Iron catalysts containing amine(imine)diphosphine P-NH-N-P ligands catalyze both the asymmetric hydrogenation and asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1021/om500479q

When activated with base, the iron(II) complexes with tetradentate amine(imine)diphosphine ligands, (S,S)-trans-[FeCl(CO)(PAr₂-NH-N-PAr′₂)]BF₄ (1: Ar, Ar′ = Ph; 2: Ar = Ph, Ar′ = 4-MeC₆H₄; 3: Ar, Ar′ = 3,5-Me₂C₆H₃), are very active for the asymmetric transfer hydrogenation (ATH) of ketones in KO^tBu/2-propanol. For ATH, better enantioselectivity, but lower catalytic activity, was observed in general when using catalyst precursors with the bulkier dixylylphosphino groups compared to those with diphenylphosphino groups. The complexes were much less active for the pressure hydrogenation of ketones, where 1 and 2 produced racemic product alcohols, while 3 yielded chiral alcohols with an enantiomeric excess of up to 70% (R) at turnover frequencies up to 80 h^-1 and turnover numbers of 100 for a range of ketones at 50 °C and 20 atm H₂. This is a rare example of asymmetric pressure hydrogenation using an iron complex. Unlike the case of ATH, there is no effect on the rate upon the addition of KO^tBu beyond the 2 equiv needed to convert the precursor complex to the active amido(ene-amido) and amine(ene-amido)hydrido forms. Both AH and ATH reactions share the same iron hydride intermediate formed by reaction of the amido(ene-amido) iron complex with either dihydrogen or 2-propanol. Kinetic studies on the H₂ hydrogenation of acetophenone catalyzed by 1, activated by base in benzene, using the method of initial rates indicated that the heterolytic splitting of the dihydrogen at the amido(ene-amido) iron complex is the turnover-limiting step of the catalytic cycle for hydrogenation. For 1 in benzene at 323 K over the ranges of concentrations [1] = (2.4-4.8) × 10^-4 M and [ketone] = (3.6-7.2) × 10^-2 M, and of H₂ pressures = 10-20 atm, the rate law is rate = k[1][H₂], with k = 0.16 ± 0.01 M^-1 s^-1, ΔH^? = 10.0 ± 0.2 kcal mol^-1, and ΔS^? = -31.0 ± 0.5 cal mol^-1 K^-1. Detailed DFT calculations also support the finding that the barrier for H₂ splitting is the turnover-limiting step. The higher barrier for H₂ activation compared to isopropanol activation in order to generate the active amine(ene-amido)hydrido form explains why this system is biased toward ATH over AH.

Full text of DOI:10.1021/om500479q

Article
pubs.acs.org/Organometallics
Iron Catalysts Containing Amine(imine)diphosphine P‑NH-N‑P
Ligands Catalyze both the Asymmetric Hydrogenation and
Asymmetric Transfer Hydrogenation of Ketones
Weiwei Zuo, Sebastian Tauer, Demyan E. Prokopchuk, and Robert H. Morris*
Department of Chemistry, University of Toronto, 80 Saint George St., Toronto, Ontario M5S3H6, Canada
*
S Supporting Information
ABSTRACT: When activated with base, the iron(II) complexes with tetradentate
amine(imine)diphosphine ligands, (S,S)-trans-[FeCl(CO)(PAr -NH-N-PAr′ )]BF
2
2
4
(
1: Ar, Ar′ = Ph; 2: Ar = Ph, Ar′ = 4-MeC H ; 3: Ar, Ar′ = 3,5-Me C H ), are very
6
4
2
6
3
t
active for the asymmetric transfer hydrogenation (ATH) of ketones in KO Bu/2-
propanol. For ATH, better enantioselectivity, but lower catalytic activity, was
observed in general when using catalyst precursors with the bulkier
dixylylphosphino groups compared to those with diphenylphosphino groups.
The complexes were much less active for the pressure hydrogenation of ketones,
where 1 and 2 produced racemic product alcohols, while 3 yielded chiral alcohols
with an enantiomeric excess of up to 70% (R) at turnover frequencies up to 80 h and turnover numbers of 100 for a range of
−1
ketones at 50 °C and 20 atm H . This is a rare example of asymmetric pressure hydrogenation using an iron complex. Unlike the
2
t
case of ATH, there is no effect on the rate upon the addition of KO Bu beyond the 2 equiv needed to convert the precursor
complex to the active amido(ene-amido) and amine(ene-amido)hydrido forms. Both AH and ATH reactions share the same iron
hydride intermediate formed by reaction of the amido(ene-amido) iron complex with either dihydrogen or 2-propanol. Kinetic
studies on the H hydrogenation of acetophenone catalyzed by 1, activated by base in benzene, using the method of initial rates
2
indicated that the heterolytic splitting of the dihydrogen at the amido(ene-amido) iron complex is the turnover-limiting step of
−4
the catalytic cycle for hydrogenation. For 1 in benzene at 323 K over the ranges of concentrations [1] = (2.4−4.8) × 10 M and
−
2
−1 −1
[
ketone] = (3.6−7.2) × 10 M, and of H pressures = 10−20 atm, the rate law is rate = k[1][H ], with k = 0.16 ± 0.01 M s ,
−1 −1 −1
2
2
⧧
⧧
ΔH = 10.0 ± 0.2 kcal mol , and ΔS = −31.0 ± 0.5 cal mol K . Detailed DFT calculations also support the finding that the
barrier for H splitting is the turnover-limiting step. The higher barrier for H activation compared to isopropanol activation in
2
2
order to generate the active amine(ene-amido)hydrido form explains why this system is biased toward ATH over AH.
INTRODUCTION
and amines obtained from these iron catalysts are >99% for
some substrates.
Iron amido(ene-amido) isomers (4a, 4b) and iron hydrido-
■
The asymmetric hydrogenation (AH) and asymmetric transfer
hydrogenation (ATH) of prochiral ketones and imines are
valuable transformations because they allow the production of
enantiopure alcohols and amines for the use in the1
pharmaceutical, fragrance, food, and materials industries.
Previously, the predominant catalysts of these asymmetric
transformations were based on rare and expensive metals such
as ruthenium and rhodium. Replacing these precious metals
with common metals such as iron has been the subject of
(
amine)(ene-amido) (5) intermediates were characterized for
the diphenylphosphino system (1), showing that the ATH
catalysis proceeds by the outer sphere pathway shown in
2
q,s,x
simplified form in Scheme 1.
First, the iron hydride amine
complex attacks the ketone in the outer sphere (eq 1, Scheme
1), and then, the hydride amine is regenerated by reaction with
2-propanol (eq 2). We ask the question here whether the key
iron hydride of eq 1 can be regenerated by reaction with
hydrogen gas as in eq 3 so that the system can perform
2
significant investigations, as iron is cheaper and potentially less
toxic and more environmentally friendly.
2aa
As reviewed recently, we have developed catalysts based
on iron(II) for the efficient asymmetric transfer hydrogenation
of ketones and imines. The most effective catalysts contain a
variety of amine−imine−diphosphine hybrid ligands (P-NH-N-
asymmetric hydrogenation (AH). Only a few AH catalysts
2c,k,y,z
based on iron have been reported.
The advantages of AH
over ATH include the prevention of erosion of ee of the
product observed sometimes for ATH, the use of higher
2
x
P) (Chart 1). Upon activation with 2−8 equiv of base, these
imine−amine iron complexes showed exceptionally high
catalytic activity in the hydrogenation of ketone substrates by
transferring hydrogen from the 2-propanol solvent, with the
Special Issue: Catalytic and Organometallic Chemistry of Earth-
Abundant Metals
−1
highest TOF (turnover frequency) greater than 200 s . The
Received: May 5, 2014
enantiomeric excesses (ee values) of the final chiral alcohols
©
XXXX American Chemical Society
A
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Article
Chart 1. Iron(II) P-NH-N-P Complexes for Asymmetric Transfer Hydrogenation and the Catalytically Active forms of 1
Scheme 1. General Equations for the ATH and AH of
Prochiral Ketones Catalyzed by Metal Complexes with
Ancillary Ligands L and Amine Ligand NH2R
of ee (entry 3 vs 4). The enantiomeric excess of (R)-1-(2-
pyridinyl)ethanol was increased by 19% by use of 3 (entry 9 vs
10). The exception was the reduction of 3-methyl-2-butanone
to 3-methyl-2-butanol with higher catalytic activity, but lower
enantioselectivity (entry 7 vs 8).
Asymmetric Pressure Hydrogenation of Ketones. The
H2 hydrogenation of ketone substrates catalyzed by iron
catalysts was conducted by first reacting the precatalysts (1−3)
t
with KO Bu in THF in the glovebox to form the amido(ene-
amido) iron complexes, followed by injecting the THF
solutions of the catalysts to the reactor that was charged with
H and THF solution of the substrate. Full conversion of
2
concentrations of ketone or imine substrate, and the economics
of using hydrogen gas over other hydrogen donors.
acetophenone at a turnover number (TON) of 100 was
achieved in 4.5 h for 1 at 20 atm and 50 °C (Table 2, entry 1;
Figure S1, Supporting Information).
1
b,3
Certain ruthenium and osmium catalysts are thought to
catalyze both ATH via eqs 1 and 2 and AH via eqs 1 and 3 (or
similar ones involving additional alcohol or potassium
However, the products obtained with catalysts containing
phenyl and para-tolyl substituents on the phosphine atoms (1
and 2) are racemic (Table 2, entries 1−5). Decreasing the
temperature or lowering the hydrogen pressure led to a
decrease of the TOF with still no enantioselectivity (entries 2
and 3). At higher temperature, the reduction of acetophenone
occurs faster and it takes a shorter time for the completion of
the reaction (entry 4). The use of other solvents that do not
react with the amido(ene-amido) iron complex (benzene,
hexane, triethylamine) gave similar results as that in THF,
whereas using dichloromethane and tert-butyl alcohol led to
deactivation of the catalysis. The R-isomer of 1-phenylethanol is
produced in 35% ee after 1 h of reaction (18% conversion) by
use of the enantioselective precatalyst 3 having meta-xylyl
substituents. Unfortunately, the erosion of the enantiomeric
excess continues as the reaction continues until racemic
products are finally obtained. Unlike the case of transfer
3
b,4
5
alkoxide).
Others are strongly biased toward AH over
6
ATH or can switch depending on the basicity of the system.
Some ruthenium complexes without N-H groups catalyze both
AH and ATH via other Ru-H routes. The factors that favor
7
one type of catalysis over the other are still not well-defined.
We have done a small study of the effects of the substituents
attached to the phosphorus atoms in catalyst precursors 1−3
on the enantioselectivity of ketone reduction and have found
that the catalyst precursor (S,S)-3 with meta-xylyl groups on the
phosphorus atoms provides higher ee values of (R)-1-
phenylethanol and (R)-1-[3,5-bis(trifluoromethyl)phenyl]-
ethanol than the catalyst precursor 1 with diphenylphosphino
2n,x
groups.
In this report, we will describe further applications
of these catalyst precursors in ATH as well as their reaction
with H and use in pressure AH reactions.
2
2x
hydrogenation, the presence of excess base (more than 2
equiv) has no clear influence on the activity and enantiose-
lectivity (entry 6 vs entry 7). As in the transfer hydrogenation,
the reduction of 3,5-bis(trifluoromethyl)acetophenone pro-
vided a higher ee value for the chiral product (entry 11) than
that of acetophenone (entry 6). A much lower catalytic activity
was observed in the reduction of α-tetralone, but the
enantioselectivity was good (entry 12). Interestingly, as in the
case of transfer hydrogenation, the ee of the 1-tetralol product
did not drop with time.
RESULTS
■
ATH of Ketones Catalyzed by 3. Our initial report on the
applications of complexes 1−3 focused on the ATH of ketones
mainly with complex 1. Here, we report a comparison of
results of ATH of ketone substrates of 3 vs 1 as catalyst
precursors in basic 2-propanol at 28 °C (Table 1).
Generally, under the same conditions, precatalyst 3 exhibits
lower activity than 1 for most substrates, as observed in the
reduction of acetophenone. However, for 3-methyl-2-butanone,
the rate of reaction was higher (entry 7 vs 8). The conversions
except for α-tetralone were similar to those obtained by use of
as the catalyst does not shift the reaction equilibrium, but the
enantiomeric excesses for most substrates were slightly superior
to those obtained with 1. In each case, the same configuration
R) was obtained in excess using the (S,S)-catalyst. Of note, the
2x
In order to understand the mechanistic details of this iron-
catalyzed H hydrogenation of ketones, the reaction of the
1
2
amido(ene-amido) iron complex with H was studied in an
2
attempt to identify the potential amine iron hydride
intermediate. The reaction of 1 with 2 equiv of base and
(
α-tetralone can be converted into the corresponding alcohol
followed by reaction with H at 20 atm in THF at room
2
with much higher enantioselectivity and with little deterioration
temperature for 30 min produces a mixture of an amine iron
B
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Article
a
, ,
b c
Table 1. Asymmetric Transfer Hydrogenation of Ketones
a
General conditions: [Catalyst] = 6.73 × 10−5 M, [KO Bu] = 5.45 × 10 M, [substrate] = 0.412 M, [2-PrOH] = 12.4 M, 28 °C. The TOF at 29%
t
−4
b
c
conversion. At 60 s, since early times gave unreliable ee due to the small conversion.
hydride complex 5 and a neutral amido(ene-amido) iron
complex 4a in a 4:3 ratio (Scheme 2).
atures (50 °C), the hydride complex easily decomposes in the
absence of a ketone substrate.
1
A doublet of doublet hydride H NMR pattern at −2.3 ppm
HP
Kinetics of H Hydrogenation Reactions Catalyzed by
2
(2
J
= 70.0 and 70.8 Hz; see Figure S2, Supporting
1. The kinetic studies on the H2 hydrogenation of
acetophenone catalyzed by 1 were conducted by the initial
rate method in benzene. The linear formation of 1-phenyl-
ethanol as a function of time was plotted for a series of different
Information) and the chemical shifts of the protons in the P-
NH-N-P ligand are exactly the same as those found in the
product of the reaction of 1 with base and 2-propanol (Figure
2
x
1
). The IR (KBr pellet) spectrum of the reaction mixture also
concentrations of acetophenone, H , and catalyst and different
2
−1
shows a CO stretch at 1872 cm for the amine hydride
complex and 1906 cm for the amido(ene-amido) complex 4a.
temperatures. The reactions were initiated by injecting a
catalyst solution in benzene of a small volume into the reactor
−1
This unstable iron hydride slowly isomerized in C D to
that was charged with H and acetophenone dissolved in
6
6
2
another hydride compound in the absence of substrate; this
observation was also reported for the hydride species in the
ATH mechanism. Furthermore, both of the two hydride
benzene. To make sure that the temperature inside the reactor
was the same as that of the outside water bath, the benzene
solution of acetophenone was pre-equilibrated at the preset
temperature for more than 30 min prior to the injection of the
catalyst solution. The catalyst solution was prepared by reacting
1 with base in THF initially in the glovebox, followed by
evaporating THF under reduced vacuum and extracting the
product with benzene. The reactions were sampled at timed
2
x
species react with acetophenone in C D6 to produce 1-
6
phenylethanol. It was also found that the ratio of the hydride
complex to the unreacted amido(ene-amido) iron complex was
not significantly affected by either the reaction time or the
reaction temperature, although, under higher reaction temper-
C
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a
Table 2. Asymmetric Pressure H Hydrogenation of Ketones
2
aConditions: [Catalyst] = 3.48 × 10−4 M, [substrate] = 3.48 × 10−2 M in THF (30 mL), S/C = 100.
t
Scheme 2. Dihydrogen Activation by the Amido(ene-amido) Iron Complex Generated in Situ by Reaction of 1 with KO Bu
intervals, and the degree of conversion was determined by gas
chromatography (GC) analysis. The dependence of initial rates
on the reaction parameters together with the reaction
conditions is shown in Figures 2−5 and Table 3.
acetophenone. On the basis of the calculated relative free
energies, this was postulated to be the turnover-limiting step
when isopropanol is used as the reductant. The hydride (FeH−
NH) and alkoxide (Fe(OCHMePh)−NH) compounds were
found to be the lowest-energy species, acting as possible resting
states in the catalytic cycle. Thus, once the FeH−NH complex
is formed in solution, as shown in Scheme 2, we expect that the
same mechanism is operational to reduce ketonic substrates,
The initial rate of 1-phenylethanol formation is first-order in
catalyst concentration and H pressure but independent of the
2
ketone concentration. This is indicative of a turnover-limiting
dihydrogen splitting step in the catalytic cycle, consistent with
5b
that of our previous ruthenium catalysts, but in contrast to
the Knolker’s iron complex where the hydrogen transfer from
with the only difference now being that H gas is responsible
2
̈
for regenerating the FeH−NH complex. Since H splitting was
2
8
the iron hydride to the carbonyl group is the rate-limiting step.
Therefore, the rate law at 323 K for the range of ketone,
found to be the turnover-limiting step during catalysis, our
focus will be on calculating H splitting barriers using a
2
catalyst, and H concentrations studied is given by eq 4, where
simplified version of complex 5 and comparing this with the
calculated energies of the full system 5, which includes all of the
phenyl substituents.
2
−1 −1
the rate constant is k = 0.16 ± 0.01 M s , assuming that all
the catalyst precursors were converted to the active species.
We have calculated the barrier for H splitting on the same
2
rate = d[alcohol]/dt = −d[ketone]/dt = k[cat.][H2]
simplified amido-eneamido system, using the same level of
(4)
2s
theory as in our previous work and also using the M06-L
The activation parameters obtained from an Eyring plot of
the data of Table 3 (see the Supporting Information) will be
compared with those calculated by DFT as discussed below.
Density Functional Theory (DFT) Calculations on the
Mechanism of AH with 1. We have demonstrated in a
previous DFT study that the mechanism of ATH using
simplified models of 4b and 5 (Scheme 2) involves stepwise
proton/hydride transfer from FeH−NH complex 5 to
functional with the TZVP/TZVPfit basis set (see the
Experimental Section). The latter functional/basis set combi-
nation was shown to be an efficient and accurate method in
comparing thermochemical values between theory and experi-
ment for other organometallic transformations. In addition,
solvation effects were taken into account by using a THF
10
2s
solvent continuum. Scheme 3 shows that the H splitting
2
barriers for both functional/basis set combinations are
D
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1
2x
1
Figure 1. (a) The H NMR (400 MHz, C D ) spectrum of the products of the reaction of 1, base, and 2-propanol in 2-propanol. (b) The H
6
6
NMR (600 MHz, C D ) spectrum of the reaction of 1, base, and H at 20 atm in THF. In (a) and (b), the signals at δ 4.5, 4.3, 4.0 (broad), and 3.8
6
6
2
ppm along with hydride resonances at −2.3 ppm (dd) correspond to protons of the amine iron hydride complex 5, while the resonances at δ 4.7, 4.2,
and 3.9 ppm originate from the neutral amido(ene-amido) complex 4a, and the signal at δ 4.4 ppm is H gas. The other major signals along with
2
2
x
hydride resonances at −9.2 ppm (dd) in (a) belong to a second amine iron hydride complex that forms more slowly (FeH).
Figure 2. Dependence of initial rate on the acetophenone
−2
concentration. Conditions: [acetophenone] = 3.6 × 10 and 7.2 ×
−
2
−4
1
0
M and [catalyst] = 3.6 × 10 M in benzene (30 mL); H2
pressure = 20 atm; temperature = 50 °C.
Figure 3. Dependence of initial rate on the H pressure. Conditions:
2
−2
−4
[
acetophenone] = 3.6 × 10 M; [catalyst] = 3.6 × 10 M in
benzene; temperature = 50 °C; H pressure = 10, 20 atm.
2
⧧
comparable (G° (TS4bH,5bH) = 17.2 vs 18.0 kcal/mol), with the
relative free energies differing by only 0.8 kcal/mol relative to
4
b plus all relevant small molecules. Formation of the FeH−
H
NH complex 5b is exergonic by 9.0 kcal/mol (M06/6-31+
+
tively. The metrical parameters for TS4bH,5bH are very similar
using both levels of theory, and the structure is presented in
Figure 6.
phosphorus. As noted earlier, M06-L/TZVP/TZVPFit (see the
Experimental Section) was found to be an energetically
accurate functional/basis set combination for organometallic
systems, with efficient optimization times, even on complete
systems incorporating cyclohexyl- and phenylphosphine
ligands. Thus, for all further calculations discussed, we
chose to use M06-L/TZVP/TZVPFit to optimize ground-state
and transition-state structures.
H
G(d,p)) and 7.1 kcal/mol (M06-L/TZVP/TZVPfit), respec-
10
We were also interested in optimizing structures and
obtaining H splitting barriers using a full structural analogue
of 1, which included (S,S)-dpen and all phenyl substituents on
2
E
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Organometallics
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(
Figure 7), similar to the orientation of the NH group in
complex 1.
Our attempts at trying to find an H splitting transition state
2
between 4aH2 and the FeH−NH complex 5a were
unsuccessful. In order for heterolytic H splitting to occur
2
across the metal−amide moiety, the nitrogen atom must orient
its electron pair toward the σ* molecular orbital of hydrogen.
The pyramidal inversion at nitrogen might be too energetically
unfavorable, since the hydrogen atoms on the alkyl groups
attached to nitrogen are in a diaxial position; pyramidal
inversion would then require the entire ligand system to
reorient itself in order to relieve this diaxial strain (Scheme 4).
Calculations were performed where the ligand is initially
reoriented to relieve this unfavorable diaxial interaction, but
Figure 4. Dependence of initial rate on the catalyst concentration.
2
attempts to find both an η -H ground-state structure and an
−2
2
Conditions: [acetophenone] = 3.6 × 10 M; [catalyst] = 2.4, 3.6, and
−4
H splitting transition state were also unsuccessful (see the
2
4
.8 × 10 M in benzene; H pressure = 20 atm; temperature = 50 °C.
2
Supporting Information). Furthermore, the energy of the
FeH−NH complex 5a (G° = 5.5 kcal/mol) is substantially
higher than the free energies of 4b and 5b (vide infra).
H
Starting with complex 4b (G° = −1.4 kcal/mol relative to
2
4
a), an η -H ground state was found (4bH ), which is only
2
2
about 0.5 kcal/mol lower in energy than 4aH . However, in this
2
case, the amide lone pair is oriented on the same side as
coordinated dihydrogen. Comparing bond length pairs in 4aH2
and 4bH (Figure 7) reveals that there is little difference
2
between the two structures, but there is obviously a dramatic
difference in the orientation of the P-Namido portion of the
ligand with respect to coordinated dihydrogen. From 4bH , an
2
⧧
H splitting transition state was found (ΔG° (TS
− 4b) =
2
4b,5b
1
7.5 kcal/mol), generating hydride complex 5b, which is
exergonic by 6.9 kcal/mol (when compared with amido(ene-
amido) compound 4b). The calculated structure of TS4b,5b is
shown in Figure 7, and bond lengths are strikingly similar to its
simplified analogue TS4bH,5bH (Figure 6).
Figure 5. Dependence of initial rate on the temperature. Conditions:
−2
−4
[
acetophenone] = 3.6 × 10 M, [catalyst] = 3.6 × 10 M in benzene;
H pressure = 20 atm; temperature = 25, 30, 35, and 50 °C.
2
We were also interested to know why complexes 1−3 do not
exhibit the same activity and enantioselectivity for ATH and
AH. Table 4 lists the calculated and experimentally measured
When 1 reacts with 2 equiv of base, two enantiomers form in
solution (4a and 4b), where the carbonyl ligand is located on
⧧
⧧
⧧
activation parameters (ΔG° , ΔH° , ΔS° ) in both ATH and
2x
AH, relative to the free energy of amido(ene-amido) complex
either side of the PNNP ligand plane (Scheme 4). Simplified
complex 4b , as discussed above, is structurally analogous to
4b
ATH for the turnover-limiting step (hydride transfer to
acetophenone from 5b ) were taken from our previous
H
for ATH and 4a for AH. The relative free energies (G°) in
H
4
b. Using molecule 4a as our free energy reference point, along
with all relevant small molecules, we wanted to investigate why
H
2q
2s
H splitting selectively occurred with complex 4b, leaving 4a
experimental and theoretical studies on the mechanism of
transfer hydrogenation using these amido(ene-amido) systems.
2
untouched (Scheme 2).
First, coordination of H to 4a successfully leads to
Table 4 clearly shows that the experimental and calculated H
2
2
2
optimization of the η -H complex 4aH , which is 13.8 kcal/
splitting free energy barrier for AH are both higher than the
turnover-limiting step for ATH and that there is good
agreement between the experiment and theory for the case of
AH.
2
2
mol higher in energy than 4a. Carefully inspecting the
orientation of the amide ligand of 4aH reveals that the
2
2
nitrogen lone pair is pointing away from the η -H ligand
2
Table 3. Observed and Calculated (eq 4) Rates of Reactions
a
rate (v ) (M s−1)
k = v /([Fe][H ]) (M s−1
−1
entry
[Fe] (M)
temp (K)
[H2] (atm/M)
[ketone] (M)
)
0
0
2
4
−2
−2
−6
1
2
3
4
5
6
7
8
3.6 × 10−
3.6 × 10−
3.6 × 10−
2.4 × 10−
4.8 × 10
3.6 × 10−
323
323
323
323
323
298
303
308
20/6.1 × 10
3.6 × 10
3.6 × 10
0.16 ± 0.01
0.17 ± 0.01
0.17 ± 0.01
0.15 ± 0.01
0.16 ± 0.01
0.043 ± 0.004
0.060 ± 0.005
0.074 ± 0.007
4
4
4
4
4
4
4
−2
−2
−6
20/6.1 × 10
7.2 × 10
3.7 × 10
−2
−2
−6
10/3.0 × 10
3.6 × 10
1.8 × 10
−2
−2
−6
20/6.1 × 10
3.6 × 10
2.2 × 10
−
−2
−2
−6
20/6.1 × 10
3.6 × 10
4.7 × 10
−2
−2
−7
20/5.4 × 10
3.6 × 10
8.3 × 10
−
−2
−2
−6
3.6 × 10
3.6 × 10−
20/5.6 × 10
3.6 × 10
1.2 × 10
−2
−2
−6
20/6.0 × 10
3.6 × 10
1.6 × 10
a
The H concentration in benzene was calculated using Henry’s law based on the data of ref 9.
2
F
dx.doi.org/10.1021/om500479q | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
a
Scheme 3. Calculated Structures Starting with Simplified Amido(ene-amido) Complex 4b (1 atm, 298 K)
H
a
Relative free energies (G°) are presented in kcal/mol.
up to 50 h− at 45 °C, 50 atm H ), but highly enantioselective,
1
2
catalysts generated in situ using Fe (CO) and a macrocyclic
3
12
2z
phosphorus nitrogen ligand. The current systems have
activities comparable to the latter group but are not as
enantioselective. Nevertheless, they are interesting because a
comparison between ATH and AH can be made due to their
well-defined kinetics.
We propose that catalysis proceeds mainly via the cycle
shown in Scheme 5. This cycle accounts for our spectroscopic
observation of the conversion of 1 to produce the amido(ene-
amido) isomers 4a and 4b and the reaction of 4b with
dihydrogen (or with isopropanol in ATH) to give the reactive
dihydride 5. The structure and role of the dihydride 5 in ATH
have already been elucidated, and this complex in the (S,S)
configuration is known to react with prochiral ketones
enantioselectively and rapidly at room temperature to give
Figure 6. Calculated structure of TS4bH,5bH (ν = 1074i). Distances are
in angstroms (Å).
2x
alcohols in the (R) configuration with high ee. This sense of
enantioinduction is also observed when (S,S)-3 is used as a
catalyst for ATH or AH. This simplified cycle does not explain
why the precursors 1 and 2 give alcohols in high ee for ATH, at
DISCUSSION
■
Asymmetric pressure hydrogenation of ketones catalyzed by
iron complexes is rare, but recently, a family of enantioselective
catalysts with TOF up 2000 h at 50 °C and 5 atm H have
been reported. There is also a recent report of less active (TOF
2x
least under the short reaction times (minutes), but racemic
products for AH, in reaction times of hours at room
temperature. The as yet uncharacterized side reactions that
−1
2
a
Scheme 4. Calculated Structures Starting with Amido(ene-amido) Complex 4a or 4b (1 atm, 298 K)
a
Relative free energies (G°) are presented in kcal/mol. Conformational isomers of 4b and 4bH have also been calculated, but these conformers do
2
2
not facilitate η -H coordination or H splitting (see the Supporting Information).
2
2
G
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Organometallics
Article
Scheme 5. Proposed Simplified Mechanism for the Major
AH Catalytic Cycle (in Black) and the Mechanism for ATH
(
in Gray)
lead to a second hydride species and possibly alkoxide
complexes, as well as the role of the apparently less reactive
amido(ene-amido) complex 4a, still need to be clarified. Side
reactions with alcohols are clearly important since the current
work has shown that AH is suppressed by use of tert-butanol as
the solvent. In addition, an isopropoxide complex was
2s
calculated to be of comparable energy to the hydride 5.
This cycle along with DFT calculations helps to explain why
these iron catalyst systems are biased toward ATH over AH.
The barrier for the formation of the reactive hydride 5 is higher
for AH than ATH. The reaction of amido(ene-amido) with
dihydrogen is calculated to have a barrier of 16 kcal/mol,
whereas that with isopropanol is 12 kcal/mol (Table 4). The
experimentally determined barrier for the former is 20 kcal/mol
at 50 °C and 20 atm, although side reactions, currently under
investigation, might be responsible for the discrepancy between
experiment and theory.
CONCLUSIONS
In addition to being a highly efficient catalyst for the
asymmetric transfer hydrogenation of ketones, the amine-
■
Figure 7. Calculated structures of 4aH , 4bH , and TS (ν =
4b,5b
2
2
1
089i). Distances are in angstroms (Å). Phenyl hydrogens have been
(
imine)diphosphine iron complexes also catalyze the H2
omitted for clarity.
hydrogenation of ketone substrates with low activity and
Table 4. Comparison of Experimental and Calculated (from DFT) Activation Parameters for Hydride Transfer to
a
Acetophenone in ATH Relative to 4b , and H Splitting in AH Relative to 4b
H
2
b
c
d
d
parameter
ATH exptl.
ATH calcd.
AH exptl.
AH calcd.
⧧
ΔH° (kcal/mol)
6.0 ± 0.2
−28 ± 1
14.3 ± 0.5
−3
−48
12
10.0 ± 0.2
−31.0 ± 0.5
20.0 ± 0.5
7
−29
16
⧧
ΔS° (cal/mol·K)
⧧
ΔG° (kcal/mol)
a
ATH calculations are at the M06/6-31++G(d,p) level of theory with isopropanol solvent continuum, and AH calculations are at the M06-L/TZVP/
b
TZVPFit level of theory with tetrahydrofuran solvent continuum. Reference 2q. There are potentially large errors associated with these data due to
the multiparameter kinetic modeling involved and the difficulty in separating the kinetics of catalyst activation from the kinetics of the catalytic cycle.
c
d
Reference 2s. 20 atm, 323 K.
H
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Organometallics
Article
enantioselectivity. The same structure of the amine iron
hydride intermediate formed by reacting the amido(ene-
amido) iron complex with dihydrogen as that obtained by
reacting with 2-propanol suggests a similar reaction mechanism
in both hydrogenation reactions. The zero-order of reaction
rate on the ketone concentration and the first-order on the H2
pressure and catalyst concentration indicate that the heterolytic
splitting of dihydrogen across the polar iron−nitrogen double
bond is the turnover-limiting step in AH, an observation
supported by detailed DFT calculations. The system is biased
toward ATH over AH because the barrier for isopropanol
addition to the iron amido species (Scheme 1, eq 2) is a lower-
energy process than addition of dihydrogen (Scheme 1, eq 3).
In contrast to the case of transfer hydrogenation catalysis, the
base concentration has no effect on the hydrogenation rate and
enantioselectivity when the number of equivalents of the base
relative to the precatalyst is greater than a 2:1. Further
investigation into the role of the base, the side reactions that
lead to lower rates and enantioselectivity for catalytic
hydrogenation, and changes in catalyst design in order to
Synthesis of the Cyclic Phosphonium Dimers with meta-
Xylyl Substituents at the Phosphorus Atoms. In an argon
glovebox, a THF (50 mL) solution of bis(3,5-dimethylphenyl)-
phosphine chloride (1.30 g, 4.70 mmol) was added to lithium powder
(0.16 g, 23.5 mmol) in a round-bottom flask charged with a stirring
bar. The resultant mixture was stirred at 25 °C for 30 min with the
formation of a red solution. The dark red solution was then filtered via
a sintered glass crucible to remove a black precipitate. Chloroace-
taldehyde diethyl acetal (0.72 g, 4.70 mmol) was added, and the
mixture was stirred at 25 °C overnight. The flask was taken out of the
glovebox, and diluted hydrochloric acid (10 mL, 1.17 M) was added.
The mixture was stirred overnight to cause the white precipitate. The
white suspension was filtered to obtain a white solid, and the solution
was discarded. The white solid was washed with water (20 mL) by
stirring the suspension for more than 3 h. The white suspension was
filtered to obtain a white solid, which was further washed with a 1:1
mixture of hexane/ethyl acetate. The final product was dried under
vacuum for more than 12 h. Yield: 1.2 g, 80%. Two diastereomers in a
obtain more efficient H hydrogen catalysts are ongoing in our
2
lab.
EXPERIMENTAL SECTION
■
General Considerations. All procedures and manipulations
involving air-sensitive materials were performed under an argon or
nitrogen atmosphere using Schlenk techniques or a glovebox with
nitrogen or argon. Solvents were degassed and dried using standard
procedures prior to all manipulations and reactions. The catalyst
2
x
precursors 1−3 were synthesized following our previous procedure.
Acetophenone and liquid ketone substrates were distilled under argon
and stored under molecular sieves in a glovebox prior to reduction
reaction, while the solid substrates were purified by sublimation.
Deuterated solvents were purchased from Cambridge Isotope
Laboratories and distilled and dried over activated molecular sieves.
All of the other reagents used in the procedures were purchased from
commercial sources and utilized without further purification. NMR
spectra were recorded at ambient temperature and pressure using
1
ratio of 4:5 were observed. For the major isomer: H NMR (400 MHz,
CDCl + 2 drop CD OD) δ: 2.30 (s, 12H, CH ), 3.64 (m, 2H, CH ),
3
3
3
2
3.96 (m, 2H, CH ), 5.91 (m, 2H, CHOH), 7.23 (m, ArH), 7.43 (m,
2
1
3
1
ArH), 7.51 (m, ArH), 7.57 (m, ArH). C{ H} NMR (100 MHz;
CDCl + 2 drop CD OD) δ: 21.0 (s, CH ), 21.1 (s, CH ), 23.5 (d, J
3
3
3
3
CP
1
Varian Gemini 600, 400, and 300 MHz spectrometers [ H (600, 400,
= 42.0 Hz, PCH ), 61.6 (d, J = 65.7 Hz, PCHOH), 115.7 (d, JCP
=
2
CP
and 300 MHz), 13C{ H} (150, 100, and 75 MHz), and P{ H} (242,
1
1
31
1
83.1 Hz, ArC), 116.7 (d, JCP = 81.8 Hz, ArC), 129.6 (d, JCP = 9.6 Hz,
ArC(o)), 130.5 (d, JCP = 9.9 Hz, ArC(o)), 136.9 (d, JCP = 3.1 Hz,
61, and 121 MHz). The 3 P NMR spectra were referenced to 85%
1
H PO4 (0 ppm). Elemental analyses were performed using a
ArC(p)), 137.4 (d, JCP = 2.9 Hz, ArC(p)), 140.0 (d, J = 13.8 Hz,
3
CP
ArC(m)), 141.2 (d, JCP = 13.2 Hz, ArC(m)). 31P{ H} NMR (161
1
PerkinElmer 2400 CHN elemental analyzer at the Department of
Chemistry at the University of Toronto. The electrospray ionization
mass spectrometry (ESI-MS) data were collected on an AB/Sciex
QStar mass spectrometer with an ESI source.
1
MHz; CDCl + 2 drop CD OD) δ: 11.8. For the minor isomer: H
3
3
NMR (400 MHz, CDCl + 2 drop CD OD) δ: 2.27 (s, 6H, CH ),
3
3
3
2.28 (s, 6H, CH ), 3.64 (m, 2H, CH , overlap with the major isomer),
3
2
All DFT calculations were performed using Gaussian 09 (Revision
3.96 (m, 2H, CH , overlap with the major isomer), 6.00 (m, 2H,
CHOH), 7.23 (m, ArH, overlap with the major isomer), 7.43 (m, ArH,
2
11
B.01 or D.01). Two different combinations of density functionals
1
2
13
and basis sets were used: M06 /6-31++G(d.p) (only for complexes
overlap with the major isomer), 7.51 (m, ArH, overlap with the major
14
15
13
1
4
b , 4b H , TS
, and 5b ) or M06-L /TZVP (also known as
isomer), 7.57 (m, ArH, overlap with the major isomer). C{ H} NMR
(100 MHz; CDCl + 2 drop CD OD) δ: 21.0 (s, CH ), 21.1 (s, CH ),
H
H
2
4bH,5bH
H
def-TZVP) with the TZVPFit density fitting basis set. Either normal
3
3
3
3
(
opt) or tight (opt = tight) convergence criteria were used for all
23.3 (d, JCP = 47.0 Hz, PCH ), 61.4 (d, J = 66.4 Hz, PCHOH), 114.7
2 CP
optimizations, and a pruned (99 590) integration grid was used
throughout (grid = ultrafine). Optimizations were performed in
tetrahydrofuran (THF) solvent using the integral equation formalism
(d, JCP = 80.9 Hz, ArC), 115.5 (d, JCP = 82.5 Hz, ArC), 129.5 (d, JCP
10.0 Hz, ArC(o)), 130.4 (d, JCP = 10.0 Hz, ArC(o)), 137.0 (s, ArC(p)),
137.4 (s, ArC(p)), 140.4 (d, J = 13.6 Hz, ArC(m)), 140.8 (d, JCP
=
=
CP
16
31
1
polarizable continuum model (IEF-PCM) with radii and non-
13.9 Hz, ArC(m)). P{ H} NMR (161 MHz; CDCl + 2 drop
CD OD) δ: 14.3. FT-IR (KBr, cm ): 561w, 690s, 864s, 953m, 1071s,
3
1
7
−1
electrostatic terms from the SMD solvation model (scrf = smd). Full
vibrational and thermochemical analyses (1 atm, 298 K) were
performed on optimized structures to obtain solvent-corrected free
energies (G°) and enthalpies (H°). For direct comparison of activation
parameters between calculated and experimental species (Table 4), the
freqchk utility was used (20 atm, 323 K) to obtain solvent-corrected
free energies (G°) and enthalpies (H°). Optimized ground states were
found to have zero imaginary frequencies, while transition states had
exactly one imaginary frequency. Open-shell optimizations were not
considered in this study. Three-dimensional visualizations of calculated
3
1139s, 1215w, 1270s, 1380m, 1420s, 1440s, 1600s, 2865s, 2920s,
2989s, 3028s, 3368s. HRMS (ESI-TOF, MeOH/CH Cl = 1:1) m/z
2
2
+
calculated for [C H OP] 285.1408, found: 285.1406; calculated for
methanol adduct [C H O P] 317.1671, found: 317.1674. Anal.
18
22
+
1
9
26
2
Calcd for C H Cl O P ·H O: C, 65.53; H, 7.03. Found: C, 65.62; H,
36
44
2
2
2
2
7.20.
Preparation of Complex 3. This complex was synthesized as
2x
reported, and the spectroscopic properties were identical. Anal.
Calcd for C H BClF N OP Fe: C, 64.24; H, 5.92; N, 2.94. Found:
51
56
4
2
2
18
structures were generated by ChemCraft.
C, 63.92; H, 5.94; N, 2.84.
I
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General Procedure for the Asymmetric Transfer Hydro-
genation of Ketone Substrates Using 3 as the Catalyst
Precursor. For comparison with 1 and 2, the reaction conditions
for the asymmetric transfer hydrogenation of acetophenone and other
ketone substrates catalyzed by 3 were kept the same as our previous
vial in the argon glovebox was charged with 1 (100 mg, 1.20 mmol)
and KO Bu (27.0 mg, 2.40 mmol), and THF (25 mL) was added. The
reaction mixture was allowed to stir at room temperature for 10 min to
yield a dark blue solution. The THF solution was transferred via a
syringe equipped with a 12 in. needle under a hydrogen flow of 5 atm
to a stainless steel 50 mL Parr hydrogenation reactor that was flushed
t
2q
standard conditions. The final concentrations of the reagents were
−5
adjusted to be as follows [ketone] = 0.412 M, [3] = 6.73 × 10 M,
several times with hydrogen gas prior to use. The H pressure was
2
t
−4
i
[
KO Bu] = 5.45 × 10 M, and [PrOH] = 12.4 M. The quantity of the
adjusted to 20 atm, and the solution was stirred at room temperature
for 30 min. The pressure was reduced to 5 atm, and the product
solution was sucked into a syringe equipped with a 12 in. needle under
a hydrogen flow of 5 atm. This solution was then transferred into a
Schlenk flask that was charged with inert gas. The solvent was
removed under vacuum, and the product was extracted with C D for
precatalyst for each single catalytic reaction was measured via a stock
solution method. A concentrated stock solution was made by
dissolving complex 3 (19 mg, 0.0197 mmol) in 6.08 g of cold
dichloromethane. After all the solids were dissolved, the solution was
immediately sucked into a syringe. The solution was then divided into
several equal portions in several vials such that each portion has 0.2 g
of the stock solution, and then dichloromethane was evaporated to
obtain a yellow solid. These operations led to a precatalyst quantity of
6
6
1
NMR analysis. The H NMR spectrum (600 MHz, C D ) indicated
6
6
the presence of two major products: the amine iron hydride 5 and the
2
amido(ene-amido) complex 4a. For 5: δ: −2.25 (dd, J = 70.0 and
HP
−
7
6
.48 × 10 mol in each vial. The base was prepared by dissolving
70.8 Hz, FeH), 3.80 (dd, J
= 10.8 Hz, J
= 11.4 Hz, 1H,
HH
HH
t
i
KO Bu (10 mg, 0.089 mmol) in PrOH (1.02 g, 1.30 mL). These
CH(Ph)NH), 4.00 (m, NH), 4.35 (dd, JHP = 2.2 Hz, JHH = 4.4 Hz, 1H,
−1
solutions were used only after all the solids were completely dissolved
PCH), 4.52 (d, JHH = 10.8 Hz, CH(Ph)N). FT-IR (KBr, cm ): 1523
i
and for less than 2 days. PrOH (6.63 g, 8.44 mL), the ketone substrate
(ν ), 1872 (νCO), 3500 (νNH). For 4a: δ: 3.89 (dd, JHP = 3.7
NCHCHP
−3
(
3.95 × 10 mol), and a clean stirring bar were added to the vial that
Hz, J = 3.7 Hz, 1H, PCH), 4.22 (m, 1H, CH(Ph)), 4.70 (m, 1H,
HH
−1
contains the precatalyst, and the solution was stirred for several
minutes until all the precatalysts were dissolved. A 0.06 g portion of
CH(Ph)). FT-IR (KBr, cm ): 1906.
Kinetics. The above hydrogenation catalysis procedure was utilized
for the kinetic study except that the solvent was benzene.
−6
the base stock solution (5.24 × 10i mol of base, 8 equiv) was added
into a vial that contains 0.501 g of PrOH, and the mixed solution was
then added into the above solution to initiate the catalytic reaction.
The samples were taken by injecting small portions of the reaction
mixture into septa-sealed GC vials containing aerated 2-propanol for
efficient quenching of the reaction. Samples were analyzed using a
PerkinElmer Autosystem XL chromatograph with a chiral column (CP
chirasil-Dex CB 25 m × 2.5 mm). Hydrogen gas was used as a mobile
phase at a column pressure of 5 psi. The injector temperature was 250
ASSOCIATED CONTENT
Supporting Information
A typical reaction profile in terms of formation of 1-
phenylethanol with time catalyzed by 1 in THF; the H
■
*
S
1
NMR spectrum of the product from the reaction of 1, base, and
20 atm H ; and the Eyring plot for the calculation of activation
2
°
C, and the FID temperature was 275 °C. The amount of 1-
parameters. This material is available free of charge via the
Internet at http://pubs.acs.org.
phenylethanol in the sample was determined relative to the amount of
the acetophenone.
General Procedure for the High-Pressure H Hydrogenation
2
AUTHOR INFORMATION
Corresponding Author
E-mail: rmorris@chem.utoronto.ca.
Notes
■
of Ketone Substrates Using 1−3 as the Catalyst Precursors.
Hydrogenation reactions were carried out at constant pressures of H2
using a stainless steel 50 mL Parr hydrogenation reactor. The
temperature was maintained using a constant temperature water bath.
The reactor was flushed several times with hydrogen gas at 5 atm prior
to the addition of substrate and catalyst. For a standard catalysis, the
catalyst was generated by first reacting the precatalysts (0.01 mmol)
*
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
t
■
with KO Bu (0.02−0.04 mmol) in THF (5 mL) in the glovebox to
NSERC Canada is thanked for a Discovery Grant to R.H.M.
and a Doctoral Scholarship to D.E.P. The Deutscher
Akademischer Austauschdienst (DAAD) is thanked for support
for S.T. The Canadian Foundation for Innovation, project
number 19119, and the Ontario Research Fund provided
funding of the Centre for Spectroscopic Investigation of
Complex Organic Molecules and Polymers.
form the amido(ene-amido) iron complex. A THF (25 mL) solution
of the substrate (1 mmol) was injected into the reactor via a syringe
equipped with a 12 in. needle under a hydrogen flow of 5 atm. This
solution was pre-equilibrated in a water bath at a preset temperature
for more than 30 min. The catalysis was initiated by injecting the
catalyst solution into the reactor with rigorous stirring under a
hydrogen flow of 5 atm, followed by adjusting the H pressure to the
2
preset value. Small aliquots of the reaction mixture were sampled at
regular time intervals from a stainless-steel sampling dip tube attached
to a modified Parr reactor. The dip tube was 30 cm in length with an
inner diameter of 0.01 in., and a swing valve was attached to the end of
the sampling tube. Samples were analyzed using a PerkinElmer
Autosystem XL chromatograph with a chiral column (CP chirasil-Dex
CB 25 m × 2.5 mm). Hydrogen gas was used as a mobile phase at a
column pressure of 5 psi. The injector temperature was 250 °C, and
the FID temperature was 275 °C. The amount of 1-phenylethanol in
the sample was determined relative to the amount of the
acetophenone. For the catalysis carried out in other solvents, the
real catalyst was still generated in THF in the glovebox. THF was then
removed under vacuum, and the employed solvent (5 mL) was added
to extract the amido(ene-amido) iron complex. Other procedures were
the same as above. A typical reaction profile in terms of formation of 1-
phenylethanol with time catalyzed by 1 and 2 equiv of base in THF is
shown in Figure S1 (Supporting Information).
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dx.doi.org/10.1021/om500479q | Organometallics XXXX, XXX, XXX−XXX