Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis

Article abstract of DOI:10.1126/science.1230704

Piperidines are prevalent in natural products and pharmaceutical agents and are important synthetic targets for drug discovery and development. We report on a methodology that provides highly substituted piperidine derivatives with regiochemistry selectively tunable by varying the strength of acid used in the reaction. Readily available starting materials are first converted to dihydropyridines via a cascade reaction initiated by rhodium-catalyzed carbon-hydrogen bond activation. Subsequent divergent regio- and diastereoselective protonation of the dihydropyridines under either kinetic or thermodynamic control provides two distinct iminium ion intermediates that then undergo highly diastereoselective nucleophilic additions. X-ray structural characterization of both the kinetically and thermodynamically favored iminium ions along with density functional theory calculations provide a theoretical underpinning for the high selectivities achieved for the reaction sequences.

Full text of DOI:10.1126/science.1230704

Proton Donor Acidity Controls Selectivity in Nonaromatic Nitrogen
Heterocycle Synthesis
Simon Duttwyler et al.
Science 339, 678 (2013);
DOI: 10.1126/science.1230704
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REPORTS
Although local flexural stresses or structural con- planets, because the first ~700 My of planetary
20. J. W. Head III, L. Wilson, Planet. Space Sci. 41, 719
1993).
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212 (2012).
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(
trol can alter the orientations of intrusions (7), the evolution is poorly preserved in the geological
LGAs are distributed uniformly across the Moon records of all planets.
and show no clear preferred orientations or as-
2
1
sociation with known flexurally supported loads.
This pattern indicates largely isotropic horizontal
extension, as would be expected to arise from
global expansion. However, the lunar lithosphere
is thought to have been in a state of compression
throughout most of its history as a result of in-
terior cooling and global contraction (28). Super-
imposed stresses associated with the outward
migration of the Moon, with or without contem-
poraneous true polar wander, are similarly incon-
sistent with the locations and orientations of the
LGAs (7, 29). At the time of the intrusive activity
inferred here, the lithosphere must have been in a
horizontally extensional stress state to accommo-
date the inflation of the vertical tabular intrusions.
Taking the total length of the probable intrusion
population of 5300 km and the typical best-fit
widths of 5 to 40 km, the resulting horizontal
extensional strain of 0.035 to 0.27% equates to an
increase in the lunar radius by 0.6 to 4.8 km.
However, this estimate is complicated by the pos-
sibility of viscous accommodation of some of the
growth of the intrusions or lithospheric extension
not accompanied by intrusive activity that would
go undetected by GRAIL.
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Acknowledgments: The GRAIL mission is a component of
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to the Massachusetts Institute of Technology and the Jet
Propulsion Laboratory. J.C.A.-H., J.W.H., W.S.K., I.M., P.J.M.,
F.N., and G.J.T. were supported by grants from the NASA
GRAIL Guest Scientist Program. The data used in this study
will have been archived in the Geosciences Node of the NASA
Planetary Data System by the time of publication.
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Planet. Sci. 29, 489 (2001).
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Supplementary Materials
www.sciencemag.org/cgi/content/full/science.1231753/DC1
Materials and Methods
Supplementary Text
Figs. S1 to S13
1
1
1
6. J. C. Andrews-Hanna, J. Geophys. Res. 117, E04009
(
2012).
7. M. E. Purucker, J. W. Head III, L. Wilson, J. Geophys. Res.
17, E05001 (2012).
Tables S1 to S6
References (31–47)
1
Such a period of early extension was pre-
dicted by some thermal history models (28), de-
veloped to account for the absence of a global
population of large thrust faults on the Moon sim-
ilar to those found on Mercury. The thermal mod-
18. A. Gudmundsson, J. Volcanol. Geotherm. Res. 64, 1 (1995). 19 October 2012; accepted 27 November 2012
19. J. W. Head III, L. Wilson, Geophys. Res. Lett. 18, 2121
Published online 5 December 2012;
(1991).
10.1126/science.1231753
els best matched that constraint with an initial Proton Donor Acidity Controls
condition that included a 200- to 300-km-deep
magma ocean and a cooler deep interior, leading
to coupled warming of the interior and cooling
of the outer shell, with net expansion in the first
Selectivity in Nonaromatic Nitrogen
billion years followed by modest global contrac- Heterocycle Synthesis
tion. Cooling and contraction of the lunar litho-
1
1
1
1
sphere could also have contributed to extensional
strain at the depths of these intrusions within the
first few tens of millions of years after lunar
crustal formation. This thermal inversion may be
a natural outcome of the post-accretional temper-
ature profile of the Moon (30). Thermal history
models that satisfy the constraint of <1 km de-
crease in radius over the past 3.8 billion years
Simon Duttwyler, Shuming Chen, Michael K. Takase, Kenneth B. Wiberg,
2
1
Robert G. Bergman, Jonathan A. Ellman *
Piperidines are prevalent in natural products and pharmaceutical agents and are important
synthetic targets for drug discovery and development. We report on a methodology that
provides highly substituted piperidine derivatives with regiochemistry selectively tunable by
varying the strength of acid used in the reaction. Readily available starting materials are
first converted to dihydropyridines via a cascade reaction initiated by rhodium-catalyzed
carbon-hydrogen bond activation. Subsequent divergent regio- and diastereoselective protonation
of the dihydropyridines under either kinetic or thermodynamic control provides two distinct
iminium ion intermediates that then undergo highly diastereoselective nucleophilic additions.
X-ray structural characterization of both the kinetically and thermodynamically favored iminium
ions along with density functional theory calculations provide a theoretical underpinning for the
high selectivities achieved for the reaction sequences.
(Gy) also predict 2.7 to 3.7 km of global ex-
pansion during the first ~1 Gy, with the highest
rates occurring during the first 0.5 Gy (28), con-
sistent with our proposed period of expansion.
The amount of predicted expansion is sensitive
to the depth of the magma ocean and the initial
temperature of the deep interior. However, no
direct geological evidence for this early expan-
sion has previously been found, as a consequence
of the intense cratering of the surface at that time.
This earliest epoch of lunar expansion is now
revealed by GRAIL gravity data, which allows us the most well-known pharmaceuticals, as ex- portance of the piperidine scaffold are consistent
to see through the surface geology to the hidden emplified by traditional drugs such as quinine, with recent retrospective analyses of drug-
structures beneath. This result places a constraint morphine (and its many synthetic analogs such discovery research suggesting that renewed
on lunar evolution and raises important questions as oxycodone), as well as a number of more re- emphasis should be placed on the preparation,
regarding the early evolution of other terrestrial cent blockbusters, including plavix for the treat- evaluation, and development of compounds with
iperidines are saturated, nonplanar nitro- ment of stroke, cialis for erectile dysfunction,
gen heterocycles upon which the display and aricept for Alzheimer’s treatment (Fig. 1A)
P
of functionality has provided some of (1). The physical properties and therapeutic im-
678
8 FEBRUARY 2013 VOL 339 SCIENCE www.sciencemag.org

REPORTS
increased saturation and nonplanar display of hydride, a range of carbon nucleophiles have
functionality (2–4). also been added to both iminium intermediates trol was achieved using two equivalents of a
C–H bond functionalization has emerged as 5 and 6 to provide even more densely substi- weaker acid and equilibration over 12 to 16 hours
a powerful approach for the synthesis and mod- tuted derivatives of 7 and 8. at room temperature. Treatment with (PhO) PO H
ification of planar, aromatic N-heterocycles from Consider the addition of a proton, the simplest in tetrahydrofuran (THF) at room temperature gave
Protonation of 4a under thermodynamic con-
2
2
cheap and readily available precursors (5–11). of all electrophiles, to highly substituted 1,2- g-protonated trans-6a with >95% regio- and
Recently, we reported on a cascade reaction com- dihydropyridine 4a (Fig. 2). The four most likely diastereochemical purity. Solutions of trans-6a
prising rhodium-catalyzed C–H activation of imines products are cis and trans stereoisomers of reactive remained unchanged at room temperature over
1
with coupling to alkynes 2 to give azatrienes 3 iminium ions 5a and 6a, obtained by protonation weeks and upon heating to 80°C for 1 day, in-
followed by electrocyclization to provide densely at the a and g positions, respectively. Each of these dicating that the thermodynamically most stable
substituted 1,2-dihydropyridines 4 (Fig. 1B) reactive intermediates might also be expected to ion had formed. From a practical point of view,
(
12–15). These relatively unstable nonaromatic undergo additional transformations to give un- benzenesulfonic acid and diphenyl phosphoric
N-heterocycles can readily be aromatized to desired by-products such as enamine tautomers acid not only permit the directed formation of 5a
stable pyridines. Dihydropyridines 4 can also or dimers and higher-order oligomers. and 6a but also have the advantage of being
be converted to more highly saturated hetero- Despite the large potential number of products, easily weighable solids that provide iminium salts
cycles (16); however, densely substituted deriv- we directed our efforts at the selective formation that are soluble in organic solvents.
atives have previously been difficult to access of single iminium isomers (18, 19). When a strong To rigorously define the relative stereochem-
and pose a particular challenge in terms of regio- acid with a pK (where K is the acid dissociation istry and obtain a better understanding of the
a
a
and stereochemical transformation. Recently, constant) several units below that of 4a is used, a conformations of the products of protonation, x-ray
we demonstrated an in situ protonation/reduction protonation occurs under kinetic control to give structures were obtained for kinetically favored
sequence that provides tetrahydropyridines 7 5a as the major product (Fig. 2). Preferred kinetic iminium ion cis-5a and thermodynamically favored
with very high regio- and diastereoselectivity (17). protonation at the a position is consistent with elec- iminium ion trans-6a. Moreover, for kinetic iminium
Here, we demonstrate that tetrahydropyridines trophilic attack reported for conjugated dienolates ion cis-5a, a fast crystallization process (2 hours),
8
with an alternative substitution pattern and (20). A screening of acids and solvents showed rather than the typically preferred slow crystal for-
stereochemical display can be accessed by tuning that arylsulfonic acids in dichloromethane afford mation, was necessary to prevent iminium equil-
the strength of the acid used. In addition to a-protonated cis-5a as a single diastereomer with ibration. The ring in kinetic ion cis-5a adopts a
>95% selectivity. Thus, treatment of 4a with 1.1 boatlike conformation with the C3-Me and C6-Et
equivalents of PhSO H in dichloromethane at substituents in pseudoaxial positions (Fig. 3A1).
3
1
Department of Chemistry, Yale University, New Haven, CT
6520, USA. Division of Chemical Sciences, Lawrence Berkeley
room temperature resulted in complete protonation The piperidine ring in the thermodynamic ion
2
0
1
within 15 min as evidenced by H nuclear mag- trans-6a exhibits a more planar geometry of the
National Laboratory, and Department of Chemistry, University of
California, Berkeley, CA 94720, USA.
netic resonance (NMR) spectroscopy. Isomeriza- N–C1–C2–C3 moiety with the C5-Et and C6-Et
tion to other species, eventually trans-6a, took substituents now disposed in pseudoaxial posi-
*To whom correspondence should be addressed. E-mail:
jonathan.ellman@yale.edu
place with a half life of 38 hours.
tions (Fig. 3A2). Presumably, the pseudoaxial
Fig. 1. (A) Drugs containing a multiply substituted piperidine core. (B) Rhodium-catalyzed synthesis of dihydropyridine intermediates leading to
piperidine derivatives.
www.sciencemag.org SCIENCE VOL 339 8 FEBRUARY 2013
679

REPORTS
orientation of the substituents on the saturated spectra of the crude product mixture; its relative improvement of diastereomeric ratio was possible
carbons for both the kinetic and thermodynamic configuration of the saturated ring carbon atoms using a sterically more demanding reducing agent.
iminium ions avoids unfavorable A-1,2-interactions. was established unambiguously by x-ray crystal- Tolerance of different N-substituents (8a–c), un-
Density functional theory (DFT) calculations lography (fig. S4). Starting from differently sub- symmetrical and functionalized alkynes (8d–f), as
were carried out at the B3LYP/6-311G+(d,p) level stituted imine and alkyne precursors, products 8b–i well as (hetero-)aryl substituents (8g–i) under-
of theory to further characterize the energies and were obtained in high overall yields of 61 to 87% scored the generality of the methodology.
conformations for the four possible protonation (Fig. 4). More importantly, very high diastereo-
Through this sequence, the piperidine products
products (21). The kinetic iminium ion cis-5a selectivities were observed uniformly except for 8b 8 were obtained via the direct generation of iminium
was calculated to adopt a boatlike conformation and 8g, which were obtained as a 10:1 and 8.5:1 ions 6 from imine and alkyne inputs. Isolation of
with the C3-Me and C6-Et groups in pseudoaxial mixture of two diastereomers, respectively. In the the dihydropyridine intermediate 4 before proto-
3
positions, consistent with the x-ray structure (Fig. case of 8g, reduction using Li[i-Bu BH] increased nation and reduction was only necessary for the
3B1). The alternative boatlike conformation with the diastereoselectivity to >95% and showed that preparation of products 8e and 8f. All other highly
the C3-Me and C6-Et groups in pseudoequatorial
positions was calculated to be higher in energy
by 8.3 kcal/mol, consistent with the unfavorable
A-1,2-interactions imparted by adjacent alkenyl
methyl groups (22). The thermodynamic protona-
tion product trans-6a was calculated to be the
most stable of the four possible iminium ions by
H Et
H Et
acid H–A with
pKa << pKa(4a–H ) Bn
Et
+
Bn
Et
H
N
N
H+
α-prot.
H+
γ-prot.
typically:
Me
Me
Me
PhSO3H (1 equiv)
CH2Cl2, RT, 15 min
Me
H Me
Et
cis-5a
cis-6a
Bn
Et
>
3 kcal/mol, consistent with its being the only
observable isomer under thermodynamic control
Fig. 3B2). The overall geometry, bond distances,
N
Me
Me
(
Me
and angles obtained with the DFT calculations
are in very good agreement with the structures
obtained for both cis-5a and trans-6a.
4a
H Et
H Et
acid H–A with
H
dihydropyridine
+
Bn
Et
Me
Bn
pKa < pKa(4–H )
Et
~
N
N
H+
α-prot.
H+
γ-prot.
The conditions developed for kinetic and ther-
modynamic protonation to provide single diaster-
eomers of reactive iminium ions set the stage
for an extremely efficient protocol to prepare
distinct regio- and diastereomeric tetrahydropyr-
idines 7 and 8 with multiple stereogenic centers.
Dihydropyridines 4 are first prepared by the afore-
mentioned Rh-catalyzed cascade process from
commercially available alkynes 2 and imines 1,
which are in turn readily prepared from common
enones and primary amines. Kinetic protonation
of 4 at the a position provides iminium ions 5,
which upon nucleophilic addition should provide
tetrahydropyridines 7. Alternatively, thermody-
namic protonation at the g position provides ions
Me
Me
Me typically:
(PhO)2PO2H (2 equiv)
THF, RT, 12–16 h
Me H
Me
trans-6a
trans-5a
Fig. 2. Four possible iminium ions resulting from protonation of dihydropyridine 4a. RT, room
temperature.
6, to which nucleophilic addition should provide
tetrahydropyridines 8, respectively. Variation of
the substitution pattern in each starting component
should result in a vast number of potential per-
mutations for the differential display of function-
ality in the stable piperidine derivatives 7 and 8.
We first sought to explore reductions to pro-
vide hydride addition products 7 and 8 obtained
from kinetic and thermodynamic protonation, re-
spectively (Fig. 4). We recently reported that upon
formation of dihydropyridine 4 treatment with
3
Na[(AcO) BH] in the presence of acetic acid pro-
vides 7 (Nu = H) in good overall yields based upon
starting imine 2 with uniformly very high stereo-
selectivity (17). This reaction presumably pro-
ceeded by in situ formation and then reduction
of kinetic iminium 5.
To explore reduction of the thermodynami-
cally favored iminiums 6, formation of 6a under
thermodynamic control was followed by reduc-
–
tion with the mild hydride donor [(AcO)
3
BH] in
THF to afford tetrahydropyridine 8a in an 80%
overall yield with respect to imine 1a (Fig. 4, Fig. 3. X-ray crystal structures (displayed with 50% displacement ellipsoids) of iminium ions (A1) cis-5a
conditions B and C). Compound 8a was formed and (A2) trans-6a; calculated structures of (B1) cis-5a and (B2) trans-6a. Numbers are bond lengths in
as a single diastereomer as evidenced by NMR Å; H atoms have been omitted except when attached to saturated ring atoms.
680
8 FEBRUARY 2013 VOL 339 SCIENCE www.sciencemag.org

REPORTS
substituted piperidine derivatives required only a curred. Organometallic reagents R–[M] of high reagents, respectively. Organometallic reagents were
single workup and purification at the end of the Brønsted basicity, such as alkyllithiums and alkyl selected that favor electrophilic addition over com-
sequence. Grignard reagents, led to mixtures of C2-addition petitive deprotonation pathways (23).
Successful hydride reduction of the iminium products 7 or 8 and dihydropyridines 4 resulting Addition reactions to both cis-5 and trans-6
ions suggested the feasibility of diastereoselective from deprotonation. We identified several nucleo- proceeded in high yields and excellent diastereo-
addition of carbon nucleophiles, although compet- philes that underwent clean 1,2-addition and af- selectivities (Fig. 4). For these transformations, the
itive deprotonation pathways posed a challenge. forded only minor amounts of undesired elimination dihydropyridine intermediates 4 were separated
Iminium ions 5 and 6 both exhibited C-electrophilic products. Allyl, benzyl, alkynyl, and ester groups from the rhodium catalyst by filtration through alu-
C2 positions but also Brønsted-acidic a and g sites could be introduced using allyl–[CeCl
2
], ArCH
2
–
3
mina, converted to the iminium ions with PhSO H
where protonation of the p system of 4 had oc- [CeCl ], RC≡C–[MgCl], and ROC(O)CH –[ZnBr] or (PhO) PO H, and added to an excess of the
2
2
2
2
carbon nucleophile in THF or diethyl ether. Tetra-
hydropyridines 7a–g and 8j–q were obtained in
yields of 66 to 94% and with diastereoselectiv-
ities of 94:6 or higher. NMR spectra of the crude
products confirmed that the diastereoselectivities
were not a result of selective isolation of one
particular stereoisomer. In analogy to the hydride
reductions of 6, exclusive 1,2-addition (no 1,4-
derivatization) was observed. Relative configu-
rations were inferred on the basis of crystal
structures of 7a (17), 7e, and 8m (figs. S3 and S5)
and the similarities of the NMR spectra of the two
sets of products. Compounds 7 exhibited all-cis
imine
alkyne
1
+
2
A
R6
R6
R6
R6
R6
R3
H
H
R1
R5
R1
R2
R5
R4
R1
R5
R4
R1
R2
R1
R5
R5
N
E
N
D
N
B
N
C
N
Nu
R2
R4
R2
R4
Nu
R2
R4
H R3
H R3
R3
R3
(
±)-7
5
4
6
(±)-8
Et
Et
Et
t-Bu
i-Pr
H
H
H
H
H
Bn
Ph
Cy
Bn
Bn
Et
Et
Et
Me
2
CO Me
2
3
N
N
N
N
N
stereochemistry of the substituents R , R , and
H
H
Me
H
H
Me
H
Me
6
5
6
6
2
Me
Me
Me
Me
Me
R , whereas for 8 trans-R /R and trans-R /R ste-
Me
Me
Me
Me
8b 87%
10:1 dr
Me
Me
Me
8e 69%
>95% dr
reochemistry was observed. Thus, the facial se-
†
†
†
8
a 80% (89% )
8c 72% (82% )
>95% dr
8d 72% (83% )
>95% dr
lectivity for the addition step was the same for
>95% dr
–
[
(AcO)
3
BH] and the organometallic reagents, sug-
Et
Et
H
Et
H
i-Pr
gesting that the preferred trajectory was mainly
determined by the geometry of the iminium ions 5
and 6 and to a lesser extent by the nature of the
nucleophile. Tetrahydropyridine 8q features seven
different substituents as a result of coupling of a
differentially substituted imine with an unsymmet-
rical alkyne and addition of an alkynyl nucleophile.
Such a level of directed placement of substituents
around a piperidine ring has not been reported to
the best of our knowledge (21, 22).
The x-ray structures of the reactive iminium
ions cis-5a and trans-6a offer prospective in-
sight into the high diastereoselectivities that were
consistently observed in the nucleophilic addi-
tion steps. Nucleophilic addition to ion cis-5a
is most likely directed by the pseudoaxial C3
substituent, which exerts the strongest steric
hindrance to nucleophiles approaching the C2
electrophilic center. The relatively planar C2–
C3–C4 moiety of trans-6a provides little facial
steric bias for the incoming nucleophile. We there-
fore hypothesize that the conformation of the
benzyl group might govern diastereoselectivity
in the addition step.
Although pharmaceutical researchers now
routinely and reliably separate enantiomers by
preparative chiral high-performance liquid chro-
matography (24, 25), an asymmetric variant of the
present reaction sequence could be contemplated
through the use of chiral directing groups or
asymmetric electrocylization catalysts (26, 27).
Moreover, the addition of many other types of
nucleophiles should be possible, and the 1,2-
dihydropyridine intermediates 4 could conceiv-
H
H
Bn
Bn
H
Bn
Bn
Et
Et
O
Et
CONMe2
N
N
N
N
H
Me
H
Et
H
Me
Ph
Me
NMe
Me
Me
8i 69%
>95% dr
Me
8
f 61%
95% dr
8g 74% 8.5:1 dr
(68% >95% dr
8h 71% (49%†)
>95% dr
‡
>
)
Et
N
Et
H
Et
Et
H
H
H
Bn
O
Bn
Bn
N
Bn
Et
Et
Et
Et
N
N
Ph
MeO
Me
Me
n-Bu
Me
Me
Me
Me
Me
Me
Me
j 90%
Me
8k 66%
>95% dr
Me
Me
8
8l 92%
>95% dr
8m 92%
>95% dr
>95% dr
Et
H
Et
Et
i-Pr
H
H
H
Bn
Et
Bn
Bn
N
N
Bn
Et
Et
CO Me
N
N
2
O
O
O
Et
NMe
i-Pr3Si
i-Pr3Si
Et
Me
Et
Me
Me
8
n 70%
8o 94%
>95% dr
8p 91%
95% dr
8q 67%
>95% dr
>
95% dr
Et
Et
Et
Et
Bn
Et
Bn
N
Et
Bn
N
Et
Bn
Et
Me
N
N
Ph
Me
Me
n-Bu
Me
i-Pr3Si
Me
Me
Me
Me
H Me
H Me
H Me
H Me
7d 86%
>95% dr
7
>
a 71%§
7b 74%
>95% dr
7c 86%
>95% dr
95% dr
Et
N
Et
Et
Bn
O
Et
Bn
Et
Bn
Et
O
N
O
N
O
MeO
Me
3
i-Pr Si
MeO
Me
Et
H
H Me
H Me
7f 90%
>95% dr
7
e 94%
95% dr
7g 89%
94% dr
>
Fig. 4. Substrate scope for the synthesis of products 7 and 8. Conditions: (A) 1:2 [RhCl(cyclooctene)
Me NC H -PEt (1 to 2.5 mol %), PhMe. (B) (PhO) PO H, THF. (C) Na[(AcO) BH], THF or R–[M], THF or Et O.
2 2
] /4-
2
6
4
2
2
2
3
2
(
D) PhSO H, CH Cl . (E) R–[M], THF or Et O; for experimental details, see the supplementary materials. ably react with electrophiles other than protons to
3
2
2
2
†
[Rh] step run in THF, and reaction carried out as a one-pot procedure; ‡[Rh] step run in THF, and enable the regio- and stereoselective synthesis of
BH]; §(17).
even more densely substituted products.
reduction conducted using Li[i-Bu
3
www.sciencemag.org SCIENCE VOL 339 8 FEBRUARY 2013
681

REPORTS
References and Notes
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Acknowledgments: This work was supported by NIH grant
GM069559 (to J.A.E.). R.G.B. acknowledges funding from the
Director, Office of Energy Research, Office of Basic Energy
Sciences, Chemical Sciences Division, U.S. Department of
Energy, under contract DE-AC02-05CH11231. S.D. is grateful
to the Swiss National Science Foundation for a postdoctoral
fellowship (PBZHP2-130-966). Metrical parameters for the
structures of compounds 5a, 6a, 7e, 8a, and 8m are available
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Supplementary Materials
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Materials and Methods
Figs. S1 to S5
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25 September 2012; accepted 3 December 2012
10.1126/science.1230704
1
cheaper than our previous complex, it constitutes
a major step forward in the understanding of
A Functional [NiFe]Hydrogenase
Mimic That Catalyzes Electron
[
NiFe]H ases. Here, we describe the synthesis of
2
this model and report its chemical and struc-
tural features.
II
II
Model complex ([Ni (X′)Fe (MeCN){P(OEt)
3 3
} ]
and Hydride Transfer from H
1,2,3
2
2
21,2
(BPh {[1](BPh , where X′ = N,N'-diethyl-
4
)
2
)
4 2
Seiji Ogo,
* Koji Ichikawa, Takahiro Kishima, Takahiro Matsumoto,
1,2
4
5
Hidetaka Nakai, Katsuhiro Kusaka, Takashi Ohhara
Chemists have long sought to mimic enzymatic hydrogen activation with structurally simpler
compounds. Here, we report a functional [NiFe]-based model of [NiFe]hydrogenase enzymes.
This complex heterolytically activates hydrogen to form a hydride complex that is capable of
reducing substrates by either hydride ion or electron transfer. Structural investigations were
2
as necessary for a [NiFe]H ase model complex: a
bimetallic core, a m-S bridge between the metal
centers to allow close approach, and ligands ca-
pable of accepting p-back donation from the Fe
performed by a range of techniques, including x-ray diffraction and neutron scattering, resulting in (or Ru) center. The three most important develop-
crystal structures and the finding that the hydrido ligand is predominantly associated with the Fe
center. The ligand’s hydridic character is manifested in its reactivity with strong acid to liberate H
ments in this complex are the replacement of Ru
with Fe, the replacement of an aryl ligand with
2
.
three triethylphosphite {P(OEt)
3
} ligands, and,
ickel-iron hydrogenase enzymes are currently the focus of much research across crucially, the use of sodium methoxide (MeONa)
(
[NiFe]H ases) catalyze the transfer of many disciplines.
as a base instead of water.
2
N
electrons from hydrogen gas (H
2
) to a
We have previously reported a [NiRu]model
The structure of 1, bearing a MeCN ligand at
II
II
redox partner (1–5). This activation of H for complex ([Ni (X)(H O)(m-H)Ru (C Me )](NO ) the vacant site, was determined by x-ray diffrac-
the release of electrons and/or hydride ions has {[3](NO
tremendous potential applications from energy 1,9-dithiolato and Me indicates a methyl ( H NMR) spectroscopy (fig. S2), and mass spec-
2
2
6
6
3
3
), where X = N,N'-dimethyl-3,7-diazanonane- tion (fig. S1), proton nuclear magnetic resonance
1
generation to industrial synthesis, and so H
2
ases group}) that can mimic the chemical functions trometry (fig. S3) (8). The Ni···Fe distance is
of [NiFe]H ases (6, 7). Based on the [NiRu] core, 3.3189(6) Å. The Ni–S–Fe angles are 94.93(4)
2
2
this complex could activate H in water, at room and 94.79(4)°.
1
World Premier International Research Center Initiative– temperature, and use the extracted electrons to
Complex 1 heterolytically activated H in
2
International Institute for Carbon-Neutral Energy Research
reduce substrates as part of a catalytic cycle. A MeCN/MeOH at room temperature and at-
central finding of this study was that the so-called mospheric pressure. Abstraction of a proton
hydride complex actually took the form of a three- from bound H by a strong base (MeONa) re-
2
(
WPI-I2CNER), Kyushu University, 744 Moto-oka, Nishi-ku,
2
Fukuoka 819-0395, Japan. Department of Chemistry and
Biochemistry, Graduate School of Engineering, Kyushu Uni-
versity, 744 Moto-oka, Nishi-ku, Fukuoka 819-0395, Japan. center Ni–H–Ru bond—in other words, the elec- sulted in formation of hydride-bearing complex
3
I
I
II
II
Core Research for Evolutional Science and Technology (CREST),
trons from the hydride were used to form a Ni –Ru
([Ni (X′)(m-H)Fe {P(OEt)
3 3 4 4
} ](BPh ){[2](BPh )}) (8).
Japan Science and Technology Agency (JST), Kawaguchi Center
Building, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
bond with the proton. Because no functional
hydride-type model had been reported, we were 2 was determined by x-ray diffraction (Fig. 1),
The structure of the hydride-bearing complex
4
Frontier Research Center for Applied Atomic Sciences, Ibaraki
1
University, IBARAKI Quantum Beam Research Center (IQBRC) confident that the protic form was the best de- neutron scattering (fig. S4), H NMR (fig. S5)
Building, 162-1 Shirakata, Tokai, Ibaraki 319-1106, Japan. scriptor of the active state of [NiFe]H
ases.
and infrared (IR) spectroscopy (fig. S6), and
2
5
Research Center for Neutron Science and Technology, Com-
As a result of our efforts to improve this mass spectrometry (fig. S7). The Ni atom adopts
original model, we can now report a functional the same planar structure as in 1, and the Ni···Fe
model complex based on a [NiFe] core. Further- distance is 2.7930(6) Å, which is also compa-
more, this complex bears a true hydride ion in rable to the Ni···Ru distance in 3. These distances
the reactive form. Not only is this catalyst far are, however, longer than the Ni···Fe separation in
prehensive Research Organization for Science and Society,
IQBRC Building, 162-1 Shirakata, Tokai, Ibaraki 319-1106,
Japan.
*
To whom correspondence should be addressed. E-mail:
ogotcm@mail.cstm.kyushu-u.ac.jp
682
8 FEBRUARY 2013 VOL 339 SCIENCE www.sciencemag.org