deactivation we

propanol as the hydrogen source.¹⁹Collectively, however, encountered during TH reactions (vide infra).

there are comparatively few reports on transfer

hydrogenations of ketones in alcohols in the presence of nickel structures are similar in several respects, particularly insofar as

catalysts. they both exhibit aquation of metal ion with varying degrees of

Fig. 1 summarizes the key X-ray data for 7 and 8, whose

As part of our continued investigation of late transition halide ion substitution; they are hence best classified as inner-

metal-catalysed TH reactions of ketones,²⁰we herein report sphere hydrates. The Ni(II) ion is six-coordinate in both cases

the use of iron(II) and nickel(II) complexes of three and coordinated to tridentate L3, which deviates somewhat

(pyrazolyl)pyridine-based ligands as TH catalysts for a range of from planarity in both cations. The largest two absolute

ketone substrates (compounds

catalysts for ketones typically operate via an induction phase

(activation of a precatalyst to an active catalytic species), they root mean square deviation (RMSD) for all non-H atoms is

are intrinsically difficult to delineate mechanistically, especially 0.098 Å. In the case of , these values are 0.179 Å (C12) and

when paramagnetic intermediates are involved. We have 0.162 Å (Ni1), with a RMSD of 0.092 Å. The origin of the

accordingly attempted to understand some of the structural nonplanar structure of L3 in may be traced primarily to a

and electronic factors of the precatalysts that potentially short nonbonded intermolecular C⋅⋅⋅C contact of 3.284(2) Å

impact on the reactivity of using a combination of DFT between C14 of one molecule (a pyrazole carbon) and C8 (the

simulations and solid angle calculations. By combining the pyridine -carbon) of the closest neighbour in the lattice (Fig.

1–

9, Scheme 2). Since TH perpendicular out-of-plane atomic deviations for L3 in complex

7⋅

4H₂O measure 0.217 Å (C13) and 0.146 Å (C12), while the

8

1–9

γ

information from the experimental kinetics and insights gained S6), i.e. crystal packing effects as opposed to intramolecular

from DFT simulations we have proposed a 4-step catalytic steric strain within the chelating ligand.

cycle (after induction) that accounts for the data at hand.

The bromide salt 7⋅4H₂O exhibits a maximally hydrated

coordination sphere with three water ligands occupying

coordination sites in the meridional plane perpendicular to the

mean plane defined by L3. An additional solvate water

molecule is hydrogen-bonded to the aqua ligand bound to Ni1

within the plane of the three N-donors of L3. The bromide

Results and discussion

Synthesis of Fe(II) and Ni(II) complexes

The ligands 2-(pyrazolylmethyl)pyridine (L1), 2,6-bis-(pyrazolyl-

methyl)pyridine (L2), and 2,6-bis(3,5-dimethyl-1H-pyrazol-1-

counterions in 7⋅4H₂O participate in discrete hydrogen bonds

with both the metal-bound and the free water molecules,

yl)pyridine (L3) and their iron(II) and nickel(II) complexes 1–9,

leading to a complex extended structure (Table S2). In the

were synthesized following previously reported procedures in

good yields (61–95%).²¹A combination of microanalyses,

magnetic moment determinations, and mass spectroscopy

were used to confirm the structures of paramagnetic

complexes 1–9. The effective magnetic moments of the Ni(II)

and Fe(II) complexes were in the range of 2.89–3.79 BM and

4.98–5.01 BM, respectively, consistent with high-spin Ni(II) and

Fe(II).²²Moreover, analysis of the mass spectral fragmentation

structure of 8⋅2H₂O, the two water molecules are bound to the

Ni(II) ion both axially and equatorially and are hydrogen-

bonded to the chloride counterion. The extended structure

comprises one-dimensional H-bonded chains stabilized by

centrosymmetric cation and anion pairs (Fig. 1c). The cation

pairs are held together by a pair of hydrogen bonds involving

the water molecule of one cation and the axial chloride ligand

of the partner cation, forming (in graph set notation)²³an 8-

membered 2-donor/2-acceptor ring, R²₂(8). The centro-

symmetric anion pair linking adjacent centrosymmetric cation

dimers in the chain is characterized by the anions each

accepting three hydrogen bonds from the metal-bound water

ligands in neighbouring cations to form an 8-membered 4-

donor/2-acceptor ring, R²₄(8), between the cation pairs in the

one-dimensional chain. The Ni–O–H⋅⋅⋅Cl^–hydrogen bond

distances are in the range 2.26–2.47 Å and are consistent with

the range (2.10–2.46 Å) determined from 1013 X-ray

structures of non-coordinated O_W–H⋅⋅⋅Cl^–hydrogen bond

distances in Steiner’s analysis of hydrogen bonding,²⁴

patterns of

1

–

9

confirmed the dihalide structures depicted in

fragments into several

Scheme 2. For instance, the M⁺ion of

5

diagnostic moieties (Fig. S1): the base peak at m/z = 188

reflects a 2-pyrazolyl(methyl)pyridine fragment derived from

the parent ligand (L2). The peaks at m/z = 355 (M⁺– 2Cl; 20%

relative abundance) and m/z = 340 (M⁺– 2Cl – CH₃; 18%

relative abundance) correspond to two stable high molecular

weight fragments of

fragment at m/z = 386 (M – Cl^–– 2H⁺) is consistent with the

largest intact net anionic fragment, M^–, derived from

by loss

5. Finally, the highest molecular weight

5

of one chloride ligand and two protons (effectively loss of HCl

and H⁺).

suggesting that the O–H donors of the aqua ligands in

are relatively unaffected by coordination to Ni(II).

8⋅2H₂O

X-ray crystal structures

The chelating bis(pyrazolyl) ligand in

7 and 8 induces an in-

Attempted crystallization of

4 and 6 afforded only the 2:1

plane distortion of the Ni(II) coordination sphere away from

ideal octahedral coordination mainly due to the fact that the

Ni(II) ion fits rather poorly into the adjacent 5-membered

chelate rings of the tridentate ligand. This is especially evident

from the trans N_pz–Ni–N_pzangles, which deviate significantly

ligand:metal adducts 4a and 6a as a result of ligand exchange

during re-crystallization in dichloromethane/hexane mixtures.

As neither 4a nor 6a were used as TH catalyst precursors, their

X-ray structures are given in the ESI (Figs. S2–S5). The stability

of these six-coordinate Ni(II) and Fe(II) complexes is of possible

from 180° and measure 155.53(7) and 154.52(4)° for

7 and 8,

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Table 2 Rate data for the transfer hydrogenation of acetophenone to 1-phenylethanol

catalyzed by 1–9^a

Table 1. Coordination group metrical parameters for Ni(II) complexes of 2,6-

bis(pyrazole)pyridines compiled from X-ray data in the CSD^a

Catalyst

Conv. 48 h (%)^b

10⁵k_obs(s^–1

)

R²(fit)

0.983

0.980

0.988

0.951

0.999

0.986

0.964

0.952

0.970

1

2

3

4

5

6

7

8

9

95

85

96

94

70

94

96

99

3.4(5)

1.6(3)

3.5(3)

2.2(5)

4.3(2)

3.7(5)

0.88(31)

2.1(5)

2.9(5)

Compound

KUFTUB

Ni–N_py

2.023

Ni–N_pz

2.132

2.112

2.113

2.104

2.109

2.099

2.101

2.123

2.119

2.094

2.106

2.116

2.122

2.137

2.064

2.091

2.083

2.078

2.059

2.101

2.103

0.021

2.059

2.137

N_pz–Ni–N_pz

153.3

N_py–Ni–N_pz

76.8

76.5

76.7

76.8

76.7

76.8

77.1

76.9

77.1

78.5

77.2

77.7

78.2

77.6

77.4

77.6

78.0

77.6

77.1

77.2

0.5

KUFVAJ

NASTAD

NEQZUE

2.036

2.026

153.5

152.9

^aConditions: acetophenone, 2.00 mmol; catalyst, 0.02 mmol (1.0 mol%); base,

°

0.40 M KOH in 2-propanol (5 mL); temperature, 82 C. ^bDetermined by ¹H NMR

2.012

2.014

153.8

spectroscopy at t = 48 h.

aquated in 2-propanol when aqueous KOH or NaOH are used

as bases) would require the exchange of Ni-bound water

molecules for ketone, alcohol, or alkoxide substrates, it is

possible (assuming further that the Ni–O bond length is

proportional to reactivity) to speculate that substitution of the

sterically-accessible axial water molecules at the metal centres

NERBER

1.995

1.985

155.7

155.9

OFOTIN

7•4H₂O

8•2H₂O

2.005

2.016

154.9

155.5

154.5

of

7

and

8

precedes substitution of the in-plane aqua ligand. In

, the Ni–N_pzbonds are inequivalent, fall in the

both

7

and

8

range 2.005–2.101 Å and average 2.080(17) Å. The central Ni–

N_pybonds are somewhat shorter, averaging 2.011(8) Å for the

two complexes. From the data compiled in Table 1, it is clear

that the Ni–N_pybonds are normal for this class of compounds,

matching the mean of 2.012(15) Å. Although the bonds

mean

s.u.

2.012

0.015

1.985

2.036

154.4

1.1

min.

max.

152.9

155.9

76.5

78.5

between the metal ion and pyrazole nitrogen atoms in

7 and 8

^aAbbreviations: CSD, Cambridge Structural Database; N_py, pyridyl nitrogen atom;

N_pz, pyrazole nitrogen; s.u., standard uncertainty.

are shorter than the mean [2.103(21) Å] for this class of

chelates, they are equivalent within one standard deviation of

the mean (1σ). Because of the rigidity of the 2,6-

bis(pyrazole)pyridine Ni(II) chelate for all entries in Table 2, the

relative invariance of the Ni–N bonds is to be expected in this

class of compounds and, furthermore, appears to be

insensitive to whether the pyrazole moieties are alkylated or

respectively. These values match the mean N_pz–Ni–N_pzangle

for all crystallographically characterized Ni(II) complexes of

2,6-bis(pyrazole)pyridine currently available in the CSD²⁵(Table

1). The same observation holds for the N_py–Ni–N_pzbond

angles. Inspection of the data in Table 1 reveals that there is

surprisingly little variation in the bond angles subtended at the

metal ion for this class of compounds, consistent with an

essentially inflexible chelating ligand. The fact that the mean

endo-N_py–Ni–N_pzbond angle deviates significantly from 180°

reflects the geometric constraints of the ligand framework

which precludes attainment of the an “ideal” trans-N_py–Ni–N_pz

bond angle of 180° for a six-coordinate Ni(II) complex.

not. Finally, it is noteworthy that the chloride salt 8⋅2H₂O is

structurally and crystallographically isomorphous with the

bromide salt reported by Tastekin et al.,²⁶namely diaqua-

bromo-(2,6-bis(3,5-dimethylpyrazolyl)pyridine-N,N',N'')-

nickel(II) bromide.

Transfer hydrogenation (TH) of ketones

Complexes 1–9 were investigated as catalysts for the TH of

acetophenone as a model substrate using KOH as the base and

2-propanol as the hydrogen donor. The conversions of

acetophenone to the product (1-phenylethanol) were

determined by ¹H NMR spectroscopy by comparing the

intensity of the methyl signal of acetophenone (s, δ 2.59 ppm)

and methyl signal of 1-phenylethanol (d, δ 1.49 ppm) of the

crude product.

The strained coordination geometry for

possibly significant structural consequences for the aqua

ligands. In , the axial Ni–O_Wdistances average 2.096(24) Å

7 and 8 has

7

and are considerably longer than the in-plane coordination

distance of 2.041(2) Å (Ni1–O1). The closer approach of the in-

plane water molecule is evidently favoured by reduced steric

encumbrance from the widened in-plane exo-N_py–Ni–N_pzbond

angle (205°). A similar disparity exists for the Ni–O_Wbond

Effect of catalyst structure: Complexes

1–9 produced

species that were active catalysts for the TH of acetophenone

under the chosen reaction conditions, with conversions to

product ranging from 70–96% after 48 h (Table 2, Fig. 2). The

distances of

8 for the same reason. Since catalysis by these

complexes (assuming that they might be partially or fully

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observed rate constants suggest that the catalytic activity of the more reactive half of the series delineated in Fig. 2.

the complexes follows the order: Despite and having the same ligand (L1), the activity of

. For the Ni(II) chelates, the chloride complexes were more (Fe²⁺catalyst) was markedly higher than that of (Ni²⁺

reactive than the bromide complexes in the case of the catalyst). This reactivity difference for the present series of

tridentate ligands L2 and L3, but not the didentate ligand L1 complexes probably reflects the higher electropositivity and

5

>

6

>

3

>

1

>

9

>

4

>

8

>

2

>

2

3

7

2

.

The Ni(II) and Fe(II) complexes of L2 (5 and 6, respectively) had hardness of Fe(II) compared with Ni(II) and, consequently, the

29

the longest induction phases, but achieved maximum tendency of iron to form hydride intermediates^28,from 2-

31

conversion more quickly than the remaining compounds, while propanol (as postulated for other TH catalysts)^30,

more

complexes

acetophenone to product after 48 h (≤ 85%, Table 2). Notably, acetophenone, the present Fe(II) chelates are relatively

although and had significant induction periods, they inactive compared with the Fe(II) carbonyl complexes reported

2 and 5 afforded the lowest fractional conversion of readily than nickel. Despite their efficacy in the TH of

5

6

effected rapid conversion of acetophenone to product once by Morris and co-workers (which give 93% conversion to

activated (hence the order of the rate constants illustrated in product in only 30 min).^{6, 14}The present Ni(II) catalysts, on the

Fig. 2). In the case of

reducing the overall % conversion. The kinetic data for

suggest that catalyst deactivation competes with turnover of Ni(II) TH catalysts. For example,

2

and

5

, the graphs saturate rapidly, other hand, exhibit activity profiles that more closely parallel

and the limited data available in the literature for homogeneous

has comparable activity (95%

2

5

1

the substrate to a significant extent.

conversion; 48 h) to the Ni(II) complex of a PNO-donor chelate

One explanation for the behaviour of

2

and

5

is ligand employed as an ATH catalyst reported by Dong et al. (98%

conversion; 48 h).¹⁹

exchange and formation of catalytically inactive species. For

2,

competing formation of a less-reactive dinuclear complex such

Further analysis of the structural and electronic factors that

as 2a during the reaction could, in principle, diminish turnover impact on the reactivity order of

1–9 in the TH of

of the catalyst. Dinuclear halide-bridged species such as 2a are acetophenone is discussed within the context of our DFT

stable and, in the case of the bromide analogue, have been simulations (vide infra). Noteworthy here is the fact that there

crystallographically characterized.²⁷The marked deactivation appears to be no single dominant variable that succinctly

of

high post-induction reactivity of the complex (cf. steep slope inherently complex mechanism. The exact catalytic species in

between 10 and 20 h). At present, we have no experimental 2-propanol for have, furthermore, not been unequivocally

5 evident in Fig. 2b is noteworthy, particularly in view of the accounts for the reactivity order of 1–9, attesting to an

1–9

data to account for this phenomenon, but note that both the established. For TH catalysts, which typically have induction

formation of a dinuclear species and a 2:1 ligand:metal adduct periods, this is a notoriously difficult task, especially with

(such as crystallographically characterized 4a in Fig. S2) could paramagnetic complexes and intermediates. Complexes

1–9

drain (i.e., poison) the catalytically active species during the are almost certainly precatalysts which have to undergo initial

reaction, culminating in premature saturation of the kinetics.

ligand exchange, e.g. displacement of metal-bound halide ions

by the solvent or iPrO^–, before M–H formation, substrate

uptake, and thence hydrogen transfer. The X-ray structures of

7⋅4H₂O and 8⋅2H₂O are revealing in this regard because they

highlight how two or three O-donor ligands may substitute the

metal-bound halide ions of the initial metal complexes to give

stable species. Halide-substituted species are evidently

important intermediates in the present TH reactions, as

discussed later.

Comparison of the iron and nickel complexes reveals that

the Fe(II) derivatives afford catalytic species that encompass

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Table 4 Effect of substrate scope on the TH reactions catalysed by complexes 1 and 9^a

Table 3 Effect of base and catalyst concentration on the TH of acetophenone catalysed

by complex 1^a

^aConditions: ketone, 2.0 mmol; catalyst, 0.02 mmol (1.0 mol%); base, 0.4 M in 2-

propanol (5 mL); time, 48 h; temperature, 82 ^°C. ^bDetermined by ¹H NMR

spectroscopy. ^c0.01 mmol catalyst (0.50 mol%); ^d0.03 mmol catalyst (1.50 mol%).

Effect of reaction conditions on TH reactions: To establish

the optimum reaction conditions for the transfer

hydrogenation of acetophenone, we studied the effect of

catalyst loading and type of base on the catalytic performance

of complex 1. Increasing the catalyst loading from 0.5 mol% to

1.0 mol% resulted in a significant increase in activity from 60%

to 95% conversion (Table 3, entries 1 and 5). However, a

further increase in catalyst concentration to 1.5 mol%

engendered a marked decline in activity (59% conversion;

Table 3, entry 6). Deactivation with increasing catalyst

concentration often reflects aggregation, oligomerization, or

^aConditions: ketone, 2.0 mmol; catalyst, 0.02 mmol (1.0 mol%); base, 0.4 M KOH

in 2-propanol (5 mL); time, 48 h; temperature, 82 ^°C. ^bDetermined by ¹H NMR

reductive demetallation,^{32, 33}which typically limits the number spectroscopy.

of reacting species due to loss or steric obstruction³⁴of the

reactive metal sites.²⁷In the case of

1, the dinuclear bromide-

reaction medium (and hence the probability of forming

reactive metal hydride intermediates, vide infra).

bridged analogue of 2a is well known;²⁷its formation during

turnover of the reaction could well account for the observed

TH rate decrease at higher catalyst concentrations (as noted

earlier). From the data in Table 3, the optimum catalyst

concentration for TH reactions of acetophenone using complex

Variation of ketone substrates: To delineate the scope of

ketone substrates suitable for hydrogenation by the present

complexes (specifically

methylacetophenone,

1

and

9

), we studied the TH of 2-

2-chloroacetophenone,

2-methyl-

1

was 1.0 mol%. The effect of the base was also investigated

by comparing the activities in tBuOK, KOH, NaOH and Na₂CO₃

(Table 3). The highest TH activity with was realized with

cyclohexanone, benzophenone, 3-pentanone, and 2-acetyl-

pyridine relative to acetophenone (Table 4). Introduction of

electron-donating or withdrawing groups at the ortho-position

of acetophenone did not significantly alter the catalytic

1

tBuOK as the base; the lowest activity was observed with

Na₂CO₃. This trend parallels the pK_B(base strength) values for

the bases, consistent with earlier literature showing that

stronger bases such as tBuOK generate more active catalytic

species in TH reactions.³⁵These observations presumably

reflect an increase in the fraction of iPrOK generated in the

performance of

conversions

1

and 9 (Table 4). For instance, uniformly high

of

≥

95%

were

2-chloroacetopheone,

acetophenone with both complexes and

obtained

for

2-

methlyacetophenone,

and

1

9. These findings

are consistent with the literature for conversion of 2-

substituted acetophenone substrates to their corresponding

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9

alcohols with structurally related Ru(II) catalysts,^7,

but ligand’s structure is amply highlighted by the structures shown

somewhat different to the data reported for the chiral Ni-NPO in Figs. 3 and S8. The metal ion is evidently less accessible to

catalyst studied by Dong et al. in 2012,¹⁹wherein conversion nucleophilic attack when the chelating ligand is tridentate L2

efficiencies were highest for electron-rich 3- and 4- The impact of the chelating ligand’s structure coupled with the

.

methylacetophenone (

acetophenone (81%).

≥

96%) and lower for unsubstituted size of the coordinated halide ion on the TH kinetics involving

is explored in considerable detail below in our attempts to

1–9

Significantly, we observed diminished catalytic activity for delineate quantitative structure-activity relationships (QSARs)

2-methylcyclohexanone (77% conversion) and 3-pentanone for the compounds.

(56% conversion) using

that and exhibit marked substrate specificity with aromatic precatalysts employed in this study, the question of the

ketones being favoured over aliphatic ketones. Even 2- accuracy of the DFT simulations for structural simulations must

acetylpyridine was efficiently reduced (96% conversion) by be addressed. Unfortunately, few crystallographically

1

(or

9) as the catalyst. This suggests

Since we have not been able to crystallize all of the

1

9

9,

indicating that potentially coordinating heterocyclic aromatic characterized complexes with a single chelate ligand of the

ketones may be equally efficiently reduced to the type L1 or L2 bound to either Ni(II) or Fe(II) exist in the

corresponding alcohol. Finally, benzophenone was the least literature for comparison with the DFT-calculated geometries

favourable aromatic ketone substrate for

9 (89% conversion), of 1–9. A single, pertinent X-ray structure exists with L1

consistent with increased steric hindrance to reduction coordinated to Ni(II) for comparison, namely that of the

engendered by the additional aryl ring appended to the related t-butyl-substituted complex dibromo-(2-((3,5-di-tert-

carbonyl carbon.

butyl-1H-pyrazol-1-yl-N₂)methyl)pyridine-N)-nickel(II)

S9).²⁷Comparison of the DFT-calculated structure of

(Fig.

1

with the

DFT-simulated structures of 1–9

foregoing experimental structure indicates that the

We have used DFT simulations at the HSEH1PBE /6-311g(d,p) coordination group bond distances are within 0.5% (M–N) to

level of theory in a 2-propanol solvent continuum to gain a 2% (M–Br) of the experimental bond distances and that the

conceptual understanding of the structures of the initial metal ligand conformation is accurately reproduced. A second test of

complexes in solution that are likely to be precatalysts in the the DFT method and basis set is possible for compound 9;

transfer hydrogenation of acetophenone. A further goal was to excellent agreement (bond distances, within 0.5% (M–N) to 4%

attempt to understand the structural features of the (M–Cl); bond angles, <2% difference) between the DFT-

complexes that might impact on the reaction kinetics.

Table 5 summarizes selected bond distances and angles for the least-squares fit wherein the rigid geometry of the

; representative structures are given in Figs. 3, S7, and S8. chelating ligand of the X-ray structure is especially well-

The Fe(II) chelates and have longer bond distances for the reproduced (Fig. S10). The present simulations at the

calculated and experimental X-ray structure³⁷is evident from

1–9

3

6

intrachelate interactions (M–N_pyand M–N_pz) than the Ni(II) HSEH1PBE/6-311g(d,p) level of theory thus offer accurate

complexes due to the larger ionic radius of high-spin Fe(II), structural parameters for the compounds investigated, an

0.78 Å, relative to that of Ni(II), 0.69 Å.³⁶For complexes with essential requirement for any attempt to delineate structure–

didentate L1

(

1

–

3

), the M–X distances (for the same halide and activity relationships for the TH kinetics (vide infra).

Regarding the electronic structures of , the data in

metal ion) are about 5–7% shorter than for the complexes with

1–9

the tridentate ligand L2. From Fig. 3, elongation of the M–X Table 5 confirm the high-spin states for the Ni(II) and Fe(II)

bonds for complexes of L2 reflects the increase in steric compounds determined by magnetic susceptibility measure-

repulsion between the metal-bound halide ions and the ments on the powders. The unpaired spin density on the metal

methyl substituents of the coordinated pyrazole rings. As ion ranges from 1.728 to 1.774 e for the Ni(II) complexes and

expected from the ionic radii of the halide ions within the two more narrowly from 3.798 to 3.812 e for the Fe(II) complexes.

chelate categories (di- or tridentate), the M–Cl bonds are The partial cationic charge on the metal ion is relatively

shorter than the corresponding M–Br bonds. Qualitatively, invariant, ranging from 1.419 to 1.469 e for the Ni(II)

steric hindrance about the metal ion due to the chelating complexes and from 1.514 to 1.536 e for the Fe(II) complexes.

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Table 5 Selected geometric, electronic, and steric parameters for DFT-calculated structures of 1–9^a,b

M–X

(Å)

M–N_py

(Å)

M–N_pz

(Å)

N_py–M–N_pz

(°)

92.5

X–M–X

(°)

N_py–M–X

(°)

Q

ρ^S

G^T_M(ꢀꢁꢂꢃꢄꢅꢆ)

(%)^e

ω

Cpd.

Symm.

(M, e)^c

1.419

1.466

1.514

1.433

1.467

1.536

1.427

1.469

1.527

(M, e)^d

1.771

1.774

3.802

1.728

1.748

3.812

1.737

1.750

3.798

(°)^f

1

2

3

4

5

6

7

8

9

C₁

C₂

C₁

2.430(2)

2.292(6)

2.311(4)

2.602(0)

2.445(0)

2.438(0)

2.497

2.023

2.022

2.149

2.068

2.072

2.198

1.988

1.990

2.158

1.987

140.7

141.0

136.2

164.1

160.6

158.9

145.3

148.8

108.8

100.9(7)

100(2)

69.4

159.5

159.6

151.8

203.5

203.2

192.1

181.8

181.7

171.4

1.987

92.6

62.9

2.075

88.8

102.0(8)

98.0(0)

99.7(0)

100.6(0)

107.4(0)

105.6(0)

126(1)

58.4

2.023(0)

2.031(0)

2.137(0)

2.060

93.4(0)

92.4(0)

89.6(0)

77.7

78.6

73.8

68.1

78.7

2.366

2.062

77.7

72.5

2.39(8)

2.159(0)

72.8

66.3

^aAbbreviations: Symm.; symmetry of minimum energy structure; M = Ni or Fe; X = Cl or Br; N_py, pyridyl nitrogen; N_pz, pyrazolyl nitrogen. ^bStandard uncertainties are

given in parentheses for bonds or angles where mean values are reported. ^cPartial charge (NBO) on the metal ion. ^dUnpaired spin density (Mulliken) localized on the

metal ion. The total atomic spin density (all atoms) in each Ni(II) and Fe(II) complex summed to 2.00 and 4.00, respectively, consistent with the triplet and quintet spin

states assigned in the simulation and the room temperature magnetic moments determined for 1–9 in this work. ^eThe percentage of the metal ion’s surface shielded

by the ligand donor atoms in the theoretically-derived structure of the complex. ^fEquivalent cone angle, ECA, corresponding to the solid angle of the ligand.

Of considerable interest for an analysis of the factors that the metal centre of

5 is sterically more restricted than that of

might control the TH kinetics for reactions involving 9 is the 2, principally due to crowding of the metal ion by the methyl

1–

degree of steric shielding of the metal ion. We used the groups (C28 and C36) of the two pyrazole moieties of

program SOLID-G (2008) written by Guzei³⁸to calculate the tridentate L2. From Table 5, the metal ion steric shielding

ligand solid angles, equivalent cone angles, and overlap parameter, G_M^T

(

complex), quantitatively confirms the effect

between the ligands for all final DFT-calculated structures of since only 62.9% of the metal ion’s surface is shielded in the

in Table 5. The two most useful parameters calculated by case of compared with 73.8% in the case of . Increased

the program are G^T_M

complex) (the percentage of the metal steric crowding in the complex is evidently paralleled by

ion’s surface screened or shielded by all of the donor atoms of commensurate elongation of the Ni–N and Ni–Cl bonds in (by

the directly coordinated ligands in the theoretically-derived ca. 2.5% and 6.5%, respectively) relative to those for . The

structure of the complex) and (the equivalent cone angle, chloro ligands of are, furthermore, more tightly held by

ECA, for the chelating ligand determined from its specific intramolecular C–H⋅⋅⋅Cl hydrogen bonds involving, for example,

coordinated geometry in the complex). The steric shielding H29 and H14. From Fig. 2(b), it is clear that the kinetics for

parameter G^T_M

complex) indicates that the screening of the follow a standard first order exponential growth curve (zero or

metal ion follows the expected order for the chelating ligands negligible induction phase), while a long induction phase of ca.

based on their structures and the degree to which they 2–4 h exists for . The kinetics for both and clearly exhibit

enwrap the metal ion (which may be separately quantified by incomplete conversion, in all likelihood due to catalyst

): L1 L3 L2. This is paralleled by the expected order of deactivation, with the effect being most pronounced for

G^T_Mcomplex) for the halide ions, Cl^–< Br^–, which reflects their Interestingly, rate constants for

and required fits of the

1–

9

2

5

(

5

2

ω

5

2

(

5

2

5

ω

<

5.

(

5

6

ionic radii. Similarly, the Fe(II) complexes are less sterically data with the Gompertz model,⁴⁰which accounts for both

shielded than their Ni(II) counterparts because of the 13% induction and inhibition, the latter consistent with catalyst

larger ionic radius of the Fe(II) ion,³⁹which accommodates the deactivation. The foregoing DFT calculations on the

ligand donor atoms more spaciously over the surface of the precatalysts (Fig. 3, Table 5) suggest that an explanation for

metal ion sphere.

the unique behaviour of both 5 and 6 (long induction phase,

different kinetic model) compared with the remaining

compounds involves both the increased steric restriction of

Kinetic QSARs based on DFT-calculated parameters

As noted above, acetophenone TH conversions (Table 2) the metal ion and the enhanced intramolecular H-bonding to

ranged from ca. 70% to 99%; both the nature of the ligands the metal-bound halide ions (particularly in ). These two

5

and the metal ion were systematically varied to understand factors evidently work in unison, slowing the rate of formation

some of the factors that might contribute to the reactivity of an active catalyst species in which one or both halide ions

profiles of the compounds (precatalysts). The product yield are substituted by iPrOH (or iPrO^–) on the pathway to attaining

data after 48 h for

L2) reflect the most pronounced ligand-dependence for the catalysts have been reviewed by Morris and involve M–

compounds studied. (Note that the rate constants in Table 2 OCH(CH₃)₂alkoxide species.^{28, 41}

and Fig. 2 measure mainly the initial catalyst activity and do Although one might anticipate that the initial reactivity of

2 (85%, didentate L1) and 5 (70%, tridentate the transition state species. (Postulated transition states for TH

)

not necessarily correlate with the reaction yields after 48 h, the precatalysts could be straightforwardly delineated from

which are subject to yield-limiting factors such as catalyst their structures, we found no linear correlation between the

deactivation, as discussed below.) From Fig. 3, it is clear that initial percentage conversion of acetophenone to product (t =

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6 h) when the catalytic activity was plotted against either the

However, k_obsclearly correlates linearly with M–N_py

DFT-calculated M–X bond distance or the equivalent cone distance. Furthermore, the complexes appear to be split into

angle, ECA (or ), of the ligand (Fig. S11). However, as shown two independent groups (Fig. 5c). The reason for this is

ω

by Fig. 4, the relationship between precatalyst structure and unclear, but the general trend is that longer M–N_pybonds lead

catalytic activity in the TH of acetophenone is more to faster TH rates. This is readily understood in terms of the

complicated, being simultaneously dependent on these two typical reactive species involved in TH reactions, namely metal

uncorrelated variables. The three-dimensional plot, a bivariate hydrides coordinated cis to the ketone substrate in the case of

linear regression fit of the % conversion after 6 h as a function inner-sphere reduction mechanisms.^41-43Based on the

of the M–X bond distance and

ω for the chelating ligand structures of the present compounds and the prevailing

(where X = Cl or Br and M = Fe or Ni), shows that the initial mechanisms in the literature, it is not unreasonable to suggest

activity of the complexes increases monotonically with that elongation of the M–N_pybond promotes in-plane

increasing M–X distance, but decreases progressively with extrusion of the metal ion from the chelating ligand, thereby

increasing ω. Since ω is a steric size parameter that effectively “priming” (exposing) the metal ion for formation of a reactive

gauges the type of chelating ligand, the available data are M–H species trans to the pyridyl nitrogen. Indeed, the

cleanly differentiated into two groups (A and B). Group A calculated structures of the postulated hydride intermediates

complexes are chelated to the sterically less-encumbered in the catalytic cycle (Figs. 6 and S12, vide infra) confirm the

ligand L1, which screens the metal ion to a smaller extent, existence of longer M–N_pybonds; complexes with intrinsically

giving commensurately less obtuse values of

complexes, in contrast, are chelated by the more bulky, yet for the formation of reactive hydrides. The analysis of the

structurally-related tridentate ligand L2 which screens initial conversion efficacies above (Fig. 4) clearly reveals that

significantly more of the metal ion surface, as reflected by the TH rates increase with increasing M–X distance. This is

more obtuse values. From the DFT-calculated geometries of evidence that one or both of the halide ions dissociate from

and (Fig. 4, Table 5), the more obtuse value for L2 is the metal ion to form the reactive species in this system. On

ω. Group B longer M–N_pybonds are thus likely to be more pre-organized

,

ω

1

4

ω

consistent with the tridentate nature of the ligand and the the basis of our analysis of the precatalyst structures, initial

additional steric encumbrance of the metal ion caused by the rate data above, and the current literature on TH reaction

methyl groups appended to the two pyrazole moieties of the mechanisms,^41-44it is possible to suggest candidate structures

ligand. Since the slope of the plot decreases with increasing

(steric hindrance), the % conversion of the substrate is lower brevity, we have restricted this speculation to solution species

for more hindered complexes, consistent with expectation if derived from and because three key experimental insights

steric effects influence the reactive intermediates. exist (the X-ray structures of

2H₂O and 9³⁷and the substrate

The significant 3D bivariate correlation of Fig. 4 did not, specificity data for in Table 4) to guide our DFT simulations

ω

that might be relevant to the TH mechanisms of 1–9. For

8

9

8

⋅

9

however, extend to complexes of L3, possibly because the and ideas on reaction intermediates.

latter tridentate ligand differs significantly from the former

Possible mechanism

two in structure as it lacks the bridging methylene carbon and

is an inherently more rigid, electronically-delocalized system. There are two commonly invoked transition state (TS) species

These (and possibly other) factors unique to L3 evidently in the TH of ketones when iPrOH is the reductant: (a) those

impact on the initial rates of the TH reactions of 7–9 such that derived from transient outer-sphere associations in which M–

the QSAR delineated for

L3

1–

6

is not applicable to complexes of H and ligand X–H groups interact with the ketone carbonyl C-

and O-atoms, respectively, typically in a pericyclic 6-membered

.

In Fig. 5 we have analysed the rate constant for TH of ring (TS1), and (b) those derived from inner-sphere adducts,

acetophenone, k_obs, as a function of G_M^T

complex) and the M– which generally involve coordination of the substrate ketone

N_pybond distance. The graphical illustration of G_M^T

for , and

(

41

(

complex) carbonyl group cis to a reactive M–H group (TS2).^28,(The

3

,

9

4 shown in Fig. 5a highlights the effect that reactive M–H groups are formed by hydride transfer from

changing the size of the chelating ligand, halide ions, and metal-bound iPrO^–, which subsequently dissociates as

metal ion has on the fraction of the metal ion’s surface propanone.) Such states are depicted in Scheme 3 for transient

sterically shielded from substrate and solvent molecules in the species that could be derived from compounds

reaction medium. Clearly, Fe(II) complexed to didentate L1 and substrate such as acetophenone. (In Scheme 3, the tridentate

two chloride ions (i.e., complex ) will be the least sterically ligand L3 is represented as the half-disk with pyridyl, py, and

shielded, as discussed above (Table 5). The observed rate pyrazolyl, pz, nitrogen atoms marked.)

constant increases with decreasing G_M^T

complex) (i.e., reduced In principle, the hydride ion could occupy any one of three

8 or 9 with a

3

(

steric shielding of the metal ion) to some extent and, more meridional sites in these species, but substitution of chloride

significantly, with increasing M–N_pydistance. For all complexes by iPrO⁻would be expected to place the O-bound iPrO⁻ion

(excluding 1, 5, and 8) these dependencies underpin the 3D above or below the plane of L3 for steric efficiency and so the

bivariate correlation of Fig. 5b. It is noteworthy that k_obsshows transfer of hydrogen from the iPrO⁻C–H donor to the metal

effectively no independent linear correlation with ion most likely places the hydride ion in an equatorial position

G_M^T

(complex), suggesting that steric shielding alone within the plane of L3. Such a site is only mildly sterically

inadequately accounts for the TH rates.

restricted by the flanking methyl groups from L3 and would

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readily accommodate a small anionic ligand. Formation of TS1 the catalyst, 9a. One mole of iPrOH is therefore consumed for

could then occur if a solvent molecule occupied the vacant site each mole of ketone reduced.

left by dissociating propanone; TS2 requires that

acetophenone binds directly to the metal ion via its carbonyl due to its relevance to the experimental substrate specificity of

oxygen to form an inner-sphere adduct. (Table 4). Significantly, 9c is characterized by an offset

Despite being reasonable postulates for the transition state interaction of the pyridine ring of the chelate with the aryl ring

structures involved in the TH of acetophenone with or of the ketone substrate (i.e., a 1.91-Å lateral shift). The ring

Fig. 7 highlights the structure of π-adduct 9c in more detail

9

8

9,

neither transition state satisfactorily explains the large centroid separation, C_g1⋅⋅⋅C_g2, and perpendicular displacement

difference in the conversion efficiencies observed between measure 3.50 Å and 2.93 Å, respectively, and the associated

aliphatic and aromatic ketone substrates (Table 4), mainly slip angle is 33.1

because no significant interaction between the ketone the established empirical dispersion scheme from the APFD

substituent groups and the catalyst exists in either TS1 or TS2

functional⁴⁵to augment the HSEH1PBE functional⁴⁶used here.

Indeed, our DFT simulations for (Table S4) suggest that there Based on the experimental metrics of stacking in metal–

°. Note that the structure was modelled using

.

8

π–π

is no thermodynamic discrimination between aliphatic and aryl pyridyl complexes reported in Janiak’s seminal review of the

ketone substrates during the formation of the pre-transition subject,⁴⁷wherein offset parallel stacking (laterally-shifted

state structure of TS2 (which is predicted to be endergonic at aromatic rings) is emblematic, centroid⋅⋅⋅centroid separations

298 K).

As noted earlier, irrespective of the ring substitution angles average 27

pattern, all ketone substrates with a single aromatic ring are structure of -adduct 9c is consistent with X-ray data for

practically completely converted (96–99%) to the several thousand -stacked metal–pyridine ring systems.

Because the two aromatic rings exhibit a tilt angle

, the reactive hydride ion (H18) is canted towards the

typically range from 3.4 to 4.2 Å (tight interactions), and slip

°

for over 7600 structures, the simulated

π

corresponding alcohol product. An explanation for this key

ꢀ of

observation is that the pre-transition state structure for TH is 11.2

°

unique for this system and likely involves formation of a stable carbonyl carbon (C1) of the substrate such that the H18⋅⋅⋅C1

-adduct between the aromatic ligand of the catalyst and the distance is only 3.76 Å in the pre-transition state structure. A

ketone substrate. (Aromatic ketones would be expected to second noteworthy feature of 9c is the short interaction

π

promote the formation of a

turnover of the reaction.)

π

-adduct, favouring higher distance (2.78 Å) between Fe19 and C4 of the benzophenone

phenyl ring. This distance is significantly less than the sum of

A possible catalytic cycle for the system that reflects the the van der Waals radii of Fe (2.05 Å) and C (1.70 Å),⁴⁸and,

experimental facts with

conditions, tBuOK as base). DFT-calculated structures for

are given in detail in Fig. S12. Briefly, the role of the added between Fe (

9

is depicted in Fig. 6 (ideal anhydrous based upon the NBO-calculated⁴⁹partial charges of 9c (Fig.

9d S13), may be regarded as a significant electrostatic attraction

, +1.446 e) and C4 ( , –0.264 e). Evidently, π-

9–

δ

base (tBuOK) is to deprotonate iPrOH; the position of this adduct 9c is stabilized by well-defined attractive electrostatic

equilibrium, and thus the effective concentration of iPrOK, is interactions, dispersion forces between the aromatic rings,

dependent on the strength of the base (Table 3). Precatalyst

reacts with iPrOK to form 9a by substitution of the coordinated The latter seemingly involves overlap of the highest singly-

halide ion, consistent with the dependence of the initial yield occupied MO (HSOMO, with predominantly dx²–y²and

of product on the M–X bond distance (Fig. 4) and the symmetry Fe–H bond character) and the LUMO ( *) of

9

and a favourable frontier molecular orbital (FMO) interaction.

σ

-

π

observation that more weakly-bound halide ions favour higher acetophenone (Fig. S14). The interaction stabilizes the HSOMO

initial rates. Compound 9a is the active catalyst; hydride of 9c by 0.155 eV (14.9 kJ mol^–1) relative to the energy of this

migration from the methine CH group of the metal-bound orbital in the non-interacting hydride, FeCl(H)(L3), and

iPrO⁻ion in step 1 affords the reactive metal hydride species provides a familiar basis for understanding the association of

9b, as with many other TH catalysts.^{4, 41}Transient coordination FeCl(H)(L3) with acetophenone. From Fig. 7b, simple lateral

of the oxidized product (propanone) is possible (though not translation (surface slippage) of the ketone carbonyl carbon

obligatory) given the inner-sphere nature of the hydride atom (C1) towards the metal-bound hydride ion (H18) would

transfer step. Uptake of the aryl ketone substrate as a

π

adduct in step 2 displaces propanone and forms the stable attack of C1 by the hydride ion with concerted formation of an

-

ostensibly culminate in a TS from which S_N2-type nucleophilic

species 9c. The fact that aliphatic ketone substrates are poorly O–Fe bond would afford the corresponding iron-bound aryl

converted to product (Table 4) suggests that formation of a

π

adduct (enhanced by the presence of an aryl ring) is important catalytic cycle gives the aryl alcohol reduction product and

-

alkoxide 9d. Protonation of 9d by iPrOH in the last step of the

in the catalytic cycle of this system. The ketone carbonyl regenerates the catalyst (Fig. 6).

oxygen is positioned close to the reactive M–H group in 9c

,

The exact nature of the TS for step 3 in the catalytic cycle

facilitating nucleophilic hydride transfer to the carbonyl carbon unfortunately remains elusive; numerous attempts to locate

in step 3. The addition product (an aryl alkoxide) binds to the the TS using standard computational methods were

metal ion via its O^–donor (9d). In the final step, isopropyl unsuccessful. Part of the problem is that the initial (9c) and

alcohol protonates the metal-bound aryl alkoxide to release final

(9d) structures linked by the TS on the reaction

the reduction product (racemic 1-phenylethanol), regenerating coordinate for step 3 have to be calculated with different

model chemistries. Thus, while a functional with an empirical

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dispersion correction is mandatory for accurate calculation of secondary alcohols. The 1:1 ligand:metal complexes were

-adduct 9c, the same functional is in fact deleterious to moderately active catalysts for the TH of ketones. In most (but

structural simulation of 9d This limitation aside, it is not all) cases, the Fe(II) complexes were more active than their

noteworthy that the aryl ketone may form the -adduct by Ni(II) analogues possibly because Fe(II) is harder than Ni(II),

π

.

π

stacking with either face of the aryl ring in contact with the thereby favouring the formation of alkoxide and hydride

accessible face of the catalyst (which naturally orients the intermediates. The catalytic performance was dependent, in a

carbonyl group to the left or right of the M–H group). complex way, on the ligand structure, the metal-bound halide

Consequently, the resulting two mirror image forms of 9c will ions, and the nature of the ketone substrate (aryl ketones

give equivalent yields of the two enantiomers of 1- were preferable substrates to aliphatic ketones).

phenylethanol if the TS for step 3 retains some of the

π

stacked character of 9c. An intermediate such as 9c in the shielding of a metal ion in a ligand field) and DFT simulations

-

A combination of solid angle calculations (measuring steric

catalytic cycle clearly accounts for the racemic product were used to delineate some of the key structural and

observed in the reaction.

electronic parameters of 1–9 that have an impact on the initial

Finally, thermochemical analysis (HSEH1PBE/6-311G(d,p) conversion rates and overall substrate specificities of the

level of theory, 2-propanol solvent continuum) of the catalytic catalysts. Our analysis reveals that the initial conversion rates

cycle for

all species in the reaction at 298.15

significant insights (Fig. 8). First, the induction step for

9

(Fig. 6) using the geometry-optimized structures of increase with increasing metal–halide bond distance and

affords several decreasing steric shielding of the metal ion for (ligands L1

, which and L2). Furthermore, the observed rate constants, k_obs, for TH

K

1–6

9

involves substitution of iron-bound chloride by iPrO^–is of acetophenone increased with decreasing steric shielding of

endergonic (+85.3 kJ mol^–1); this reflects the experimental fact the metal ion and increasing M–N_pyridinebond distance. These

that the reaction only proceeds at elevated temperatures observations, in conjunction with the strong preference of

(refluxing 2-propanol). Second, the intramolecular hydride catalysts

transfer step in which the -adduct 9c converts to the aryl simple 4-step catalytic cycle (after endergonic induction)

alkoxide 9d is highly exothermic (step 3, –189.2 kJ mol^–1). Step adequately accounts for the data. A key intermediate in this

3 in the cycle clearly acts as the thermodynamic driving force cycle is a stable -adduct (9c) formed between the chelating

needed to pull the system through the preceding endergonic pyridyl ligand of the catalyst and the aromatic ketone

steps. Third, the final step in which the iron-bound aryl substrate; 9c accounts for both the substrate specificity of

1 and 9 for aryl ketone substrates, suggest that a

π

9

alkoxide is protonated by iPrOH in solution to regenerate the and the racemic alcohol product, (R,S)-1-phenylethanol,

active catalyst 9a and the product (1-phenylethanol) is only generated in the reduction of acetophenone.

mildly endergonic (+7.0 kJ mol^–1). The net Gibbs energy for the

full reaction including the induction (activation) step amounts

to 91.4 kJ mol^–1; the in-cycle thermodynamics (reaction

coordinate states 2 through 6) are commensurately more

favourable with a net Gibbs energy of +6.0 kJ mol^–1, but

nevertheless still endergonic.

Experimental methods

General methods

All reagents and solvents were obtained from Sigma-Aldrich.

The starting materials NiCl₂, NiBr₂, FeCl₂.4H₂O, isopropanol,

absolute ethanol and deuterated solvents were used as

received without further purification. Literature procedures

were used to synthesize the free ligands 2-

Overall, the calculated Gibbs energies for the postulated

catalytic cycle (with

9 as the case study) account adequately

for the induction phases observed to a lesser or greater extent

in the experimental reaction kinetics of several of the

complexes investigated here (Fig. 2) as well as the fact that TH

pyrazolyl(methyl)pyridine

pyridine (L2),²⁷and 2,6-bis(3,5-dimethyl-N-pyrazolyl)pyridine

L3).⁵¹Dichloromethane was dried over P₂O₅and distilled prior

(

L1),²⁷2-6-bis-(pyrazolylmethyl)-

reactions of acetophenone with

1–9 require relatively long

(

reaction times at 82 °C in 2-propanol for optimal conversions

to product. Lastly, although mechanistically distinct, the orders

to use. NMR spectra were recorded on a Bruker Avance 400

MHz (¹H) [100 MHz (¹³C)] NMR spectrometer. All chemical

of magnitude of the Gibbs energy changes computed here for

shifts,

performed on Thermo Scientific^TMFlash 2000 Analyzer and

mass spectra were recorded on a Waters® Micromass LCT

δ, are reported in (ppm). Elemental analyses were

the catalytic cycle of

9 are broadly in accord with the DFT-

calculated Gibbs energy changes reported by Landwehr et al.⁵⁰

for bifunctional rhenium cyclopentadienyl-type TH catalysts

(despite the different model chemistry, catalysts, and

conditions used in the simulations by these authors).

Premier^TM

Mass

Spectrometer.

Magnetic

moment

measurements were performed with a Sherwood Scientific MK

1 Magnetic Susceptibility Balance.

Synthesis of iron(II) and nickel(II) complexes

Conclusions

The synthetic procedures used to synthesize metal chelates of

Iron(II)

and

nickel(II)

complexes

of

bidentate

L1

–L3 were essentially straightforward, as described below.

(pyrazolylmethyl)pyridine (L1) and tridentate bis(pyrazolyl-

methyl)pyridine (L2) or bis(pyrazole)pyridine (L3) type ligands

have been prepared, characterized, and tested as transfer

hydrogenation (TH) catalysts for the reduction of ketones to

(2-pyrazolyl(methyl)pyridine)NiBr₂, compound 1: To

a

solution of nickel(II) bromide (0.12 g; 0.53 mmol) in CH₂Cl₂(10

mL) was added a solution of L1 (0.10 g; 0.53 mmol) (10 mL). An

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orange mixture was formed immediately. The mixture was – CH₃, 29%), 352 (M⁺– 2Cl, 5%). Anal. Calcd for C₁₇H₂₁Cl₂N₅Fe:

stirred for 24 h at room temperature. A blue solution was C, 42.64; H, 4.57; N, 13.81. Found C, 42.54; H, 4.26; N, 14.81.

filtered and the resulting blue solid was dried and weighed. µ_eff= 4.98 BM.

Yield = 0.09 g (73%). (ESI-MS), m/z (%) 326 (M⁺– Br, 91%), 188

Despite attempts to recrystallize 6 from powder re-

(M⁺– NiBr₂, 100%). Anal. Calcd for C₁₁H₁₃Br₂N₃Ni: C, 32.56; H, dissolved in CH₂Cl₂and layered with hexane, only the 2:1

3.23; N, 10.36. Found C, 32.18; H, 4.57; N, 10.06. µ_eff= 2.89 ligand:metal adduct was isolated in single crystal form suitable

BM.

(2-pyrazolyl(methyl)pyridine)NiCl₂, compound 2: The [Fe^II(

complex was prepared in a similar manner to using a solution both ligand exchange and oxidation of some of the Fe(II)

for X-ray diffraction analysis. Formation of the salt

L

2)₂][Fe^IIICl₄]₂, 6a, during crystallization evidently reflects

1

of NiCl₂(0.69 g; 0.53 mmol) in CH₂Cl₂(10 mL) and L1 (0.10 g; present in the system to Fe(III), culminating in the formation of

0.53 mmol) (10 mL). The resulting yellow mixture gave a the tetrahedral [Fe^IIICl₄]^–counter-ions. The molecular structure

purple solution upon stirring. The solution was filtered and the of 6a is given in Fig. S5 (Supporting Information).

resulting blue solid was dried and weighed. Yield = 0.11 g

(61%). (ESI-MS), m/z (%) 188 (M⁺– NiCl₂, 100%). Anal. Calcd for 7: Complex

C₁₁H₁₃Cl₂N₃Ni: C, 41.70; H, 4.14; N, 13.26. Found C, 42.05; H, described for

5.48; N, 13.03. µ_eff= 3.08 BM.

(2-(pyrazolylmethyl)pyridine)FeCl₂, compound 3: The (63%). (ESI-MS), m/z (%) 406. (M⁺– Br, 100%), 404 (M⁺– Br,

complex was prepared in a similar manner to using a solution 73.5%). µ_eff= 2.39 BM. Anal. Calcd for C₁₇H₂₁Br₂N₅Ni: C, 29.44;

of FeCl₂(0.11 g; 0.53 mmol) and L1 (0.10 g; 0.534mmol). A H, 4.15; N, 11.69. Found C, 29.22; H, 4.38; N, 11.36. Re-

green solution was filtered and the resulting green solid was crystallization of by slow evaporation of the solvent (reagent

dried and weighed. Yield = 0.12 g (73%). (ESI-MS), m/z (%) 188 grade CH₂Cl₂, ≥ 0.02% water) under ambient conditions

(M⁺– NiCl₂, 100%). Anal. Calcd for C₁₁H₁₃Cl₂N₃Fe: C, 42.08; H, afforded X-ray quality crystals of the tri(aqua) complex

4H₂O

(2,6-bis(3,5-dimethylpyrazolyl)pyridine)NiBr₂, compound

7

was synthesized according to the procedure

1

using NiBr₂(0.10 g; 0.46 mmol) and L3 (0.122 g;

0.46 mmol) and was isolated as a green solid. Yield = 0.14 g

1

7

7⋅

4.17; N, 13.38. Found C, 42.16; H, 4.03; N, 13.10. µ_eff=5.01 BM. as a mono(hydrate) species displaying full substitution of the

(2,6-bis(pyrazolylmethyl)pyridine)NiBr₂, compound 4: The halide ions by water.

complex was prepared using a similar manner to

(0.10 g; 0.46 mmol) in CH₂Cl₂(10 mL) and L2 (0.14 g; 0.46 8: Complex

mmol) (10 mL). The resulting blue solution was filtered and the described for

1

using NiBr₂

(2,6-bis(3,5-dimethylpyrazolyl)pyridine)NiCl₂, compound

8

was synthesized according to the procedure

1

using NiCl₂(0.10 g; 0.77 mmol) and L3 (0.21 g;

isolated purple solid was dried and weighed. Yield = 0.22 g 0.77 mmol) and was isolated as a lime-coloured solid. Yield =

(95%). (ESI-MS), m/z (%) 354 (M⁺– 2Br, 20%), 340 (M⁺– 2 Br – 0.14 g (47%). (ESI-MS), m/z (%) 360 (M⁺– Cl, 100%), 362 (M⁺–

CH_3,18%). Anal. Calcd for C₁₇H₂₁Br₂N₅Ni: C, 36.10; H, 3.87; N, Cl, 70.8%), 364 (M⁺– Cl, 18.6%). µ_eff= 2.76 BM. Anal. Calcd for

11.70. Found C, 35.86; H, 5.56; N, 11.99. µ_eff= 3.05 BM.

C₁₇H₂₁Cl₂N₅Fe: C, 33.30; H, 4.77; N, 12.94. Found C, 33.56; H,

by slow evaporation of

Efforts to recrystallize 4 from powder re-dissolved in CH₂Cl₂4.89; N, 13.12. Recrystallization of

8

and layered with hexane afforded the 2:1 ligand:metal adduct the solvent (reagent grade CH₂Cl₂, ≥ 0.02% water) under

[Ni(L2)₂]Br₂, presumably as a result of ligand exchange, eqn (1): ambient conditions afforded X-ray quality crystals of the

bis(aqua) complex

substituted by water.

(2,6-bis(3,5-dimethylpyrazolyl)pyridine)FeCl₂, compound

9: The method reported here for complex differs to that

The presence of excess free ligand (L2) in the crystallization reported earlier in the literature,³⁷since we employed the

solution could, if present, also result in the formation of 4a general procedure described for using FeCl₂(0.10 g; 0.50

The molecular structure of 4a is given in Figs. S2–S4 mmol) and L3 (0.13 g; 0.50 mmol). The reaction product was

(Supporting Information). isolated as an orange solid (a solvate with ca. 2.5 CH₂Cl₂

(2,6-bis(pyrazolylmethyl)pyridine)NiCl₂, compound 5: The solvent molecules per formula unit). Yield = 0.05 g (25%, dry

complex was prepared in a similar manner to

using NiCl₂weight) (ESI-MS), m/z (%) 358 (M⁺– Cl, 11%), 296 (M⁺– 2Cl –

(0.10 g; 0.77 mmol) and L2 (0.23 g; 0.77 mmol). The blue 2CH₃50%). µ_eff4.52 BM. Anal. Calcd

solution that was formed was subsequently filtered and the C₁₅H₁₇Cl₂N₅Fe 2.5(CH₂Cl₂): C, 34.66; H, 3.66; N, 11.55. Found C,

8⋅2H₂O in which a single halide ion is

Ni(L2)Br₂+ Ni(L2)Br₂

⇌

[Ni(L2)₂]Br₂+ NiBr₂

(1)

4

4a

9

.

1

=

⋅

resulting blue solid was dried and weighed. Yield = 0.30 g 34.90; H, 2.95; N, 12.28.

(92%). (ESI-MS), m/z (%) 355 (M⁺– 2Cl, 3%), 340 (M⁺– 2Cl –

X-ray crystallography

CH₃, 18%). Anal. Calcd for C₁₇H₂₁Cl₂N₅Ni: C, 42.40; H, 4.55; N,

13.73. Found C, 42.40; H, 5.65; N, 14.13. µ_eff= 3.79 BM.

Single crystal X-ray diffraction studies for complexes 4a

,

6a, 7,

(2,6-bis(pyrazolylmethyl)pyridine)FeCl₂, compound 6: and

8 were carried out with a Bruker Apex II Duo equipped

Complex

6

was synthesized according to the procedure with an Oxford Instruments Cryojet operating at 100(2) K and

using FeCl₂(0.10 g; 0.50 mmol) and L2 (0.15 g; an Incoatec I S Mo micro source operating at 30 W power.

described for

1

ꢁ

0.50 mmol). The reaction between the metal and the ligand The data were collected with Mo Kα radiation (λ = 0.71073 Å)

afforded a yellow solution. The pale-yellow solution was at a crystal-to-detector distance of 50 mm. The following

filtered to isolate a solid product, which was dried and conditions were used for the data collection: omega and phi

weighed. Yield = 0.19 g (90%). (ESI-MS), m/z (%) 370 (M⁺– 2Cl scans with exposures taken at 30 W X-ray power and 0.50º

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Journal Name

frame widths using APEX2.⁵²The data were reduced using Unless otherwise noted, DFT simulations were effected with

outlier rejection, scan speed scaling, as well as standard Gaussian 09 Revision C.01 (WIN64)⁵⁷at the HSEH1PBE/6-

58

Lorentz and polarization correction factors. A semi-empirical 311G(d,p) level of theory.^46,

A spin-unrestricted wave

absorption correction was applied to the data in each case function was employed for all paramagnetic species

(SADABS⁵³). Structures were solved with either SHELXS-97⁵⁴(UHSEH1PBE model). Simulations were carried out both in

(direct methods) or charge-flipping (SUPERFLIP⁵⁵) and refined vacuo and in a 2-propanol solvent continuum; the latter

with SHELXL-97⁵⁴within Olex2.⁵⁶All non-hydrogen atoms were calculations employed the SCRF-PCM method.⁵⁹In all cases,

located in the difference density map and refined frequency calculations were used to verify the nature of

anisotropically before including hydrogen atoms as idealized stationary states located on the potential energy surface;

contributors in the least squares process. Their positions were structures located and discussed in this work were true

calculated using a standard riding model with C-H_aromaticminima (as indicated by the absence of negative frequency

distances of 0.93 Å (U_iso= 1.2 U_eq), C-H_methylenedistances of 0.97 eigenvalues). Population analysis of the final wave function for

Å (U_iso= 1.2 U_eq), and C-H_methyldistances of 0.96 Å (U_iso= 1.5 each geometry-optimized structure was effected with NBO

U_eq); methyl group orientations were fit to the experimental 3.0⁴⁹running in Gaussian 09. Pre-transition state structures

electron density distribution about the methyl carbon atom.

and all species involved in the catalytic cycles of 8 and 9 were

The crystal of 6a was not twinned, despite possible calculated with Gaussian 09 Revision D.01 (WIN64) initially at

twinning suggested by analysis of the structure factors. the HSEH1PBE/SDD⁶⁰level of theory in 2-propanol (PCM) and

However, the two [FeCl₄]^–counter-ions were each disordered then at the HSEH1PBE/6-311G(d,p) level of theory for

over two sites and were fit to a two-site disorder model in publication. (The two methods gave similar results, with the

which the site occupancies were allowed to freely refine. For exception of structure 9c, which was calculated to be more

the counter-ion containing Fe2, the major component of the tightly interacting with the larger basis set.) The structure of

disordered anion had a site occupancy factor of 0.83(2); that the

for the anion containing Fe3 was 0.850(18).

Frisch empirical dispersion model from the APFD functional⁴⁵

Crystal data for 4a H₂O: C₃₄H₄₄N₁₀ONiBr₂(M = 827.32 g to augment the HSEH1PBE functional.

mol^–1): monoclinic, space group C2/c (no. 15), a = 15.2365(8)

Ligand steric effects in the DFT-calculated structures were

Å, b = 12.1008(6) Å, c = 38.373(2) Å, β = 90.113(2)°, V = quantified with Guzei’s freely available SOLID-G program.³⁸In

7074.9(6) Å³, Z = 8, T = 100.15 K, μ(MoKα) = 2.851 mm^–1, D_calc

this program, the equivalent cone angle, ECA or

1.553 g cm^–3, 61086 reflections measured (4.246° ≤ 2Θ ≤ corresponds to the solid angle of the ligand. (Note that

π-adduct 9c (Fig. 7) was calculated using the Petersson-

⋅

=

ω,

ω

for

75.582°), 16101 unique (R_int= 0.0197, R_σ= 0.0260) which were the ligand is not the same as Tolman’s cone angle for

used in all calculations. The final R₁was 0.0304 (I > 2σ(I)) and phosphine ligands.⁶¹)

wR₂was 0.0683 (all data).

Transfer Hydrogenation Reactions

Crystal data for 6a⋅2CH₂Cl₂: C₃₆H₄₆N₁₀Cl₁₂Fe₃(M = 1211.78

g mol^–1): triclinic, space group P-1 (no. 2), a = 13.7303(12) Å, b Catalytic transfer hydrogenations of ketones were performed

= 14.9885(13) Å, c = 15.6987(13) Å, α = 89.620(4)°, β = in two-necked round bottom flasks under nitrogen. In a typical

64.621(4)°, γ = 63.481(4)°, V = 2542.7(4) Å³, Z = 2, T = 100.0 K, experiment, 1–9 (0.02 mmol, 1%), 0.4 M KOH in 2-propanol (5

μ(MoKα) = 1.514 mm^–1, D_calc= 1.583 g cm^–3, 36960 reflections mL) and acetophenone (0.23 mL, 2.0 mmol) were added and

measured (2.95° ≤ 2Θ ≤ 52.468°), 9820 unique (R_int= 0.0284, refluxed at 82 °C under a static N₂atmosphere. Samples were

R_σ= 0.0250) which were used in all calculations. The final R₁taken at regular intervals and the course of the reaction was

was 0.0966 (I > 2σ(I)) and wR₂was 0.2466 (all data).

Crystal data for 7

monitored by ¹H NMR spectroscopy. The percentage

⋅

4H₂O: C₁₅H₂₅N₅O₄NiBr₂(M = 557.93 g conversions were calculated using the ¹H NMR spectra by

mol^–1): monoclinic, space group Cc (no. 9), a = 10.4314(8) Å, b comparing the intensities of the methyl signal of

= 11.0104(8) Å, c = 18.8608(13) Å, β = 103.777(2)°, V = acetophenone (s, δ 2.59 ppm) and the methyl signal of (R,S)-1-

2103.9(3) Å³, Z = 4, T = 100.0 K, μ(MoKα) = 4.750 mm^–1, D_calc

=

phenylethanol (d, δ 1.49 ppm) in the crude products. The

1.761 g mm^–3, 12399 reflections measured (4.448 ≤ 2Θ ≤ solvent was removed under vacuum to obtain a brown

60.958), 4201 unique (R_int= 0.0210, R_σ= 0.0287) which were product, which was isolated, recrystallized and characterized

used in all calculations. The final R₁was 0.0150 (I > 2σ(I)) and by ¹H NMR spectroscopy.

wR₂was 0.0368 (all data).

Crystal data for 8

Kinetic data were analysed with 64-bit OriginPro 9.1.⁶²

A

⋅

2H₂O: C₁₅H₂₁N₅Cl₂NiO₂(M =432.98 g mol^–standard nonlinear first order monomolecular exponential

¹): monoclinic, space group P2₁/n (no. 14), a = 8.2878(5) Å, b = growth model, ꢇ = ꢈ(1 − ꢅ^{(ꢉꢊ(ꢋꢉꢋ )}

),

where a = amplitude,

40

ꢌ

21.2490(13) Å, c = 10.6189(6) Å, β = 107.728(2)°, V = x = time, x_c= centre, and k = rate, was used to fit the kinetic

1781.26(18) Å³, Z = 4, T = 100.15 K, μ(MoKα) = 1.409 mm^–1, data for

and . Because of the significant induction

Dcalc = 1.615 g mm^–3, 21261 reflections measured (5.82 ≤ 2Θ ≤ phases evident for

and , the kinetic data for these two

1–

4

7–9

5

6

61.072), 5429 unique (R_int= 0.0197, R_sigma= 0.0163) which systems were analysed using the Gompertz model, ꢇ =

were used in all calculations. The final R₁was 0.0212 (I > 2σ(I)) ꢈꢅ^{ꢉꢍꢎꢏ(ꢉꢊ(ꢋꢉꢋ )}, where the parameters are as described

ꢌ

and wR₂was 0.0556 (all data).

above.⁴⁰This model is often applied to tumour or microbial

cell growth as a function of time because it includes the effects

of growth inhibition.^63-65The Gompertz model is thus ideal for

DFT simulations and structural analysis

12 | J. Name., 2012, 00, 1-3

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24 T. Steiner, Angew. Chem. Int. Ed., 2002, 41, 48-76.

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,

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Acknowledgements

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National Research Foundation of South Africa (NRF) for

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Initiative of the Department of Science and Technology and

National Research Foundation of South Africa (Grant No

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FIGURES

Manuscript ID: RA-ART-05-2016-012788.R1

TITLE: Structural, Kinetic, and DFT Studies of the Transfer Hydrogenation of Ketones Mediated by (Pyrazole)pyridine

Iron(II) and Nickel(II) Complexes

Authors: Makhosazane N. Magubane,^aGeorge S. Nyamato,^aStephen O. Ojwach,*^,aand Orde Q. Munro*^,b

Note: Figures and schemes are given in the order that they should appear in the final manuscript. This document

contains half of the figures for the manuscript at a resolution of 600 dpi.

Scheme 1 Catalytic transfer hydrogenation (TH) of ketones using 2-propanol.

Scheme 2 Iron(II) and nickel(II) complexes of (pyrazole)pyridine-based ligands L1–L3 used as precatalysts

for the TH of ketones.

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Fig. 1 (a) Molecular structure of 7⋅4H₂O drawn with 60% probability ellipsoids, selected atom labels,

arbitrary H atom radii, and hydrogen bonds (dashed lines). Bond lengths (Å): Ni1–N1, 2.083(2); Ni1–N5,

2.078(2); Ni1–N3, 2.005(2); Ni1–O1, 2.041(2); Ni1–O2, 2.113(2); Ni1–O3, 2.079(2). Bond angles (°):N5–Ni1–

N3, 77.95(7); N3–Ni1–N1, 77.58(7); N1–Ni1–O1, 103.18(7); N5–Ni1–O1, 101.26(7); N5–Ni1–O3, 88.40(7);

O3–Ni1–N3, 89.31(7); O3–Ni1–N1, 91.41(7); O3–Ni1–O1, 87.34(7); O1–Ni1–O2, 89.22(6); N3–Ni1–O2,

94.13(7); O2–Ni1–N1, 88.82(7); N5–Ni1–O2, 92.83(7). (b) Molecular structure of 8⋅2H₂O drawn with 50%

probability ellipsoids, selected atom labels, arbitrary H atom radii, and hydrogen bonds (dashed lines).

Bond lengths (Å): Ni1–N1, 2.0567(8); Ni1–N5, 2.0995(9); Ni1–N3, 2.0162(9); Ni1–O1, 2.0553(9); Ni1–O2,

2.130(1); Ni1–Cl1, 2.4013(4). Bond angles (°):O1–Ni1–N1, 103.78(4); N1–Ni1–N3, 77.61(4); N3–Ni1–N5,

77.02(3); N5–Ni1–O1, 101.32(3); N3–Ni1–Cl1, 94.31(3); N1–Ni1–Cl1, 89.80(3); O1–Ni1–O2, 87.87(3); O2–

Ni1–N5, 87.97(3); N5–Ni1–O2, 87.97(3); O2–Ni1–N3, 88.04(3); N1–Ni1–O2, 88.46(3). (c) Illustration of the

one-dimensional H-bonded chain formed in 8⋅2H₂O. Selected symmetry-unique H-bond distances are

indicated along with relevant symmetry codes.

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Fig. 2 Time dependence of the catalytic transfer hydrogenation (TH) of acetophenone by complexes 1–9 in

KOH/2-propanol at 82 °C. Graphs (a)–(c) show first-order exponential fits of the kinetics with the data

grouped according to metal ion type, Ni(II) or Fe(II), and halide ion leaving groups (Br^–or Cl^–). The ligand L

is either didentate L1 (compounds 1–3) or one of the tridentate ligands L2 (compounds 4–6) or L3

(compounds 7–9). The notably long induction phases for 5 and 6 necessitated use of the Gompertz model

to fit the rate data. A steep initial rate coupled with incomplete conversion reflects an active catalyst that is

susceptible to relatively rapid deactivation under the chosen reaction conditions.

Fig. 3 DFT-calculated geometries [HSEH1PBE/6-311g(d,p) level of theory; 2-propanol solvent continuum]

of the active Ni(II) precatalysts 2 (C₁symmetry) and 5 (C₂symmetry) illustrating the different degrees of

steric hindrance about the metal centre. The upper views show the optimized geometries as bond cylinder

models with selected atom labels, bond distances (Å) and bond angles (°); the lower views depict the

structures rendered with van der Waals radii for the atoms. The % conversion data refer to the TH reaction

of acetophenone after 48 h.

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Fig. 4 Top: representative DFT-calculated structures of 1 and 4 in a 2-propanol solvent continuum (bond

distances, Å; bond angles, °). Bottom: Analysis of the initial rate data for the TH of acetophenone by 1–6 as

a function of the DFT-calculated M–X bond distance and the equivalent cone angle, ω, of the chelating

ligand for the ligand systems L1 (group A) and L2 (group B). The plane represents a least-squares fit to the

equation Z = z0 + ax + bx; % Conv. = –225(100) + 196(55)x – 1.2(3)y, where x = ECA and y = M–X distance

(R²= 0.800). The bivariate correlation reveals that the initial rate of transfer hydrogenation increases with

increasing M–X bond distance and decreasing steric restriction of the metal centre by the chelating ligand.

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Fig. 5 (a) Illustration of the degree of steric shielding (%) of the metal ion surface, G^T_Mʚcomplex), for 3, 9,

and 4. The blue shadow represents screening by the chelating ligand; the green and yellow shadows reflect

shielding by the upper and lower halide ions, respectively. (b) Graph of the rate constant for TH of

acetophenone vs. G_M^Tʚcomplex) and the M–N_pybond distance. The plane is the least-squares fit of the data

marked with red spheres; data with grey spheres are outliers. The equation of the plane, Z = z0 + ax + bx,

is: % Conv. = –2.1(5)E–4 + 1.2(2)E–4x – 1.9(1.9)E–7y, where x = M–N_pybond distance and y = G^T_Mʚcomplex)

(R²= 0.925). (c) Cross-section through the surface in Part (b) showing the linear increase in rate constant

with increasing M–N_pybond length. The linear equations are: k_obs= -2.5(3)E-4 + 1.3(2)E-4(M-N_py), R²=

0.924 (red spheres), and k_obs= -5(1)E-4 + 2.6(6)E-4(M-N_py), R²= 0.889 (grey spheres).

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Scheme 3 Typical transition states potentially of relevance to the TH mechanism of acetophenone by 8 or

9.

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Fig. 6 Postulated catalytic cycle for the TH of acetophenone by 8 or 9 in 2-propanol. Each DFT-calculated

structure (see Figure S12) in the cycle was a stable minimum at the HSEH1PBE/6-311G(d,p) level of theory

in a 2-propanol solvent continuum. The cycle is illustrated using the high-spin Fe²⁺complexes 9–9d as the

species of interest. The structure of 9c was modelled by including an established empirical dispersion

scheme in the functional.

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Fig. 7 (a) DFT-calculated structure (dispersion effects included) of 9c, the pre-transition state π-adduct

formed between the postulated hydride intermediate of 9 and acetophenone during the TH catalytic cycle.

The geometric relationship between the pyridine ring plane of the catalyst and the aryl ring of the

substrate is shown. (b) Selected views of the π-adduct with atoms rendered at their van der Waals radii. In

both parts, key bond distances and contacts are given in Å and selected atoms are labelled.

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Fig. 8 Graph of the Gibbs energy as a function of the reaction coordinate for the TH of acetophenone by 9

in 2-propanol. Thermochemical analysis including zero point vibrational energy corrections to the total

energy for all species was performed at 298.15 K (P = 1.0 atm) with geometry-optimized minima at the

HSEH1PBE/6-311G(d,p) level of theory. Steps corresponding to the full catalytic cycle in Figure 6 are

indicated; data used to construct the graph are given in Tables S5 and S6 (ESI).

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Graphical Abstract Image

39x22mm (300 x 300 DPI)

Article Doi

Structural, kinetic, and DFT studies of the transfer hydrogenation of ketones mediated by (pyrazole)pyridine iron(II) and nickel(II) complexes

DOI: 10.1039/c6ra12788f

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