P-Stereogenic PN(H)P Iron(II) Catalysts for the Asymmetric Hydrogenation of Ketones: The Importance of Non-Covalent Interactions in Rational Ligand Design by Computation

Article abstract of DOI:10.1002/adsc.201800433

The P-stereogenic PN(H)P pincer ligands (R(Me)PCH₂CH₂)₂NH (R=Cy, (S,S)-1 a; R=^tBu, (S,S)-1 b; R=Ph, (R,R)-1 c) and their iron(II) derivatives [FeBr₂(CO)(PN(H)P)] (2 a–2 c) and [FeHBr(CO)(PN(H)P)] (3 a–3 c) were developed by DFT-driven ligand design. In a preliminary study, the P(Cy)Me-based pincer (S,S)-1 a and its Fe(II) complex 3 a were prepared, tested in the asymmetric transfer hydrogenation of acetophenone, and studied by Density Functional Theory (DFT). Based on the good agreement between the experimental and calculated enantioselectivity, rational design of the pincer by DFT was attempted, which suggested high enantioselectivity for the tert-butyl and phenyl analogues 3 b and 3 c. Therefore, a new synthetic protocol was developed for (R,R)-1 c using Buono's (S)-(1-(OH)Et)P(Me)Ph?BH₃ as P-stereogenic synthon. Against the DFT prediction, 3 c gave 1-phenylethanol with 44% ee, which was reproduced by increasing the level of theory from DFT to post-Hartree-Fock M?ller-Plesset (MP2). This result can be explained by the overestimation of the enantiodeterming CH/π interaction by DFT, which reiterates the need for accurate energies in the assessment of small energy differences such as in asymmetric catalysis. (Figure presented.).

Full text of DOI:10.1002/adsc.201800433

Title: P-Stereogenic PN(H)P Iron(II) Catalysts for the Asymmetric
Hydrogenation of Ketones: The Importance of Non-Covalent
Interactions in Rational Ligand Design by Computation
Authors: Raffael Huber, Alessandro Passera, Erik Gubler, and Antonio
Mezzetti
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
P-Stereogenic PN(H)P Iron(II) Catalysts for the Asymmetric
Hydrogenation of Ketones: The Importance of Non-Covalent
Interactions in Rational Ligand Design by Computation
Raffael Huber,a Alessandro Passera,a Erik Gubler,a and Antonio Mezzetti a*
a
Dept. of Chemistry and Applied Biosciences, ETH Zürich, Switzerland
E-mail: mezzetti@inorg.chem.ethz.ch
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The P-stereogenic PN(H)P pincer ligands Therefore, a new synthetic protocol was developed for
t
(R(Me)PCH2CH2)2NH (R = Cy, (S,S)-1a; R = Bu, (S,S)-1b; (R,R)-1c using Buono's (S)-(1-(OH)Et)P(Me)Ph·BH3 as P-
R = Ph, (R,R)-1c) and their iron(II) derivatives [FeBr2(CO)- stereogenic synthon. Against the DFT prediction, 3c gave
(PN(H)P)] (2a-2c) and [FeHBr(CO)(PN(H)P)] (3a-3c) were 1-phenylethanol with 44% ee, which was reproduced by
developed by DFT-driven ligand design. In a preliminary increasing the level of theory from DFT to post-Hartree-
study, the P(Cy)Me-based pincer (S,S)-1a and its Fe(II) Fock Møller-Plesset (MP2). This result can be explained by
complex 3a were prepared, tested in the asymmetric transfer the overestimation of the enantiodeterming CH/
hydrogenation of acetophenone, and studied by Density interaction by DFT, which reiterates the need for accurate
Functional Theory (DFT). Based on the good agreement energies in the assessment of small energy differences such
between the experimental and calculated enantioselectivity, as in asymmetric catalysis.
rational design of the pincer by DFT was attempted, which
suggested high enantioselectivity for the tert-butyl and
phenyl analogues 3b and 3c.
Keywords: Asymmetric catalysis; Computational
chemistry; Iron; N,P ligands; Pi interactions.
reduction of polar double bonds,[17] they have been
applied in the catalytic hydrogenation of ketones,[11]
aldehydes,[11] esters,[12] amides,[13] nitriles,[14] de-
hydrogenation of alcohols,[15] and imine formation.[16]
Introduction
The recent, tumultuous progress in iron catalysis[1]
has been significantly driven by the development of
hybrid multidentate ligands with N and P donors, in
particular in reduction reactions.[2] Mainly responsi-
ble for this success is the combination of iron(II) and
phosphines, which stabilizes otherwise labile iron
hydrides[3] and gives access to chiral catalysts that
have been mostly used in the hydrogenation of polar
double bonds, whose products are highly interesting
to industry.[4] Thus, the iron-catalyzed asymmetric
transfer hydrogenation (ATH) of ketones has experi-
enced great progress thanks to the development of ad
hoc chiral multidentate ligands with N2P2 or N4P2
donor sets.[5-7] As Fe(II) complexes containing tetra-
dentate ligands activate H2 slowly,[8] enantioselective
iron(II) catalysts for the asymmetric direct hydro-
genation (AH) of ketones have been developing at a
slower pace, and their substrate scope is still limited.
In contrast, achiral iron(II) catalysts with pincer[9]
ligands have found extensive application in the direct
hydrogenation of polar double bonds. Substituted
pyridines[10,11] and secondary amine[12-16] have been
used as backbones for such pincer ligands, which we
dub here PNP and PH(H)P, respectively (Figure 1).
As PN(H)P ligands such as 1d feature an N–H group
that enables the bifunctional mechanism in the
PiPr2
PiPr2
H
N
N
PNP
PN(H)P (1d)
PiPr2
PiPr2
Figure 1. Pincer ligands with an NP2 donor set.
Chiral pincer ligands are still rare and are limited
to C-based stereogenic elements.[18] We have recently
reported P-stereogenic PNP pincers based on 2,6-
disubstituted pyridines and have tested their iron(II)
complexes in the AH of ketones.[19] As these studies
suggested that this backbone is too flexible to achieve
high enantiodiscrimination, we set off to prepare
chiral, P-stereogenic analogues of the achiral PN(H)P
pincer ligands in Figure 1. The secondary amine
moiety in these ligands increases the conformational
rigidity of the chelate rings and supplies the acidic
proton for the bifunctional mechanism for the
hydrogenation of polar double bonds.[17] As dialkyl-
phosphine donors have been used with success in 1d
and in PNP pincer ligands in combination with
1
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
iron(II),[11-16] we used the chiral dialkylphosphine
boranes PH(Cy)Me·BH3 (4a)[20] and PH(tBu)Me·BH3
(4b)[21] as P-stereogenic building blocks, which are
readily prepared as single enantiomers.
The experimental and computational details of these
studies are exposed below in detail.
Ligand Synthesis. We have recently shown[19] that
the enantiomerically pure secondary phosphine
borane PH(Cy)Me (4a)[20] easily yields chiral
analogues of PNP pincer ligands (Figure 1). We
extend here the use of this P-stereogenic synthon to
PN(H)P ligands with bis(2-haloethyl)-N-trimethylsil-
ylamine[27] as electrophilic building block. Deproto-
nation of the enantiopure alkylmethylphosphine
boranes P(Cy)Me·BH3 (4a) and HP(tBu)Me·BH3 (4b),
followed by alkylation with bis(2-chloroethyl)-N-tri-
methylsilylamine, gave the protected PN(H)P ligands
(S,S)-(Cy(Me)P(BH3)CH2CH2)2NH (5a) and (S,S)-
(tBu(Me)P(BH3)CH2CH2)2NH (5b) with high stereo-
retention at phosphorus, as previously observed in
other alkylation reactions.[20] The amine is depro-
tected upon aqueous workup (Scheme 1). The above
approach is ideally suited for dialkylphosphine
boranes, whose corresponding lithium phosphide
boranes are configurationally stable during the course
of the reaction.[28] The protected PN(H)P ligand 5a
was obtained with 400:1 dr and >99% ee after a
single crystallization from hot ethyl acetate (see the
Supporting Information for details).
Me
tBu
Ph
Me
Me
Cy
P
P
P
(S)
(R)
(S)
1b
1c
1a
H
N
H
N
H
N
(S)
(R)
(S)
P
P
P
Me
Ph
Me
tBu
1b
1c
1a
Me
Cy
Figure 2. Newly prepared chiral PN(H)P pincer ligands.
Preliminary results with pincer ligand 1a (Figure
2) suggested that CH/π interactions between the
PN(H)P ligand and acetophenone played a pivotal
role in enantioselection. Therefore, we used a
combined experimental and computational approach
to optimize the ligand design, which indicated meth-
ylphenylphosphine as the P-stereogenic unit of choice.
The use of DFT calculations for rational ligand
design in asymmetric reactions have been mostly
used for organocatalysis,[22] but are less documented
with transition metals.[23] In particular, noncovalent
interactions[24] have been found a posteriori to play
an important role in enantio- and diastereoselective[25]
catalytic reactions, but their systematic exploitation is
still in its infancy, in particular with transition metal
catalysts.[26] In the present paper, we illustrate
chances and pitfalls of such an approach by the
example of the first P-stereogenic analogues of 1d.
BH3
P
1) nBuLi, THF, 0 °C
N
(S)
P
(S)
P
Me
H
R
Me
Me
R
R
H
BH3
H3B
2)
N
R = Cy, 4a; tBu, 4b
R = Cy, 5a; tBu, 5b
Cl
Cl
SiMe3
Scheme 1. Synthesis of the chiral PN(H)P pincer boranes
(S,S)-5a and (S,S)-5b.
Results and Discussion
In contrast to their dialkyl analogues, arylalkyl-
phosphide boranes epimerize rapidly even at low
temperature[20] and are hence not suitable to prepare
enantiomerically pure P-stereogenic ligands. Further-
more, the resulting dialkylarylphosphines epimerize
more easily than trialkyl-substituted ones due to the
stabilization of the planar transition state by the
aromatic ring,[28] which may explain why such
ligands have been scarcely studied. To prepare the
arylalkylphosphine pincer 1c, we exploited Buono's
strategy based on masked secondary phosphine
boranes, which are a configurationally stable source
of sodium phosphide borane (Scheme 2) and give
alkylation products stereospecifically.[29] To this goal,
we prepared (SP)-(1-hydroxyethyl)methylphenylphos-
phine borane (6) from the previously reported (RP)-
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl phenyl-
phosphinate.[7b]
Strategy and Development. For the sake of clarity,
we summarize briefly the chronological development
of the project. We first prepared the P(Cy)Me- and
P(tBu)Me- based pincer ligands (S,S)-1a and (S,S)-1b
(Figure 2) and studied their Fe(II) coordination
chemistry. Ligand 1b forms unstable dibromocarbon-
yl and bromocarbonylhydride complexes that are
inactive in the AH of acetophenone. The P(Cy)Me-
analogue 1a forms a dibromocarbonyl complex (2a)
and, after reaction with NaBHEt3, a hydride complex
that hydrogenates acetophenone with enantioselectiv-
ity not exceeding 22% ee. DFT calculations indicated
that the R and S enantiodetermining transition states
are close in energy, possibly because of similar CH/
interactions. Changing cyclohexyl to phenyl in silico
selectively eliminated one of these interactions and
resulted in larger energy differences.
Therefore, we developed a protocol to prepare the
P(Ph)Me-based pincer ligand 1c and tested its iron(II)
complexes in the AH of acetophenone. Against DFT
prediction, the 1c-based catalyst gave only 44% ee.
Raising the level of theory to the MP2 method, which
is considerably more demanding than hybrid DFT,
eventually gave a satisfactory match between the
experimental and the calculated enantioselectivity.
Scheme 2. Preparation of borane-protected phenylmethyl-
phosphine pincer (R,R)-5c.
2
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
With 6 as pronucleophile, the reactivity of the
membered chelate rings adopt an envelope
conformation with the carbon atoms next to nitrogen
(C(2)/C(3)) in the endo position.
electrophile had to be carefully adjusted to avoid O-
alkylation in Williamson-type reaction.[30] However,
if the reaction is too slow, the intermediate sodium
phosphide borane may epimerize, hence decreasing
the stereospecificity of the reaction.
The elongated shape of the ellipsoids in the pincer
backbone is indicative of the presence of a minor
isomeric form where the NH proton points down,
leading to a ring flip in the metallacycles. The Fe–
P(1) and Fe–P(2) bond lengths of 2a (2.262(3) and
2.261(3) Å, respectively) are similar to those of
[FeBr2(CO)(1e)] (2e) with the PEt2-derived pincer
(Et2PCH2CH2)2NH (1e) (2.2650(8) and 2.2657(8)
Å).[13] In contrast, the PiPr2-containing 2d exhibits
significantly longer Fe–P(1) and Fe–P(2) distances
(2.3054(8) and 2.3037(8) Å), which confirms the
steric influence of bulky phosphine groups on the Fe–
P bond length.
Bis(2-chloroethyl)-N-trimethylsilylamine failed to
react with deprotonated 6, whereas bis(2-iodoethyl)-
N-trimethylsilylamine gave 1c as a single product,
with no O-alkylation observed. The protected pincer
(R,R)-(Ph(Me)P(BH3)CH2CH2)2NH (5c) was purified
by crystallization of its ammonium chloride from hot
ethanol until the specific rotation was constant, which
was typically the case after a single crystallization.
The borane-protected pincer ligands 5a–5c are
indefinitely stable upon storage in air at room
temperature and were deboronated with HBF4·OEt2
in dichloromethane[31] before complexation. After
workup, the resulting pincer ligands 1a–1c were
reacted in THF with [FeBr2(PPh3)2], which was used
instead of FeBr2 to exclude Fe(III) impurities in the
resulting complexes (Scheme 3).
Figure 3. ORTEP drawing of 2a (ellipsoids at 30% proba-
bility). Selected bond lengths (Å) and angles (°): Fe–C(9),
1.73(1); Fe–P(1), 2.262(3); Fe–P(2), 2.259(3); Fe–N(1),
2.091(7); Fe–Br(1), 2.4646(15); Fe–Br(2), 2.4712(15);
P(1)–Fe–P(2), 168.13(11); Br(1)–Fe–P(1), 89.80(7);
Br(1)–Fe–P(2), 89.93(7).
Scheme 3. Synthesis of dibromocarbonyl 2a from (S,S)-5a.
[FeBr2(CO)(1a)]
(2a). The addition of
[FeBr2(CO)(1b)] (2b). The reaction of the tert-
butylmethylphosphine PN(H)P pincer 1b with
[FeBr2(PPh3)2] in THF under CO atmosphere at room
temperature gave a brown, unidentified precipitate
[FeBr2(PPh3)2] to the deprotected ligand 1a in THF
gave a light green solution whose 31P NMR spectrum
shows a broad PPh3 peak. This hints at an equilibrium
between the five-coordinate, colorless [FeBr2(1a)]
and octahedral, green [FeBr2(PPh3)(1a)]. Indeed,
when FeBr2 was used instead of[FeBr2(PPh3)2], a
colorless solution was obtained. Upon replacing the
argon atmosphere with CO (1.1 bar), the solution
color changed to blue, the color expected for the
mer,trans-[FeBr2(CO)(1a)] (2a) (Scheme 3), which
was precipitated with pentane, filtered off, and
washed with pentane to remove PPh3.
1
that shows paramagnetically broadened H and 31P
NMR spectra. In CH2Cl2, a red-purple solution was
formed, from which a purple solid precipitated upon
addition of hexane (Scheme 4).
The two inequivalent P atoms in the C1 symmetric
complex 2a give a tight 31P NMR AB system at δ
57.6 and 58.0 (2JP,P' = 163.6 Hz) as compared to the
singlet at δ 67.8 observed for the achiral analogue
[FeBr2(CO)(1d)] (2d).[32] In the IR spectrum, the νCO
frequency at 1925 cm–1 indicates that 2a is more
electron rich than 2d (νCO = 1951 cm–1).
X-Ray quality crystals of 2a were grown from
THF / pentane (Figure 3). Complex 2a has a distorted
octahedral geometry with meridional pincer ligand
and mutually trans bromides. The P(1)–Fe–P(2)
angle of 168.28(12)° reveals the strain imposed by
the two-fold chelation of the pincer ligand. The five-
Scheme 4. Synthesis of 2b from (S,S)-5b.
The 31P NMR spectrum of the purple precipitate
shows an AB system at δ 57.8 and 56.3, whose JP,P’
of 78.1 Hz indicates facial coordination of the pincer
3
2
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
ligand. The similar chemical shift of the phosphines
is in agreement with both being trans to bromide.
Therefore, we formulate this complex as fac,cis-
[FeBr2(CO)(1b)] (2b). The preference for the facial
pincer coordination is possibly due to the steric clash
that would occur between the bulky tert-butyl group
and the bromido ligand in the meridional isomer.
Accordingly, in mer-2a (Figure 3), the nonbonded
distance between C(8) and Br(2) (3.48 Å) is shorter
than the sum of van der Waals radii (3.63 Å).[33]
Complex 2b is not stable and slowly decomposes
both in the solid state and in solution, as indicated by
the formation of a brown, unidentified precipitate in
solution and by a gradual color change from purple to
white in the solid state. This possibly originates from
CO dissociation induced by the steric repulsion be-
tween Br and the tBu group. Accordingly, [FeBr2(1f)]
(2f), which contains (tBu2PCH2CH2)2NH) (1f), does
not react with CO.[13]
3b requires CH2Cl2 as solvent, as 2b quickly
decomposes in THF. The reactions are instantaneous
upon mixing. After filtering off NaBr, the solvent
was evaporated to dryness, and the remaining brown
residues were washed with pentane to remove
residual BEt3.
The resulting hydride species are extremely air-
and moisture-sensitive, and all attempts to further
purify them, e.g. by crystallization, failed. The
P(Cy)Me derivative 3a is the most stable of the series,
whereas 3b and 3c, which contain pincer ligands 1b
31
and 1c, respectively, decompose in solution. The P
and 13C NMR spectra of these species are broad,
either due to paramagnetic impurities or because of
the dynamic behavior typically exhibited by iron
hydrides.[18a,c] However, their formulation as hydride
1
complexes was confirmed by H NMR spectroscopy
(see the Supporting Information).
1
Hydride 3a features a H NMR triplet at δ –22.9
[FeBr2(CO)(1c)] (2c). The methylphenylphos-
phine pincer ligand 1c gave [FeBr2(CO)(1c)] (2c) in
high yield when the reaction was run at –50 °C. The
complex was precipitated at that temperature with
pentane. The 31P NMR spectrum of the blue solid
(2JP,H = 52.4 Hz), in the region expected for a hydride
ligand trans to bromide.[11a] The reaction of the tert-
butyl analogue 2b with NaBHEt3 (1 equiv) gives a
mixture of hydrides with 1H NMR triplets at at δ –8.8
(2JP,H = 47.7 Hz, major, 65%) and δ –6.9 (2JP,H = 50.0
Hz, 35%), which suggest a trans arrangement of the
shows a major AB system at δ 59.3 and 56.2 (2JP,P’
=
183.0 Hz) for mer,trans-2c (Scheme 5). An additional, hydride and CO ligands.[11d] The same geometry is
low-intensity AB system (ca. 4% of total intensity) at
δ 43.2 and 35.2 (2JP,P’ = 214.7 Hz) is assigned to
mer,cis-2c based on chemical shifts observed for
[FeBr2(CO)(1g)] (2g) (1g is (Ph2PCH2CH2)2NH).[13]
plausible for P(Me)Ph derivative 2c, which gives a
mixture of three hydride species (δ –4.6 to –5.5, –5.5
to –6.3, and –11.4 to –12.7). Based on the stoichio-
metry of the reaction, we tentatively assign all these
species as monohydrides. However, this is not con-
clusive, as they are stable in solution only briefly and
start decomposing just after dissolution in C6D6 or
CD2Cl2 under argon, which rules out unambiguous
characterization. In view of their instability, all
hydride species were prepared from the dibromo-
carbonyl complexes 2a-2c and NaBHEt3, quickly
isolated by evaporating the solvent, dried at high
vacuum, and used as catalysts in the AH of aceto-
phenone within one day and without further charac-
terization.
Performing each catalytic run two or three times
with this protocol gave reproducible results, which
suggests that catalyst decomposition is negligible
under catalysis conditions, that is, in the presence of
base and H2. We assume that, under such conditions,
dihydrides 9 are formed, which are the proposed
catalytically active species. Accordingly, complexes
of the type [FeHCl(CO)(PN(H)P)] are dehydrochlo-
rinated by base to the amido derivatives
[FeH(CO)(PNP)], which then add H2 to give the
dihydride species [FeH2(CO)(PN(H)P)].[11c]
Catalysts 3a–3c: Experiment and DFT Calcula-
tions. In a series of preliminary experiments, the
P(Cy)Me-based bromocarbonylhydride 3a was tested
in the asymmetric hydrogenation of acetophenone (7)
with potassium tert-butoxide as base (5 mol%, as
used for the achiral analogue [FeBr2(CO)(1d)]
(3d).[15b] The optimization shows that precatalyst 3a
(1 mol%, room temperature) converts 7 quantitatively
in THF under 50 bar H2 after 16 h of reaction time to
give (S)-1-phenylethanol (8) with 22% ee. Toluene
Scheme 5. Synthesis of dibromocarbonyl 2c from (R,R)-5c.
Upon standing, the dark blue solid slowly bleaches
to a white solid, whereas a brown, unidentified pre-
cipitate separates from the solutions of 2c. Similarly
to 2b, this is most likely due to CO loss. The same
behavior has been observed for the PPh2 analogue
[FeBr2(CO)(1f)] (2f) (1f is (Ph2PCH2CH2)2NH).[13]
Due to their limited stability both in solution and in
the solid state, 2b and 2c were converted to the
corresponding hydrides just after preparation.
[FeHBr(CO)(PN(H)P)] (3a-3c). Following the
usual procedure,[15a] the dibromocarbonyl complexes
2a-2c were treated with NaBHEt3 (1 equiv) to convert
them to the corresponding bromocarbonylhydride
derivatives, which we tentatively formulate as
[FeHBr(CO)(1)] (3). Hydrides of type 3 are
commonly used as precatalysts for the direct
hydrogenation of acetophenone.[15b] Either THF or
CH2Cl2 solutions can be used for 3a and 3c, whereas
4
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
was the solvent of choice as it gave quantitative
conversion at lower H2 pressure (5.5 bar H2 ceteris
paribus), albeit with marginally lower enantio-
selectivity for (S)-8 (19% ee). Finally, the P(tBu)Me
derivative 3b was not active (see Scheme 6 below).
To rationalize this result, DFT calculations were
performed with the hybrid density functional
B3LYP[34] including Grimme’s D3 empirical correc-
tion for dispersion.[35] The SDD basis set with the
associated Stuttgart-Dresden pseudopotential was
used for Fe,[36] and Dunning’s basis set with triple-ζ
for all other atoms.[37] The toluene solvent was
described with the implicit polarizable continuum
model.[38]
As starting point, we chose the mechanism calcu-
lated for the achiral ligand PPh2(CH2)2N(H)-
(CH2)2PiPr2 (1d), in which the hydride transfer occurs
within the adduct between the trans-dihydride com-
plex and acetophenone.[18d] Analogously, we identi-
fied the weak diastereoisomeric adducts 10aS and
10aR (depending on the acetophenone enantioface
exposed) between trans-[FeH2(CO)(1a)] (9a) and
acetophenone by DFT, and assumed that the
transition state involving hydride transfer within them
is the enantiodetermining step of the catalytic cycle.
The diastereomeric transition states TS10aS and
TS10aR were modeled starting from the previously
reported achiral [FeHBr(CO)(1d)] (3d),[39] which was
modified by introducing the stereogenic P(Cy)Me
fragment taken from the X-ray structure of 3a (Figure
4). In both TSs, a strong hydrogen bond between the
N–H group of the ligand and the carbonyl O atom
(1.76 Å in TS10aS, 1.79 Å in TS10aR) directs the
approach of acetophenone. The hydride ligand syn to
the N–H group faces the carbonyl C atom (C–H =
1.74 Å in TS10aS, 1.73 Å in TS10aR), and the
corresponding Fe–H bond is longer (1.63 Å in
TS10aS and TS10aR) than for the hydride anti to the
N–H group (Fe–H= 1.53 Å in TS10aS and TS10aR).
(B3LYP-GD3/cc-pVTZ/Fe:SDD/IEF-PCM (toluene))
for this system. The correction for dispersion is
essential, as TS10aR resulted 0.8 kcal mol−1 more
stable than TS10aS without Grimme’s D3 empirical
correction.
Beyond the N–H···O=C hydrogen bond, the only
other substantial interaction between the reagent and
the catalyst is the CH/π contact that involves the
phenyl ring of the acetophenone and an H atom on
the C atom of the pincer ligand. Thus, in TS10aS, the
phenyl group of acetophenone has a close contact
(2.45 Å) to the ipso P–C atom of the adjacent P–Cy
group (Figure 4 left). In TS10aR, an analogous
interaction involves a P–Me group (2.39 Å). These
results suggest that the low energy difference
between TS10aS and TS10aR (0.5 kcal mol–1) may
result from the occurrence of a stabilizing CH/π
interaction in both transition states. Hence, we
wondered whether the enantioselectivity may be
increased by eliminating it selectively in one of the
diastereoisomeric transition states.
DFT-based Ligand Design. Therefore, the
P(tBu)Me and P(Ph)Me P-stereogenic units were
studied by DFT at the same level of theory[34-38] used
with pincer 1a. The P(Ph)Me pincer 1c gives the
enantiodeterming transition states TS10cS and
TS10cR, the latter being higher in energy by 1.6 kcal
mol–1 more stable than TS10cR (Figure 5). This free
energy difference between the TSs leading to (S)- and
(R)-1-phenylethanol (8),G°(S/R), corresponds to
88% ee for the S enantiomer.
Figure 5. Transition states TS10cS and TS10cR for the
hydride transfer. Relative Gibbs free energies are in kcal
mol–1. Black dashed lines depict the CH/ interaction.
The structural analysis of TS10cS and TS10cR
reveals that both feature one strong N–H···O=C
hydrogen bond. Additionally, TS10cS shows a CH/π
interaction between the centroid of the phenyl ring of
acetophenone and one H atom of the adjacent P–Me
group (2.45 Å, Figure 5). In the diastereoisomeric
TS10cR, acetophenone approaches 9c with the
opposite enantioface, and hence its phenyl group
interacts with the P–Ph group instead of with the P–
Me group. This disrupts the attractive CH/
interaction and gives a / contact with the adjacent
P–Ph group (Figure 5).
Figure 4. Transition states TS10aS and TS10aR for the
hydride transfer. Relative Gibbs free energies are in kcal
mol–1. Black dashed lines depict the CH/ interaction.
The calculated free energy difference between
TS10aS and TS10aR, G°(S/R), is 0.5 kcal mol–1 in
favor of the S enantiomer, in agreement with the
experimentally observed sense of induction (S) and
G°(S/R) (estimated to be 0.2 kcal mol–1 from the
enantioselectivity of 19% ee observed in toluene).
This good agreement validates the level of theory
Also the P(tBu)Me-based pincer 1b gives a CH/π
interaction in only one of the TSs, TS10bR (Figure
S49), which is favored by 1.5 kcal mol–1,
5
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
corresponding 86% ee (R). These results prompted us
to prepare the P(Me)tBu- and P(Me)Ph-based pincer
ligands 1b and 1c and to test the corresponding Fe(II)
dibromocarbonyl complexes 2b and 2c in the AH of
acetophenone (7) after activation with NaBHEt3.
As described in the above sections, the tert-butyl
analogue 2b is readily available, but its Fe(II)
complexes turned out to be unstable. Therefore, we
decided to take up the synthetic challenge described
above and eventually prepared the P(Ph)Me pincer
ligand 1c and its hydride derivative 3c, which was
tested in the hydrogenation of acetophenone (7).
Hydride 3c was inactive in the hydrogenation of
acetophenone under the conditions optimized for 3a
(5.5 bar of H2, room temperature, but gave (S)-1-
phenylethanol (8) quantitatively and with 44% ee
under 50 bar of H2 (Scheme 6).
Figure 6. Adducts 10cS and 10cR with CH/ interactions
and N–H···O / C–H···O hydrogen bonds as black dashed
lines. Relative Gibbs free energies are in kcal mol–1.
Also the adduct 10cR is stabilized by a CH/π
interaction (2.53 Å), but this involves acetophenone
(7) and the H atom on C(1) of the ligand framework.
In addition, the carbonyl of 7 forms a C–H···O bond
(2.39 Å) to the H atom on C(4) of the ligand. As a
result, 10cR is more stable than 10cS, but these inter-
actions constrain the N(1)–Fe–C–O angle () of 10cR
to 47° (Table 1). Hence, they are rescinded upon
hydride transfer, which requires the N–H···O and Fe–
H···C vectors to align. Accordingly, the N(1)–Fe–C–
O angle is 0° in TS10c (Figure 5). Therefore, the
formation of (S)-alcohol is favored.
Table 1. Selected distances (Å) and N(1)–Fe–C–O
dihedral angle  (°).
Scheme 6. AH of acetophenone (7) catalyzed by 3a-3c.
C–H Fe–H O···H N–H r(CH/ 

2.82 1.56
2.92 1.56
1.68 1.64
1.68 1.65
1.19 1.92
1.19 1.92
1.16 1.96
1.16 1.96
1.10 2.89
1.10 2.96
2.03 1.02
2.39 1.02
1.73 1.03
1.72 1.03
1.50 1.09
1.47 1.10
1.23 1.26
1.24 1.25
0.98 1.93
0.98 1.94
2.68
–
2.45
–
2.41
–
2.43
–
–18
47
4
11
5
1
3
2
–2
17
10cS
10cR
TS10cS
TS10cR
11cS
The sense of induction obtained experimentally
was S as predicted by DFT, but the enantioselectivity
(44% ee) was much lower than calculated on the
basis of the G°(S/R) value of 1.6 kcal mol–1 between
the diastereomeric transition states (88% ee). In fact,
44% ee corresponds to a G°(S/R) of 0.6 kcal mol–1.
This poor agreement between calculation and
experiment might be due to a) an enantiodetermining
reaction step different from hydride transfer; b) low
accuracy of the DFT calculations due to a systematic
error; or c) low precision of the DFT calculations
resulting in biased results that are not recognized as
such with only one measurement.
11cR
TS11cS
TS11cR
12cS
2.62
–
12cR
After hydride transfer, the resulting alkoxide is
hydrogen-bonded to the N–H moiety in 11cS and
11cR, which undergoes a barrierless proton transfer
to give the weak adducts 12cS and 12cR. These are
stabilized by the O–H···N hydrogen bond and release
(S)- and (R)-1-phenylethanol to give the amido
complex 13c. According to Morris' mechanism,[18d]
13c activates H2 and regenerates dihydride trans-
[FeH2(CO)(1c)] (9c). Overall, the reaction profile
reveals a two-step hydrogenation mechanism with
highly asynchronous hydride and proton transfer, as
indicated by the presence on the reaction coordinate
of intermediates 11cS and 11cR, in which 1-
phenylethoxide is H-bonded to N–H (Table 1).
DFT Mechanism. To verify that the hydride
transfer is the enantiodetermining step of the catalytic
cycle, we expanded the DFT study[34-38] to all the
steps of the catalytic cycle involving the substrate.
These start with the approach of acetophenone to
dihydride 9 and encompass the hydride and proton
transfer steps see below). Dihydrogen activation was
not investigated, as it does not involve the substrate
and hence does not influence the enantioselectivity.
Acetophenone approaches the dihydride complex
9c with either enantioface to give the adducts 10cS
and 10cR, which feature a N–H···O hydrogen bond
(Table 1) and additional weak interactions (Figure 6).
In 10cS, the H atom on the ipso carbon of the P–Me
group is involved in a single CH/π interaction with
the phenyl ring of acetophenone (r(CH/) = 2.68 Å).
6
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
Figure 7. Computed reaction pathway for the acetophenone hydrogenation with the P(Ph)Me-based catalyst 9c at level of
theory: B3LYP-GD3/cc-pVTZ/Fe:SDD/IEF-PCM(toluene). Relative Gibbs free energies are expressed in kcal mol–1.
The energy crossing that occurs between 10c and
TS10c is irrelevant to enantiodiscrimination, though,
because the weak adducts 10cS and 10cR easily
interconvert through dihydride 9c. Therefore, 10cS
and 10cR react under Curtin-Hammett conditions[40]
to the alkoxo adducts 11c after hydride transfer, and
their energies do not affect the enantiodiscriminating
step. Also, the subsequent proton transfer (11c12c)
is barrierless, and the corresponding TS11c for the
proton transfer are significantly lower in energy than
TS10c, the TSs of hydride transfer.
pseudopotential (LANL2) with the LANL2TZ(f)
basis set[46] in selected cases. The solvent was
described by the implicit polarizable continuum
model IEF–PCM,[38] but gas phase and solution with
another solvation model (SMD)[47] were also
considered (Table S3).
Overall, the tested functionals (B3LYP, PBE0, and
M06) give a narrow overall energy range of 0.5 kcal
mol–1 (1.5-2.0 kcal mol–1) in combination with triple-
ζ basis sets (Table 2). With B3LYP, very similar
results are obtained with basis sets of comparable size
(1.5-1.7 kcal mol–1). Analogously, the triple-ζ basis
set cc-pVTZ give energy values within 0.4 kcal mol–1
with different functionals. In selected instances, the
choice of ECP has no effect on the calculated
energies. In addition, the size of the basis set (double-
ζ or triple-ζ) has little impact (0.3 kcal mol–1) for
B3LYP and PBE0. Overall, different DFT methods
give similar energy values with this system, and the
deviation of the calculated energy difference from the
experimental value is not due to low precision.
We conclude that the enantiodetermining step is
indeed the hydride transfer, and that the proton
transfer is not kinetically relevant. This is an
improvement with respect to the DFT study of the
asymmetric hydrogenation of ketones catalyzed by
(S,S)-PPh2CH(Ph)CH(Me)N(H)CH2CH2PCy2,
for
which the hydride transfer was assumed to be the
enantiodetermining step because the TS for the
proton transfer was not located.[18d]
Energy Optimization: Precision. The calculated
G°(S/R), the energy difference between TS10cS and
TS10cR, deviates from the experimental value either
because of a systematic error (low accuracy) or
because the DFT method has low precision (and
hence afford biased results that are not recognized as
such with only one “measurement”).
To check the second hypothesis, we screened
different functionals (B3LYP,[34] PBE0,[41] and
M06)[42] and basis sets (Dunning’s triple-ζ basis set
cc-pVTZ or the smaller double-ζ cc-pVDZ)[37]
including Grimme’s D3 empirical correction[35,43]
(Table 2). With B3LYP, different triple-ζ basis sets
were tested (def2-TZVP from the Karlsruhe basis
set[44] and 6-311G(2df,2pd) from Pople’s[45] basis set).
For iron, the energy consistent Stuttgart-Dresden
(SDD) pseudopotential with ECP10MDF basis set[36]
was used throughout. The same energy values were
obtained using the Los Alamos National Laboratory
Table 2. G°(S/R) values (in kcal mol–1) for TS10c with
different hybrid density functionals and basis sets.[a]
B3LYP
PBE0
M06
cc-pVTZ
cc-pVDZ
def2-TZVP
6-311G(2df,2pd)
1.6 [b]
1.9 [b]
1.5
1.9
1.6
–
2.0
1.2
–
1.7
–
–
[a]
Unless otherwise stated, the ECP for Fe was SDD.
[b] The same value was obtained with LANL2 as ECP for
Fe.
Energy Optimization: Accuracy. The accuracy
issue was studied by increasing the level of theory to
post Hartree-Fock MP2[48] and double hybrid DFT
7
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
(Table 3).[49,50] To keep computation time within
reasonable limits, single point energy (SPE) calcula-
tions were performed on the structures optimized at
the B3LYP–GD3 level. With the same goal, we used
acetophenone and the catalyst are present both in
TS10aS (to the ipso H atom of the P–Cy group,
Figure S50 B) and in TS10aR (to a hydrogen atom of
the P–Me group) (Figure S50 F). Accordingly, with
catalyst 9a, in which moderate CH/π interactions are
present in both transition states (Figures 4 and S50),
both DFT and MP2 give the same G°(S/R) of 0.5
kcal mol–1 (Table 3), most probably because of error
cancellation, and the calculated value is in good
agreement with experiment.
the smaller basis sets cc-pVDZ[37] and def2-SVPP[44]
,
which we found to perform similarly to cc-pVTZ and
def2-TZVP with the B3LYP functional (Table 2).
Table 3. G°(S/R) values (in kcal mol–1) for TS10c and
TS10a with hybrid DFT (from Table 2), MP2, and double
hybrid DFT methods.[a]
TS10c
TS10a
B3LYP–GD3 / cc-pVTZ
MP2 / cc-pVDZ [b]
1.6
0.8
0.6
2.6
3.3
0.5
0.5
–
–
–
MP2 / def2-SVPP [c]
B2PLYPD [d] / cc-pVDZ [b]
B2PLYP / cc-pVDZ [b]
[a] The thermal contribution to Gibbs free energy at 298 K was
calculated from the computed harmonic frequencies of the
[b]
optimized structures.
The geometry was optimized with
[c]
B3LYP–GD3 / cc-pVTZ.
The geometry was optimized
[d]
with B3LYP–GD3 / def2-TZVP.
B2PLYP method with
Figure 8. NCI analysis plots of TS10cS (left) and TS10cR
(right). Blue, green, and red qualitatively indicate strong
attraction, weak attraction/repulsion, and strong repulsion,
respectively. Relative MP2 Gibbs free energies are in kcal
mol–1.
Grimme’s empirical correction for dispersion.[50]
The data in Table 3 show that G°(S/R) calculated
by MP2 is in significantly closer agreement with the
experimental value of 0.6 kcal mol–1 than those
obtained by DFT. Surprisingly, B2PLYPD is less
accurate than DFT. Omitting the dispersion
correction in B2PLYP additionally reduced the
accuracy, as already observed for TS10a (see above
and Table S2).
NCI Analysis of the Transition States. As the
structural analysis of TS10cS and TS10cR reveals
different kinds of non-covalent interactions (NCIs)
between catalyst and substrate (see above), we
speculated that their inaccurate description might be
the reason for the deviation of the calculated
G°(S/R) from experiment. Therefore, the interact-
tions between the catalyst and acetophenone in the
TSs with pincers 1a and 1c were studied by NCI
analysis.[51] The significant interactions are shown
individually (see Supporting Information).
As strongest non-covalent interaction, both
TS10cS and TS10cR feature N–H···O=C hydrogen
bonds of similar strength (Figure S51), which
confirms the previous structural analysis (Table 1).
Additionally, TS10cS features a strong CH/ interac-
tion (Figure 8 left) and an additional, weak off-center
CH/ contact (Figure S51, C),[52] whereas TS10cR
contains, besides the H bond, a weak / contact at
the borderline between attractive and repulsive
(Figure 8 right).[53] Therefore, the spurious G°(S/R)
value obtained by DFT most probably derives from
the overestimation of the energy of the CH/, which
is the only strong NCI and is present in the most
stable TS10cS, but not in TS10c with catalyst 9c.
The NCI analysis of TS10a corroborates the above
interpretation. Again, the N–H···O=C hydrogen bond
is the major attractive non-covalent interaction in
both TSs. In this case, however, moderately attractive
CH/ interactions between the phenyl ring of
In the next section, we discuss the issue of
accuracy of DFT and MP2 energies in connection
with CH/ interactions on the basis of literature data.
CH/π Interaction in Calculations. CH/π inter-
actions play a major role in chemistry and biology,
and their nature, geometry, and magnitude have been
studied extensively by experiment and computa-
tion.[54] In most cases, model systems have been used
though, typically CH4/benzene,[55] CH2RX/ benzene
(R = H or CH3),[56] acetylene/benzene,[57] and CH4 (or
acetylene)/aromatic ring.[58] Recently, some studies of
CH/π interactions in real molecular systems have
appeared,[59] including their application to catalyst
design,[26] but examples involving enantioselective
transition metal catalysts are still rare.[25a,60]
There is general agreement that dispersion domi-
nates CH/π interactions. The electrostatic attraction
between the partial positive charge on the H atom and
the partial negative one on the aromatic ring plays a
minor role in terms of energy,[55b,d,57c] but accounts for
the directionality of the interaction.[55b,d] The C–H
bond typically points towards the centroid Y of the
aromatic ring, and the geometry of the CH/Y
interaction is described by the distance r between the
H atom and the plane of the ring, the C–H···Y angle
, and , the angle between the C···Y vector and the
ring plane (Figure 9).[55c,56b,c,58a]
Computations quantify the interaction energy in
the range 0.5–7 kcal mol–1,[55b-d,56-58] depending on
their geometry (Figure 9),[55a-c,57] on the electron
density on the aromatic ring,[58] and the C–H acidity,
which is affected by the hybridization[57] and substitu-
ents[56] of the C–H moiety. Calculated r values range
8
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
from 2.1 to 3.0 Å.[55a-c,56a,58] The interaction energy
changes insignificantly in the r range 2.3–2.7 Å (<0.2
kcal mol–1)[55a-d,56a,58a] and is largest when  = 90° and
 = 180°. However, the directionality is not pro-
nounced, which reflects the minor role of electrostatic
interactions. Thus, tilting  by 30° reduces the
interaction energy by less than 0.05 kcal mol–1.[55c]
In particular, functionals such as B3LYP and PBE0
have been deemed inappropriate to evaluate the CH/π
interaction energy as they fail to evaluate accurately
the dispersion interaction,[55d] which is its major
component. In contrast, MP2 methods are considered
to be more accurate than DFT in the quantitative
evaluation of the CH/π interaction energy.[55c,d]
Overall, the higher accuracy obtained by MP2
methods is generally ascribed to the better description
of dispersive forces by MP2 than DFT, even when
Grimme’s empirical correction for dispersion is
applied,[35] but exceptions are documented.[59a]
As for double hybrid DFT, B2PLYP(D) methods
were even less accurate than hybrid DFT in our hands.
However, such studies are still extremely rare,[55e,58b]
and most of them were performed in the gas phase[55-
58]
rather than in solution.[59] Therefore, more
examples are needed to assess their suitability for the
description of CH/ interactions.
Figure 9. Geometric parameters of the CH/ interaction in
TS10cS.
Conclusion
In the case of TS10cS, 11cS, and TS11cS, the
geometry of the CH/π interaction is close to ideal. For
instance, TS10cS features r = 2.45 Å,  = 170°, and
 = 92–95°.[61] The energy of the off-center CH/π
contact (as in TS10cS, Figure S51, C) is about half
the energy of a CH/π interaction such as in Figure 9.
Taken together, the above studies suggest that ra-
tional ligand design based on calculation in asymmet-
ric catalysis is feasible in principle, provided that all
contributions to the energy of the enantiodetermining
step are estimated accurately, which is not (yet) the
case. In fact, DFT methods incorporating Grimme’s
dispersion fail to give accurate energy values in the
presence of CH/ interactions.
The NCI analysis of the enantiodetermining
transition states shows that the CH/π interactions
between the catalyst and the substrate, which are
stronger than the other dispersive interactions (/
and van der Waals contacts), are present only in the
most stable TSs. Hence, it is reasonable to assume
that the overestimation of the energy accounts for the
positive deviation of the calculated enantioselectivity
from experiment. Notably, also double hybrid DFT
methods overestimate CH/ energies, whereas
Møller-Plesset (MP2) accurately reproduces the
energy difference between the enantiodetermining
transition states even with the P-stereogenic P(Me)Ph
unit. This new stereogenic motif is both promising
and challenging in view of its multiple potential CH/π
and π/π interactions.
[55a,b]
Concerning the C–H substituent, we are not
aware of previous studies on the effect of a P
substituent on a CH/π interaction. Based on gas-phase
studies, the hydrogen atom acidity of P–CH3 can be
expected to be intermediate between CH3F and
CH3Cl.[62]
Accordingly, a significant CH/ interaction can be
anticipated for TS10cS, which is absent in the
diastereomeric TS10cR. This is supported by NCI
analysis, which also shows that the P(Cy)Me
analogues TS10aR and TS10aS both contain CH/
interactions. The energy values in Table 3 show that,
in the case of asymmetric CH/ interactions as with
9c, the MP2 method gives G°(S/R) value in better
agreement with the observed enantioselectivity than
hybrid DFT methods, despite the fact that the latter
include Grimme’s empirical correction for disper-
sion.[35] Combined with the NCI analysis of all TSs,
this strongly suggests that hybrid DFT methods
overestimate CH/ interactions, which is corrobora-
ted by previous observations.
In fact, hybrid DFT methods have been found to
give unreliable results when compared with experi-
ment[55c,56b] as they overestimate the energy of CH/π
interactions. This is the case both in the gas phase
(such as for benzene/CH3X)[56b] and in solution, as in
the case of bicyclic proline analogues as organo-
catalysts for stereoselective aldol reactions.[22a] In the
first case, the choice of DFT or MP2 gives the same
geometry of the CH/π interaction, but significantly
different energies,[56b] which validates our decision of
running SPE calculations starting from the DFT
optimized geometry to save computation time.
Therefore, we suggest that, after structure optimi-
zation by DFT, MP2 energy calculations should be
carried out for systems where CH/ interactions are
at the origin of the enantioselectivity. Further
investigation is required to elucidate why advanced
methods such as MP2 or double hybrid DFT give
such diverging results in the presence of CH/ inter-
actions.
Experimental Section
(S)-2-(Boranyl(cyclohexyl)(methyl)phosphanyl)-N-(2-
(boranyl(cyclohexyl)(methyl)phosphanyl)ethyl)ethan-1-
amine, (SP,SP)-5a
9
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
A THF (65 mL) solution of (SP)-4a (2.2 g, 15.4 mmol,
2.05 equiv) was cooled to 0 °C, n-butyllithium (9.9 mL,
1.6 M in hexanes, 15.8 mmol, 2.1 equiv) was added
dropwise, and the yellow solution was warmed to room
temperature over 15 min. Freshly prepared bis(2-
chloroethyl)-N-trimethylsilylamine (1.61 g, 7.5 mmol) was
dissolved in THF (8.5 mL), and the solution was added
dropwise to the first solution at room temperature. The
reaction mixture was stirred at room temperature overnight.
Saturated NaHCO3 (100 mL) was added, and the THF was
evaporated. Chloroform (120 mL) was added and the
phases were separated. The aqueous phase was extracted
with chloroform (3 × 120 mL), and the combined organic
phases were dried over MgSO4, filtered and the solvent
was evaporated. The crude was directly recrystallized from
boiling EtOAc (40 mL) to give a white crystalline solid,
which was filtered off and washed with pentane. Yield:
1.9 g (5.32 mmol, 71%; >99% ee) (see the Supporting
Information for characterization details).
pentane (1 × 20 mL) and dried in vacuum overnight to give
a blue powder. Yield: 209 mg (0.36 mmol, 67%).
Complexes [FeBr2(CO)(1b)] (2b) and [FeBr2(CO)(1c)]
(2c) were prepared similarly (see the Supporting
Information for synthetic and characterization details).[63]
Synthesis of [FeBr(CO)H((SP,SP)-1a)], 3a
To a solution of complex 2a (106 mg, 0.19 mmol) in THF
(4 mL), sodium triethylborohydride (0.19 mL, 1 M in
toluene, 0.19 mmol, 1 equiv) was added dropwise at room
temperature. After stirring the brown suspension for 3 h at
ambient temperature, the volume was reduced to ca. 1 mL,
and diethyl ether (20 mL) was added. The suspension was
filtered through a pad of celite, the resulting brown
solution was concentrated, and the brown residue was
dried in vacuum overnight. The brown solid was washed
with pentane (5 × 20 mL) and dried overnight in vacuum to
give a light brown solid. Yield: 39 mg (43%). Complexes
[FeBrH(CO)(1b)] (3b) and [FeBrH(CO)(1c)] (3c) were
prepared similarly (see the Supporting Information for
synthetic and characterization details).
Bis(2-(boranyl(methyl)(phenyl)phosphanyl)ethyl)amine
Hydrochloride, (RP, RP)-5c·HCl
A solution of (SP)-6 (1.91 g, 10.5 mmol, 2.2 equiv) in THF
(23 mL) was cooled to 0 °C, sodium hydride (660 mg,
95%, 5.5 equiv) was added in one portion and the solution
was stirred for 10 min at 0 °C. Freshly prepared bis(2-
iodoethyl)-N-trimethylsilylamine (1.89 g, 4.8 mmol) was
dissolved in THF (15 mL) and the solution was added
dropwise over 10 minutes to the first flask. The reaction
mixture was warmed to room temperature overnight.
Saturated NaHCO3 (100 mL) was added slowly, and the
THF was evaporated. The aqueous solution was extracted
with chloroform (4 × 150 mL), the combined organic
phases were washed with aqueous Na2S2O3 solution
(250 mL, 1M), dried over MgSO4, filtered and evaporated.
The crude orange oil was dissolved in diethyl ether
(300 mL), and HCl was added (3 mL, 2 M in diethyl ether,
excess). The white precipitate was filtered off, washed
with hexanes (3 × 20 mL) and recrystallized from boiling
EtOH (30 mL) to give a white solid. Yield: 251 mg (0.56
mmol, 15%) (see the Supporting Information for charac-
terization details).
Hydrogenation of Acetophenone with Complexes 3a–3c
In a glove box under argon, catalysts 3a–3c (1 mol%) and
KOtBu (5 mol%) were weighed in a 5 mL glass vial
equipped with a magnetic stirring bar. Then, acetophenone
(7, 0.416 mmol) and the solvent (3 mL) were added. The
vial was transferred to a 60 mL steel autoclave, which was
flushed with N2, then with H2, and pressurized with H2.
After stirring for 16 h at room temperature (20 °C), the
pressure was released, and an aliquot of the reaction
mixture (0.3 mL) was filtered through silica with EtOAc (3
mL) and analysed by chiral GC. See Supporting Informa-
tion for analytical details.
Computational Details
Hybrid and Double-Hybrid DFT (Density Functional
Theory) and MP (Møller-Plesset)[64] calculations were
performed with Gaussian09 (revision D.01).[65] The TSs
were calculated by DFT with the hybrid density functional
B3LYP,[34] PBE0[41] and M06[42] with and without Grim-
me’s empirical correction GD3 for the dispersion.[35] Dun-
ning basis set cc-pVDZ and cc-pVTZ,[37] Karlsruhe basis
def2-TZVP[44] and Pople basis set 6-311G(2df,2pd)[45]
were used for all the atoms except Fe. The SDD basis set
((8s7p6d2f1g)/[6s5p3d2f1g]) with the associated Stuttgart-
Dresden pseudopotential (ECP10MDF)[36] and the
LANL2TZ(f) basis set with the associated LANL2 pseudo-
potential[46] were used for Fe. The structures were studied
in gas phase and in solution. The solvent (toluene) was
described by the implicit polarizable continuum model
with the integral equation formalism variant (IEF−PCM)[38]
and the solvation model based on quantum mechanical
charge density (SMD).[47]
General Procedure for the Deprotection of Proligands
5a – 5c / 2-((S)-Cyclohexyl(methyl)phosphanyl)-N-(2-
(cyclohexyl(methyl)phosphanyl)ethyl)ethan-1-amine,
(SP,SP)-1a
The borane-protected pincer (SP,SP)-5a (150 mg,
0.42 mmol, 1 equiv) was dissolved in degassed CH2Cl2
(10 mL), and HBF4·Et2O (0.67 mL, 5.04 mmol, 12 equiv)
was added dropwise at room temperature. After 5 min of
stirring at room temperature, saturated degassed NaHCO3
(10 ml) and diethyl ether (9 mL) were added, and the
aqueous phase was basified with KOH (ca. 0.7 g) to
pH = 11. The organic phase was separated, and the
aqueous phase was further extracted with diethyl ether
(3 × 10 mL). The combined organic layers were dried over
MgSO4, filtered, and the solvent was evaporated to give a
colorless oil, which was directly used in the complex
synthesis. Yield: 125 mg (0.38 mmol, 90%) (see the
Supporting Information for characterization details).
Single point energy (SPE) calculations were performed by
MP2[48] and double-hybrid B2PLYP[49] and B2PLYPD
(with Grimme’s empirical correction for the dispersion)[50]
methods. The ultrafine pruned (99,590) grid was used.
Stationary points were characterized by vibrational
analysis (only real frequencies for minima, one imaginary
frequency for transition states) and IRC calculations were
carried out on the 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.
trans-[FeBr2(CO)((SP,SP)-1a)], 2a
To a solution of freshly prepared (SP,SP)-1a (204 mg,
0.62 mmol, 1.14 equiv) in THF (11 mL), [FeBr2(PPh3)2]
(402.5 mg, 0.54 mmol) was added in one portion at room
temperature. After the resulting green solution was stirred
for 15 min at room temperature, the Ar atmosphere was
replaced with CO (1.1 bar), which immediately led to a
color change of the solution from green to dark blue. After
15 min of stirring at room temperature, the CO atmosphere
was replaced with argon, and the solvent volume was
reduced to ca. 1 mL. Complex 2a was precipitated by
adding pentane (40 mL) dropwise to the blue solution
under vigorous stirring. The precipitate was washed with
Acknowledgements
We thank one of the Reviewers for the useful suggestions
concerning noncovalent interactions and gratefully acknowledge
10
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10.1002/adsc.201800433
Advanced Synthesis & Catalysis
financial support by SNF (grant 2-77063-16 to RH and EG) and
by ETH (grant 0-20356-17 to AP).
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FULL PAPER
P-Stereogenic PN(H)P Iron(II) Catalysts for the
Asymmetric Hydrogenation of Ketones: The
Importance of Non- Covalent Interactions in
Rational Ligand Design by Computation
Adv. Synth. Catal. 2018, 360, Page – Page
Raffael Huber, Alessandro Passera, Erik Gubler,
and Antonio Mezzetti*
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