Cooperative catalysis through noncovalent interactions

Article abstract of DOI:10.1002/anie.201208774

One of four: A chiral phosphoric acid enables asymmetric hydrogenation of imines with an achiral iridium catalyst by virtue of noncovalent interactions. These interactions lead to the formation of a highly organized ternary complex, and the hydride is transferred highly enantioselectively. Copyright

Full text of DOI:10.1002/anie.201208774

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Chemie
DOI: 10.1002/anie.201208774
Asymmetric Hydrogenation
Cooperative Catalysis through Noncovalent Interactions**
Weijun Tang, Steven Johnston, Jonathan A. Iggo,* Neil G. Berry, Marie Phelan, Luyun Lian,
John Bacsa, and Jianliang Xiao*
Noncovalent interactions, such as hydrogen bonding, electro-
static, p–p, CH–p, and hydrophobic forces, play an essential
role in the action of natureꢀs catalysts, enzymes. In the last
decade these interactions have been successfully exploited in
organocatalysis with small organic molecules.[1] In contrast,
such interactions have rarely been studied in the well-
established area of organometallic catalysis,[2] where elec-
tronic interactions through covalent bonding and steric effects
imposed by bound ligands dictate the activity and selectivity
of a metal catalyst. An interesting question is: What happens
when an organocatalyst meets an organometallic catalyst?
This unification has already created an exciting new space for
both fields: cooperative catalysis, where reactants are acti-
vated simultaneously by both types of catalyst, thereby
enabling reactivity and selectivity patterns inaccessible
within each field alone.[3] However, the mechanisms by
which the two catalysts cooperatively effect the catalysis
remain to be delineated. We recently found that combining an
achiral iridium catalyst with a chiral phosphoric acid allows
for highly enantioselective hydrogenation of imines
(Scheme 1).[4] To gain insight into the mechanism of this
metal–organo cooperative catalysis, we studied the catalytic
system with a range of techniques, including high pressure
2D-NMR spectroscopy, diffusion measurements, and NOE-
constrained computation. Herein we report our findings.
To evaluate the mechanism, a simplified achiral complex
C was used, which leads to [C+][AÀ] upon mixing, in situ or
ex situ, with the chiral phosphoric acid HA through proto-
nation at the amido nitrogen (Scheme 1). In the asymmetric
hydrogenation of the model ketimine 1a, [C+][AÀ] afforded
95% ee and full conversion. On the basis of related studies,[5]
the hydrogenation can be broadly explained by the catalytic
Scheme 1. Hydrogenation of imine with achiral C and chiral acid HA
(PMP=p-methoxyphenyl, Ar=2,4,6-triisopropylphenyl, Ts=tosyl,
Bn=benzyl).
cycle shown in Scheme 1, that is, [C+][AÀ] activates H2 to give
the hydride D and protonated 1a, which forms an ion pair
with the phosphate affording [1a+][AÀ];[6,7] hydride transfer
furnishes the amine product 2a while regenerating [C+][AÀ].
Questions pertinent to possible iridium–phosphate coopera-
tion then arise: 1) How does the chiral phosphoric acid induce
asymmetry in the hydrogenation? and 2) Does the enantio-
selectivity result from D being formed enantioselectively
from [C+][AÀ], from the phosphate salt [1a+][AÀ], or from
interactions involving all three components?
We looked first at how the formation of hydride D and its
transfer into the substrate are influenced by the chiral acid
HA. The studies were carried out in CH2Cl2 or CD2Cl2 owing
to the low solubility of the various metal complexes in
toluene. The catalytic hydrogenation is feasible in both
solvents, giving a 95% ee in toluene and 85% ee in CH2Cl2
in the case of hydrogenation of 1a with C and HA under the
conditions given in Scheme 1. The solution NMR studies
show that the ionic complex [C+][AÀ] is formed instantly on
protonation of C (0.05 mmol) with one equivalent HA in
CD2Cl2 (0.5 mL). Under H2 pressure (> 1 bar), proton trans-
fer from a [C+]–H2 dihydrogen intermediate (not observed) to
1a converts [C+] into the hydride D and affords the salt [1a+]
[AÀ].[7] Formation of D took place instantly even at À788C,
and it is observed during catalytic turnover, thus indicating
that the hydrogenation is rate-limited by the hydride transfer
step.
[*] Dr. W. Tang,[+] S. Johnston,[+] Dr. J. A. Iggo, Dr. N. G. Berry,
Dr. J. Bacsa, Prof. J. Xiao
Liverpool centre for Materials & Catalysis
Department of Chemistry, University of Liverpool
Liverpool L69 7ZD (UK)
E-mail: jxiao@liv.ac.uk
Homepage: http://pcwww.liv.ac.uk/~xiao
Dr. M. Phelan, Prof. L. Lian
NMR Centre for Structural Biology, Institute of Integrative Biology
University of Liverpool
Liverpool, L69 7ZB (UK)
[+] These authors contributed equally to this work.
[**] We thank EPRSC for funding support to W.J.T. and S.J. on grant EP/
G031444, the University of Liverpool for support of the NMR Centre
for Structural Biology, and the EPSRC National Mass Spectrometry
Service Centre for mass analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208774.
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Scheme 2. Formation of racemic hydrides D by hydrogenating C
generated from E and the X-ray structure of trans-D.[17]
Figure 1. 1H NMR spectra in [D8]toluene (0.5 mL) at 208C of a) D
(0.05 mmol) and b) D + [NBu4+][AÀ] (0.1 mmol).
Racemic D can be generated as a solid precipitate in
toluene by hydrogenation of the neutral C (Scheme 2). The
trans hydride (SIrRN)-D and its mirror image, in which the Ir-
H and N-H hydrogens are trans disposed, have been
characterized by X-ray crystallography (Scheme 2; Appen-
dix I in the Supporting Information). The 1H NMR spectrum
of D displays two hydride resonances (dH, 208C in CD2Cl2:
trans-D = À10.81, cis-D = À11.74; in [D8]toluene: trans-D =
À10.55, cis-D = À11.37 ppm) in the ratio of 10.5:1.
reveals trimolecular interactions. Thus, addition of 1a to
a solution of D at À508C does not appear to affect the
hydrides (Figure 2a,b), consistent with 1a not being reduced
by D. However, on addition of one equivalent of HA at
À508C, [1a+][AÀ] is formed instantly, and new resonances are
seen in both the hydride region, dH = À9.25 and À9.45 ppm
(Figure 2c), and at low field in the region expected for
hydrogen-bonded N-H in D, dH = 10.00 and 10.34 ppm with
an intensity ratio similar to that of the two new hydride peaks.
To gain insight into the hydrogen bonding between [AÀ],
the iminium cation, and the Ir-hydride, we treated the
chloride complex E with 20 bar H2 in CD2Cl2 in the presence
of NaBARF (sodium tetrakis[3,5-bis(trifluoromethyl)phe-
By using 1H 2D-NOESY NMR measurements taken
under 20 bar H2, we are able to assign these signals to
trans-(SIrRN)-D and its mirror image, and to the analogous cis-
(SIrSN)-D and its enantiomer (Figures S1 and S2 in the
Supporting Information), trans-D being the more abundant.
Remarkably, the enantiomers of trans-D can be resolved in
a [D8]toluene solution by addition of [NBu4 ][AÀ] (Figure 1).
+
The enantiomers of the cis hydride could not be resolved,
however. Further support for the presence of additional
isomers of D in solution is found in the X-ray crystal structure
of the analogous chloride complex E (Scheme 2; Appendix II
in the Supporting Information), in which two trans and one cis
isomers are seen.
Under catalytic conditions, the hydride D, produced from
hydrogenation of [C+][AÀ], is also racemic and can be
precipitated and isolated by performing the hydrogenation
in the presence of 2,6-lutidine in toluene. When D was used in
the stoichiometric reduction of [1a+][AÀ] at 208C in toluene
(Section 7 in the Supporting Information), 2a was formed
with the same ee (95%) as obtained under catalytic con-
ditions, thus suggesting that the asymmetric induction of the
catalysis arises in the hydride transfer step, rather than from
enantioselective generation of D. However, under the same
conditions, the neutral imine 1a cannot be reduced. This
observation, which resembles those made in related studies,[5]
indicates that it is the iminium cation that participates in the
hydride transfer.
Figure 2. 1H NMR spectra (0.5 mL CD2Cl2) of a) hydride D
(0.05 mmol; À508C); b) (a) + 1a (10 equiv); c) (b) + HA (1 equiv);
d) C (0.1 mmol) + HA (1 equiv), followed by 1a (10 equiv) and 20 bar
H2 at À788C; spectrum recorded at À508C; e) E (0.05 mmol) +
NaBARF (2 equiv) + 1a (10 equiv); 20 bar H2 charged at À788C and
spectrum recorded at À508C; f) D + NaBARF (2 equiv) + 1a
(10 equiv); g) F (0.1 mmol, Ar=2,4,6-triisopropylphenylsulfonyl) +
silver phosphate (1 equiv) + 1a (10 equiv); 20 bar H2 charged at
À788C and spectrum recorded at À508C.
1
Monitoring the H NMR spectra of stoichiometric reac-
tions of racemic D with imine and HA in the hydride region
2
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nyl]borate) and excess 1a; this afforded only the racemic
hydride D with no hydrogen-bonded hydrides observed
(Figure 2e,f).[8] Unlike the phosphate [AÀ], the BARFÀ
anion is not expected to act as a hydrogen-bond acceptor.
Similarly, on hydrogenation of [F+][AÀ] (Figure 2g), in which
the NH hydrogen atom is replaced with a methyl group, only
two hydrides, at À11.39 and À11.44 ppm, were observed in the
1H NMR spectrum, with no observable hydrogen-bonded
species. Furthermore, when D was mixed with [NBu4 ][AÀ],
+
no new hydride resonances were observed in CD2Cl2, in
contrast to the case of D being mixed with [1a+][AÀ]. These
observations suggest that in the hydrogen-bonded network
formed by D, [1a+], and [AÀ], the NH hydrogen atoms of the
former two form hydrogen bonds with the oxygen atom of the
latter. The importance of hydrogen bonding was further
elucidated by catalytic reactions (Sections 7 and 8 in the
Supporting Information), which indicate that it is the
intermolecular hydrogen bonding that makes enantioselec-
tive hydrogenation of 1a possible, at the expense of reaction
rate, however, owing to the bulkiness of the bonded species.
Figure 3. 1H NMR monitoring of hydride transfer from D to 1a in
CD2Cl2 at various temperatures. Conditions: a) D (0.05 mmol) + 1a
(10 equiv); b–g) (a) + HA (1 equiv).
Taken together, the results above suggest that the
enantioselective hydrogenation is likely to proceed via
a hydrogen-bonded supramolecular complex[11] involving all
three of D, [1a+], and [AÀ]. To shed light on the structure of
1
1
1
We also monitored, by in situ H NMR spectroscopy, the
the ternary complex, we have performed H PFGSE, H-13C
HSQC, 1H NOESY NMR and DFT/PM6 computational
studies of the model complex E, HA, and 1a or 1h.[12–13]
Pulsed field-gradient spin echo (PFGSE) measurements were
used to probe interactions between the components, while the
identification of NOE signals allowed the nature of the
interactions to be revealed and set constraints for subsequent
computational modeling.
reaction of [C+][AÀ] under 20 bar H2 in the presence of excess
of 1a when the temperature was raised from À78 to 208C. At
low temperature (À508C), both D (trans and cis isomers) and
the hydrogen-bonded hydrides were observed (Figure 2d). At
this temperature no observable hydrogenation took place.
However, contrary to the reaction at higher temperature, the
cis hydride is favored. On raising the temperature, the trans
isomer becomes the major species observed, and subsequent
cooling does not alter the equilibrium, consistent with
a kinetic effect. The lower activation energy characterizing
formation of the cis hydride may be a result of hydrogen-
bonding-assisted heterolysis of H2 (Figure S3 in the Support-
ing Information).[9] Comparing the spectra (d) and (c) in
Figure 2 shows that the intensity of the hydrogen-bonded
hydrides varies with that of free trans-D, thus suggesting that
the hydrogen-bonded hydrides arise from the trans hydrides.
1H DOSY NMR spectra of [1h+][AÀ], of a mixture of HA
and E, and of a mixture of E, HA, and 1h in the same
concentration (0.1 mmol in 0.5 mL CD2Cl2) indicate that in
the first two cases the components diffuse together, while in
the last case part of the three species diffuse together.[14]
Calculation of the hydrodynamic radii of each case shows that
there is good agreement between the experimental hydro-
dynamic radii obtained from the NMR measurements and
DFT/PM6 calculations (Section 15 in the Supporting Infor-
mation). For example, the experimental hydrodynamic radius
of the diffusing species in the mixture of E, HA, and 1h, rH =
7.89 ꢁ, is in close agreement with the computed radius of the
supramolecular complex incorporating E hydrogen-bonding
to [1h+][AÀ], rH = 7.20 ꢁ.
1
Further H NMR monitoring using an internal standard
suggests that it is the minor cis hydride that hydrogenates
[1a+] (Figure 3). We started from the free racemic hydride D
with a ratio of free trans to free cis hydride 10.8:1 at À508C in
the presence of ten equivalents of 1a (Figure 3a). After
addition of one equivalent of HA at the same temperature,
two peaks can be seen between À9.2 and À9.6 ppm. The ratio
of these two peaks added together to the free trans and cis
hydride is approximately 7:7:1, indicating again that the new
hydrogen-bonding hydrides derive from trans-D (Figure 3b).
Increase of the temperature led to continued decrease in the
content of the cis hydride, and this is accompanied with the
appearance of amine product at À208C. Thus, comparing the
conditions (a) and (g), the ratio of free trans to free cis hydride
has changed from approximately 10.8:1 to 20:1. These
observations suggest, surprisingly, that the minor cis hydride
hydrogenates [1a+], instead of the major trans hydride, which
forms observable hydrogen bonds with the organocatalyst;
this inference is reminiscent of the observations made in the
seminal study of asymmetric hydrogenation of dehydroamino
acids with Rh–diphosphine catalysts.[10]
Further, the 1H-13C HSQC and 1H NOESY NMR spectra
of a mixture of HA (0.1 mmol), E (1 equiv), and 1a (1 equiv)
at 800 MHz in CD2Cl2 (0.5 mL) allowed the identification of
a range of NOE signals. Among these, two NOE signals were
identified as being unambiguously derived from the ternary
complex. They arise from the methoxy group of [1a+] and the
isopropyl-substituted aryl ring of [AÀ], and the methyl group
of [1a+] and the tosyl ring of E (Section 13 in the Supporting
Information), thus supporting the hypothesized supramolec-
ular complex.
These NOE signals were then taken as constraints in
structural calculation and optimization. A range of structures
were generated by conformational searching using molecular
mechanics; the most popular structures, which satisfied the
key NOE signals, were optimised using the DFT (B3LYP
functional) followed by the PM6 method owing to the
complexity of the system (Section 13 in the Supporting
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Figure 4. Modeled structures of ternary complexes. a,b) [(RIrSN)-E][1a+][AÀ] (À2.7 kcalmolÀ1), arising from trans-(RIrSN)-E, [1a+], and [AÀ]; the
structure fits NOE results; c) expansion of [(RIrSN)-E][1a+][AÀ] showing lack of CH–p interactions; d,e) [(SIrSN)-E][1a+][AÀ] (À5.7 kcalmolÀ1),
arising from cis-(SIrSN)-E, [1a+], and [AÀ]; the structure fits NOE results; f) expansion of [cis-(SIrSN)-E][1a+][AÀ] to show CH–p interactions;
g) representation of the presumed transition state of hydride transfer in hydrogenation with the achiral and chiral catalysts C and HA. in (a–f):
N blue, Cl green, Ir gold, O red, P orange, S yellow.
Information).[15] This led to two ternary structures consistent
with the NOE data (Figure 4), the complex [(RIrSN)-E][1a+]
[AÀ] (À2.7 kcalmolÀ1) incorporating trans-(RIrSN)-E (Fig-
ure 4a,b), and a lower-energy cis analogue [(SIrSN)-E][1a+]
catalysis and is responsible for enantioselective hydride
transfer, and further suggest that of the four isomeric hydrides
D, the minor cis-(SIrSN)-D isomer forms the productive
ternary complex with the phosphate and an iminium ion,
through which the imino bond is reduced. The phosphate
binds to both cis-(SIrSN)-D and [1a+] through hydrogen-
bonding and CH–p interactions, allowing the hydride to add
only to the re-face of the imino bond. These interactions and
the resulting ternary complex are proposed to be the key
feature of the transition state of hydride transfer in the
catalysis (Figure 4g), which permits highly effective chirality
transfer, but a much slower rate of hydride transfer than in
hydrogenation using non-hydrogen-bonding counteranions
(Sections 7 and 8 in the Supporting Information).
[AÀ] (À5.7 kcalmolÀ1
; Figure 4d,e). In both structures,
a hydrogen bond exists between the NH proton of [1a+]
and an oxygen atom of the phosphate, the O···H distances
being similar at 1.41 ꢁ and 1.47 ꢁ, respectively. The other
phosphate oxygen forms a hydrogen bond with the NH
proton of E; however, the O···H distance is significantly
shorter in the trans complex, 2.03 ꢁ vs. 2.45 ꢁ, indicating
a weaker hydrogen bond in the cis analogue and thus
explaining why hydrogen bonding with the cis hydride D
was not observed.
Significantly, in the trans-E-derived complex [(RIrSN)-
In summary, this study has revealed that when an
organometallic catalyst is combined with an organocatalyst
to effect a reaction, nonconvalent interactions likely dictate
the catalytic activity and selectivity, resembling enzymatic
catalysis. The insight gained is anticipated to be of value for
the design of future metal–organo cooperative catalysts.
E][1a+][AÀ], the chloride faces away from the hydrogen-
bonded [1a+] (Figure 4a,b), whereas in the cis analogue the
+
=
chlorine atom faces the re-face of [1a ] with a Cl and C (C N)
separation of 4.36 ꢁ (Figure 4d,e). The cis analogue would
afford the observed S-configured amine, if the chloride of E
was replaced with a hydride, thereby lending support to the
NMR study above using the hydride D.
Received: November 1, 2012
Published online: && &&, &&&&
In addition to the hydrogen bonding, a range of CH–p
interactions are evident in both complexes.[16] The main
difference between the two ternary complexes is seen in the
cis-E-derived [(SIrSN)-E][1a+][AÀ], which exhibits favorable
CH–p interactions, ranging from 2.8 to 3.2 ꢁ, between the
CH2 groups on the backbone of E and the benzyl phenyl ring
of E, and between the former and the phenyl group of [1a+]
(Figure 4 f). These interactions are absent in the trans
analogue, thus accounting for the higher stability of the
complex derived from cis-(SIrSN)-E (Figure 4c vs. f).
Keywords: Brønsted acid · cooperative catalysis ·
.
hydrogenation · iridium · noncovalent interactions
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4
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Communications
Asymmetric Hydrogenation
W. Tang, S. Johnston, J. A. Iggo,*
N. G. Berry, M. Phelan, L. Lian, J. Bacsa,
J. Xiao*
&&& — &&&
Cooperative Catalysis through
Noncovalent Interactions
One of four: A chiral phosphoric acid
enables asymmetric hydrogenation of
imines with an achiral iridium catalyst by
virtue of noncovalent interactions. These
interactions lead to the formation of
a highly organized ternary complex, and
the hydride is transferred highly enantio-
selectively.
6
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