An efficient and chemoselective iron catalyst for the hydrogenation of ketones

Article abstract of DOI:10.1021/ja071159f

Iron complex 1 containing electronically coupled acidic and hydridic hydrogens catalyzes the hydrogenation of ketones under mild conditions. This hydrogenation catalyst shows high chemoselectivity for aldehydes, ketones, and imines, and isolated C=C, C_≡C, C-X, -NO₂, epoxides, and ester functions are unaffected by the hydrogenation conditions. Mechanistic studies have established a reversible hydrogen transfer step followed by rapid dihydrogen activation. The same iron complex also catalyzes transfer hydrogenation of ketones. Copyright

Full text of DOI:10.1021/ja071159f

Published on Web 04/17/2007
An Efficient and Chemoselective Iron Catalyst for the Hydrogenation of
Ketones
Charles P. Casey* and Hairong Guan
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
Received February 16, 2007; E-mail: casey@chem.wisc.edu
Ligand metal bifunctional catalysis has provided efficient new
precious metal catalysts (Ru, Rh, Ir) for the hydrogenation of polar
multiple bonds.1 In contrast, nature often uses iron-based catalysts
such as hydrogenase for reductions.2-4 Here we report an effective
iron-based catalyst 1 for the selective hydrogenation of aldehydes
and ketones under mild conditions (Figure 1).Our extensive studies
Figure 1. Catalysts with acidic (in blue) and hydridic (in red) hydrogens.
of a tolyl analogue 21d,5 of the active reducing agent of the Shvo
Scheme 1
ruthenium catalyst led us to investigate the possible use of Kno¨lker’s
iron complex 16 as a hydrogenation catalyst. Complex 1, like the
diiron cofactor of Fe hydrogenase 3,2c has an iron hydride and an
acidic hydrogen available for transfer to polar multiple bonds.
Stoichiometric reduction of acetophenone by 1 was observed in
toluene-d8 at room temperature (Scheme 1). 1H NMR spectroscopy
showed the formation of 1-phenylethanol complex 4a;7 the methyl
doublet at δ 1.37 and a CH3CHOH quartet at δ 4.41 were shifted
from resonances for the free alcohol. Two resonances at δ 0.36
and 0.40 were observed for the SiMe3 groups of 4a, rendered
diastereotopic by complexation of the chiral alcohol. The symmetric
alcohol complex 4b, generated from the reaction between 1 and
acetone, gave only one TMS resonance (δ 0.33). Unfortunately,
because the reduction of acetophenone did not go to completion
and because 4a slowly decomposed (>12 h) to unidentified
Scheme 2. Catalytic Cycle for the Hydrogenation of
Acetophenone
products, it was not possible to isolate and fully characterize 4a.
To test the hypothesis that partial reduction might be due to the
reversibility of hydrogen transfer, we studied the reaction of 1 with
acetophenone in the presence of 2 equiv of PPh3 as a trapping agent
for reactive intermediate A and found complete hydrogen transfer
reaction within 4 h, with clean formation of iron triphenylphosphine
complex 58 and free 1-phenylethanol. Kinetic studies showed first-
order dependence on both 1 and acetophenone and no dependence
on PPh3. When the reduction was carried out in the presence of 10
equiv of 1-phenylethanol (0.08 M) in addition to PPh3, the
disappearance of 1 was 15% slower and up to 20% of alcohol
complex 4a was detected, but 4a was then converted to 5. These
data are consistent with more rapid trapping of intermediate A by
and in acetophenone and was independent of hydrogen pressure
between 4.4 and 35 atm (k4[H2] . k-1[alcohol]).11 The second-
PPh3 than either dehydrogenation of alcohol by A or formation of
order rate constant for the catalytic process (1.1(1) × 10-2 M-1
alcohol complex 4a from A (i.e., k3[PPh3] . (k-1 + k2)[alcohol]).
The second-order rate constant k1 at 25 °C was 9.8(2) × 10-3 M-1
s-1) at room temperature was similar to that for the stoichiometric
reaction of 1 with acetophenone at 25 °C.
s-1. Rate measurements between 10 and 25 °C gave ∆Hq ) 9.0 (
0.6 kcal mol-1 and ∆Sq ) -37.5 ( 2.1 eu. The large negative
entropy of activation is consistent with a highly ordered transition
state bringing 1 and acetophenone together for hydrogen transfer.1d,9
If H2 efficiently traps intermediate A to regenerate iron hydride
1, then a catalytic hydrogenation cycle would be completed (Scheme
2). Indeed, 1 (2 mol %) catalyzed the hydrogenation of acetophen-
one under 3 atm H2 at room temperature (eq 1). In situ monitoring
with a ReactIR apparatus allowed quantitative measurement of the
rate of hydrogenation and also established that 1 (2001 and 1941
Iron complex 1 is an efficient and selective catalyst for
hydrogenation of the polar multiple bonds of aldehydes, ketones,
and imines (Table 1). Benzaldehyde was hydrogenated much more
rapidly than ketones. Ketones with electron-withdrawing groups
(entries 9 and 10) reacted unusually fast. High diastereoselectivity
(meso/dl ) 25) was seen in the hydrogenation of benzoin (entry
10). High chemoselectivity was also observed: epoxides, esters,
cm-1 10
was the only iron complex present during catalysis. This
)
implies that hydrogen transfer from 1 is the rate-limiting step in
the catalytic cycle. The rate of hydrogenation was first order in 1
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J. AM. CHEM. SOC. 2007, 129, 5816-5817
10.1021/ja071159f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Hydrogenation of Ketones and Related Substrates
Catalyzed by Iron Hydride 1a
Based on the reversibility of hydrogen transfer, we expected that
1 might catalyze the transfer hydrogenation of ketones.17 Indeed,
iron hydride 1 catalyzes the transfer hydrogenation of acetophenone
using 2-propanol as the hydrogen donor (eq 3).
In summary, we have described the first well-defined iron catalyst
for the hydrogenation of ketones. The hydrogenations can take place
at room temperature under low hydrogen pressure with high
chemoselectivity. Efforts to develop asymmetric hydrogenation of
ketones catalyzed by related chiral iron complexes are currently in
progress.
Acknowledgment. Financial support from the Department of
Energy, Office of Basic Energy Sciences, is gratefully acknowl-
edged. Grants from NSF (CHE-9208463 and CHE-9709065) and
NIH (1 S10 RR0 8389-01) for the purchase of NMR spectrometers
are acknowledged.
Supporting Information Available: Experimental details, summary
of kinetic runs, and Eyring plot. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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2006, 4, 393. (c) Shvo, Y.; Czarkie, D.; Rahamim, Y.; Chodosh, D. F. J.
Am. Chem. Soc. 1986, 108, 7400. (d) Casey, C. P.; Singer, S. W.; Powell,
D. R.; Hayashi, R. K.; Kavana, M. J. Am. Chem. Soc. 2001, 123, 1090.
(2) Iron hydrogenase enzymes: (a) Peters, J. W.; Lanzilotta, W. N.; Lemon,
B. J.; Seefeldt, L. C. Science 1998, 282, 1853. (b) Nicolet, Y.; Piras, C.;
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niline at 150 °C under 100 atm H2. Radhi, M. A.; Marko´, L. J. Organomet.
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(5) (a) Casey, C. P.; Johnson, J. B. J. Am. Chem. Soc. 2005, 127, 1883. (b)
Casey, C. P.; Bikzhanova, G. A.; Cui, Q.; Guzei, I. A. J. Am. Chem. Soc.
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a Conditions: substrate (1.5 mmol), iron hydride 1 (30 µmol, 2.0 mol %
catalyst), toluene (5 mL), 3 atm H2 at 25 °C. b Hydrogenation was performed
in diethyl ether for ease of product isolation. Hydrogenation is slower in
ether than in toluene. c Reaction run at 65 °C. d Isolated yield (NMR
conversion in parentheses).
(6) Hydride 1 was isolated as an intermediate in the synthesis of a
cyclopentadienone from a dialkyne. Kno¨lker, H.-J.; Baum, E.; Goesmann,
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Chart 1. Substrates Which Are Not Hydrogenated
(7) Early attempts to synthesize or spectroscopically observe analogous
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(8) Pearson, A. J.; Shively, R. J., Jr.; Dubbert, R. A. Organometallics 1992,
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and isolated alkenes and alkynes are not hydrogenated (Chart 1).12,13
For ketones with isolated CdC or CtC, only the ketone is
hydrogenated (entries 11-13). Iron catalyst 1 shows great functional
group tolerance. For example, carbon halogen bonds (entries 4, 5,
and 9),14 nitro groups (entry 6),15 benzyl ethers (entry 13), and
cyclopropyl rings (entry 14) survive the hydrogenation conditions.
A pyridine moiety can potentially bind iron and inhibit the catalytic
reaction; however, 2-acetyl pyridine (entry 15) was rapidly
hydrogenated. 4-Acetylbenzonitrile (entry 7) was not hydrogenated,
possibly due to the nitrile trapping of unsaturated intermediate A.
Hydrogenation of R,â-unsaturated ketones was complicated by some
reduction of the CdC double bond (eq 2).16
(9) For an alternative mechanism involving coordination of the substrate and
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Privalov, T.; Eriksson, L.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2006, 128,
14293.
(10) No 4a (1985 and 1924 cm-1 in toluene) was observed.
(11) High concentrations of added alcohol decreased the rate of catalytic
hydrogenation under low H2 pressure (see Supporting Information).
(12) Although some iron complexes can catalyze the isomerization of alkenes,13
1 neither hydrogenated nor isomerized 4-phenyl-1-butene.
(13) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104,
6217. (b) Long, G. T.; Weitz, E. J. Am. Chem. Soc. 2000, 122, 1431 and
references therein.
(14) Hydrodeiodination of aryl iodides occurs upon treatment with Fe(CO)5
and K2CO3 in methanol. Brunet, J.-J.; Taillefer, M. J. Organomet. Chem.
1988, 348, C5.
(15) The reduction of aromatic nitro compounds to anilines is catalyzed by
iron complexes. Cann, K.; Cole, T.; Slegeir, W.; Pettit, R. J. Am. Chem.
Soc. 1978, 100, 3969.
(16) See Supporting Information.
(17) For Ru-catalyzed transfer hydrogenation of ketones, see: Santosh Laxmi,
Y. R.; Ba¨ckvall, J.-E. Chem. Commun. 2000, 611.
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