METAMORPhos: Adaptive supramolecular ligands and their mechanistic consequences for asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.200705212

(Chemical Equation Presented) Adapt to react: METAMORPhos ligands are a class of flexible and adaptive hydrogen-bonded multidentate sulfonamide-based phosphorus ligands. Selective formation of complexes with two different METAMORPhos ligands (see scheme) that display unusual kinetic behavior leads to the proposal of a new mechanism. These complexes are highly reactive and enantioselective in the rhodium-catalyzed asymmetric hydrogenation of alkenes.

Full text of DOI:10.1002/anie.200705212

Communications
DOI: 10.1002/anie.200705212
Supramolecular Ligands
METAMORPhos: Adaptive Supramolecular Ligands and Their
Mechanistic Consequences for Asymmetric Hydrogenation**
Frederic W. Patureau, Mark Kuil, Albertus J. Sandee, and Joost N. H. Reek*
Bidentate ligands are an important class of ligands for
transition metal catalysis[1] even though their synthesis is
usually more tedious and time-consuming than that of their
monodentate counterparts. Supramolecular ligands[2] have
recently been introduced as a new class of ligands that form
by the self-assembly of ligand building blocks through specific
interactions. For example, it has been demonstrated that
hydrogen bonds,[3] ionic interactions,[4] and metal–ligand
interactions[5] can all be involved in the assembly process.
Interestingly, the number of supramolecular bidentate ligands
grows exponentially with the number of available building
Scheme 1. Tautomeric equilibrium of METAMORPhos ligand 1 and its
coordination behavior with [Rh(acac)(CO)2] (phenyl groups have been
omitted in the complex for clarity).
blocks, which clearly shows the power of the supramolecular
approach, therefore this approach is generally associated with
combinatorial routes to rapid catalyst discovery. The dynamic
character inherent to the class of supramolecular ligands
could also introduce new reactivity, and as such we are
currently exploring the character of this new class of ligands.
Herein we report the synthesis of METAMORPhos (from the
Greek: meta “change” + morphe “shape”), a supramolecular
ligand building block which dynamically adapts to various
tautomeric forms, even when coordinated to a metal center.
This adaptive behavior gives rise to a unique mechanism in
the asymmetric hydrogenation reaction.
METAMORPhos ligand 1 was prepared by a simple
condensation reaction between para-n-butylphenylsulfona-
mide and Ph2PCl[6] and was initially designed as a novel ligand
with a hydrogen bond motif (donor/acceptor type) close to
the phosphorus ligand. Upon characterization we found that
the compound exists as two different tautomers in CDCl3 that
are in slow exchange on the NMR time-scale (Scheme 1).[7]
The peaks of these tautomers (1a and 1b) in the 31P NMR
spectrum were assigned on the basis of their specific P-H
couplings of 7 and 490 Hz, respectively. No coalescence was
observed in the temperature window of 323 to 223 K,
although the 1a/1b ratio changed dramatically from 4.43 at
323 K to 0.85 at 223 K. This interesting exchange behavior
between the tautomeric forms of ligand 1 stimulated us to
explore the coordination properties of the ligand and their
effects on catalytic reactions.
The unusual coordination behavior of ligand 1 became
evident when two equivalents of 1 were added to a CDCl3
solution of [Rh(acac)(CO)2]. Thus, in contrast to the usually
formed cis-bis-phosphorus Rh(acac) complex, the AB pattern
observed in the 31P NMR spectrum indicated the formation of
a complexwith two different ligands, and the large P-P
coupling constant (2JP1,P2 = 335 Hz) pointed to a trans geom-
etry (Figure 1). The 1H and 13C NMR spectra show the
[*] F. W. Patureau, Prof. Dr. J. N. H. Reek
Van’t Hoff Institute for Molecular Sciences
University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV
Amsterdam (The Netherlands)
Figure 1. 31P NMR spectrum of [Rh(1a···1c)(CO)] (202.3 MHz,
12.68 mm in CDCl3, 223 K).
Fax: (+31)20-525-56-04
E-mail: reek@science.uva.nl
Homepage: http://www.science.uva.nl/research/imc/HomKat/
stoichiometric formation of acacH, thus demonstrating that
complexformation proceeds by a proton transfer from
tautomer 1b to the acac anion to yield tautomer 1c and
acacH (Scheme 1).[6] The complexwas characterized by FAB
mass spectrometry (m/z 925.31) and solution IR (n(CO) =
1986 cmÀ1) and NMR spectroscopy. A hydrogen-bonding
interaction, presumably between the NH moiety of coordi-
Dr. M. Kuil, Dr. A. J. Sandee
BASF Nederland B.V. Catalysts
Strijkviertel 67, 3454 PK De Meern (The Netherlands)
[**] The NRSC-C, BASF, and EZ are acknowledged for financial support,
Dr. P. A. Breuil for providing ligand 3, Dr. J. M. Ernsting and Dr. J.
Geenevasen for assistance withthe NMR experiments, and Dr. H.
Peeters for the mass spectrometry experiments.
À
nated 1a and the S O group of 1c, was evident from solution
IR spectroscopy—the NH vibration is shifted from 3341 (free
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
ligand) to 3281 cmÀ1 (coordinated ligand). Dilution studies
3180
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3180 –3183

Angewandte
Chemie
revealed that the signal of the hydro-
gen-bonded NH proton in the 1H NMR
spectrum is concentration independent
in the [Rh(1a···1c)(CO)] complex, in
line with the presence of an intramo-
lecular hydrogen bond between 1a and
1c (Scheme 1 and Figure 2).[6] The cal-
culated structure (by density functional
theory) shows that if the anionic ligand
1c coordinates to the metal in a P,O-
chelate fashion, the oxygen atom is in
an ideal position for hydrogen-bond
formation with the NH group of the
ligand coordinated trans to the phos-
phorus (Figure 2).
We anticipated that the dual char-
acter of the ligand—hydrogen-bond
acceptor in the anionic form and hydro-
gen-bond donor in the neutral state—
should also provide new routes for the
Scheme 2. Formation of [Rh(2···1c)(CO)] and a control experiment withligand 3.
Figure 3. 31P NMR spectrum of [Rh(2···1c)(CO)] (202.3 MHz, 298 K,
36.5 mm in CDCl3; JP1,P2 =470.8 Hz).
the neutral RhI complexes [Rh(1a···1c)(CO)] and [Rh-
(2···1c)(CO)] were found to be inactive in the Rh-catalyzed
asymmetric hydrogenation of methyl 2-acetamidoacrylate
(MAA). Interestingly, however, these neutral complexes can
be converted into their cationic analogs by simple protonation
of the ligand with HBF4·OMe2,[6] which leads to active
complexes for the hydrogenation reaction (Scheme 3).[6] For
the remaining catalysis experiments, however, the active
metal complexes were generated in situ from the commonly
used precursor [Rh(nbd)2][BF4] (nbd = norbornadiene). This
is obviously a more convenient method than activation of the
neutral complexes with HBF4·OMe2. Furthermore, because it
is difficult to precisely dose HBF4·OMe2 on a catalytic scale,
the activation route is also less reproducible. The various Rh
complexes based on homo- and hetero-METAMORPhos
Figure 2. DFT calculated structure of [Rh(1a···1c)(CO)]. C green, H
white, O red, S yellow, N purple, P orange, Rh turquoise.
selective formation of hetero-bisligated metal complexes by
mixing two slightly different METAMORPhos-type ligands.
We therefore prepared chiral ligand 2 which, in contrast to 1,
gives only one signal in the 31P NMR spectrum. Ligand 2
apparently exists in only one dominant tautomeric form,
presumably because of the different basicity of the phospho-
rus atom. Interestingly, a CDCl3 solution of ligands 1 and 2
and [Rh(acac)(CO)2] yields selectively the hetero self-assem-
bled complex[Rh( 2···1c)(CO)] which, as is clear from the
coupling constants in the 31P NMR spectrum, again has the
phosphorus ligands in the trans position (Scheme 2 and
Figure 3). In contrast, a CDCl3 solution of ligand 1, chiral
ligand 3,[8] and [Rh(acac)(CO)2] yields only the homo Rh
complexes, thereby indicating the importance of subtle
changes in the acidity of the NH group for the formation of
such supramolecular structures (Scheme 2).
We were interested in determining whether the typical
METAMORPhos coordination would also result in new
catalytic properties for its rhodium complexes. As expected,
Scheme 3. Protonation of the neutral catalytically inactive complex
[Rh(1a···1c)(CO)] withHBF 4·OMe2 gives the catalytically active
cationic [Rh(1a)2(CO)BF4].
Angew. Chem. Int. Ed. 2008, 47, 3180 –3183
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3181

Communications
Table 2: Kinetics and TOFs for the Rh-catalyzed asymmetric hydro-
genation of MAA obtained for various METAMORPhos ligands.
systems were applied in the Rh-catalyzed asymmetric hydro-
genation of MAA and the results compared to those obtained
with complexes based on ligand 3 and PPh3. All reactions
went to completion after 8 h, even when only 0.1 mol% of
catalyst was used (entries 8–14, Table 1). However, whereas
Entry
Cat. structure[a]
H2
Substrate
Catalyst
TOF[b]
1
2
3
[Rh(1a···1c)]
[Rh(2···1c)]
[Rh(2)2]
P
0
P
0
0
P
P
P
P
652
1186
574
Table 1: Rh-catalyzed asymmetric hydrogenation of MAA.
[a] Complex based on self-assembled ligand 1, ligand 2, or a combination
of both. [b] TOF [molmolÀ1 hÀ1] determined from H2 gas-uptake profiles
at 20% conversion. P: positive order; 0: zero order. Conditions: 10 bar of
H2 pressure, 0.1 mm of catalyst in CH2Cl2, witha MAA/Rhratio of 10 3:1,
(LA +LB)/Rh=2.4:1, at 298 K. Kinetics: H2 pressure 4–16 bar, substrate
concentration 50–200 mm, catalyst concentration 0.025–0.1 mm.
Entry
LA[a]
LB[a]
Rh[m m]
MAA/Rh
ee [%]
R,S
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
2
PPh3
PPh3
3
3
1
1
2
PPh3
PPh3
3
1
2
2
PPh3
3
3
1
1
2
2
PPh3
3
3
1
1
1
1
1
1
102
102
102
102
102
102
102
103
103
103
103
103
103
103
–
–
S
S
–
S
R
R
–
S
S
–
S
R
R
we know, unprecedented. Based on the coordination behavior
and the kinetics we propose a new mechanism for asymmetric
hydrogenation that is specific for METAMORPhos ligand
systems of the type 2···1 (Scheme 4). The rate-determining
step in this mechanism must be intramolecular as the reaction
rate depends only on the catalyst concentration, therefore we
suggest that this rate-determining step involves the intra-
molecular oxidative addition of the neutral ligand 1a of the
Rh(2···1a) cation to provide the cation HRh(2···1c). This
highly reactive cationic RhIII hydride species rapidly hetero-
lytically splits a molecule of H2, with the anionic ligand 1c
functioning as the base, to give the cationic RhIII dihydride
species H2Rh(2···1a).[9] Subsequent decoordination of the
oxygen atoms of the ligands creates the required vacant sites
for substrate coordination, and the cationic RhI resting state is
re-formed after hydride migration and reductive elimination
of the product.[10] Heterolytic splitting of molecular hydrogen
could also take place after substrate coordination and the first
migration reaction, but because these steps all occur after the
rate-determining step we cannot distinguish between these
different sequences. The kinetic behavior of the current
complex, which can be explained by the intramolecular
90.6
95.8
–
13.3
62.1
41.7
–
91.7
99.0
–
1
1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
3.6
65.0
46.0
3
[a] Ligands LA and LB were added in a 1:1 ratio; (LA +LB)/[Rh(nbd)2]-
[BF4]=2.4:1; solvent: CH2Cl2. Reaction performed at 10 bar H2 pressure
at 298 K for 8 h. Full conversions were obtained in all cases.
complexes based on the new ligand 2 provided the product
with the highest ee (99%; entry 10, Table 1), the hetero-
METAMORPhos ligand structure 2···1c was found to be
twice as active (TOF: 1.2 ” 103 molmolÀ1 hÀ1, Table 2) whilst
still being selective (92% ee; entry 9, Table 1).
Whereas the high selectivities displayed by the META-
MORPhos-based catalysts are inter-
esting, they do not provide much
information about the role of this
new class of ligands in the metal
complex. We therefore studied the
kinetics of the Rh-catalyzed hydro-
genation reaction using the various
METAMORPhos ligands by system-
atically varying the hydrogen pres-
sure, substrate concentration, and cat-
alyst concentration and determined
the reaction rate from the gas-uptake
profiles. Much to our surprise, the
catalysts based on ligands 1a···1c,
2···1c, and 2···2 all showed different
behavior, as summarized in Table 2
(P = positive order, 0 = zero order).
Strikingly, the most active rhodium
complex(that based on ligand 2···1c;
TOF: 1.2 ” 103 molmolÀ1 hÀ1) shows
very unusual kinetic behavior as it is
zero order in substrate concentration
and in H2 pressure which is, as far as
Scheme 4. Proposed mechanism for the Rh-catalyzed asymmetric hydrogenation of MAA based
on the hetero METAMORPhos ligand system 2···1.
3182
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3180 –3183

Angewandte
Chemie
Soc. 2003, 125, 6608 – 6609; c) M. Weis, C. Waloch, W. Seiche, B.
oxidative addition of METAMORPhos to the rhodium, is
different from any other reported in the literature[10] and is
clearly a consequence of the adaptability of METAMORPhos
ligands.
Breit, J. Am. Chem. Soc. 2006, 128, 4188 – 4189; d) C. Waloch, J.
Wieland, M. Keller, B. Breit, Angew. Chem. 2007, 119, 3097 –
3099; Angew. Chem. Int. Ed. 2007, 46, 3037 – 3039; e) Y. Liu,
C. A. Sandoval, Y. Yamaguchi, X. Zhang, Z. Wang, K. Kato, K.
Ding, J. Am. Chem. Soc. 2006, 128, 14212 – 14213.
In summary, we have introduced METAMORPhos as a
new class of supramolecular ligands that are adaptive through
tautomerism. This property gives rise to a new coordination
behavior, and the dual character also enables the selective
formation of hydrogen-bonded hetero bis-ligated metal com-
plexes. The adaptive behavior of the ligand when coordinated
to the metal center gives rise to rhodium complexes that show
unique kinetics—zero order in H2 and substrate—in the
asymmetric Rh-catalyzed hydrogenation of MAA. Since the
enantioselectivities obtained are high (above 90%), we are
currently exploring whether this strategy is suited to creating
large ligand libraries for fast catalyst discovery by a combi-
natorial approach.
[4] H. Gulyµs, J. Benet-Buchholz, E. C. Escudero-Adan, Z. Freixa,
P. W. N. M. van Leeuwen, Chem. Eur. J. 2007, 13, 3424 – 3430.
[5] a) V. F. Slagt, M. Röder, P. C. J. Kamer, P. W. N. M. van Leeu-
wen, J. N. H. Reek, J. Am. Chem. Soc. 2004, 126, 4056 – 4057;
b) V. F. Slagt, P. C. J. Kamer, P. W. N. M. van Leeuwen, J. N. H.
Reek, Chem. Commun. 2003, 2474 – 2475; c) X.-B. Jiang, L.
Lefort, P. E. Goudriaan, A. H. M. de Vries, P. W. N. M. van
Leeuwen, J. G. de Vries, J. N. H. Reek, Angew. Chem. 2006, 118,
1245 – 1249; Angew. Chem. Int. Ed. 2006, 45, 1223 – 1227; d) M.
Kuil, P. E. Goudriaan, P. W. N. M. van Leeuwen, J. N. H. Reek,
Chem. Commun. 2006, 4679 – 4681; e) M. Kuil, P. E. Goudriaan,
A. W. Kleij, D. M. Tooke, A. L. Spek, P. W. N. M. van Leeuwen,
J. N. H. Reek, Dalton Trans. 2007, 2311 – 2320; f) J. M. Takacs,
D. S. Reddy, S. A. Moteki, D. Wu, H. Palencia, J. Am. Chem. Soc.
2004, 126, 4494 – 4495; g) J. M. Takacs, K. Chaiseeda, S. A.
Moteki, D. S. Reddy, D. Wu, K. Chandra, Pure Appl. Chem.
2006, 78, 501 – 509.
Received: November 12, 2007
Revised: December 21, 2007
Published online: March 17, 2008
[6] See the Supporting Information.
[7] For related ligands see: a) P. Braunstein, Chem. Rev. 2006, 106,
134 – 169; b) O. Kꢀhl, Coord. Chem. Rev. 2006, 250, 2867 – 2915.
[8] For synthesis of ligand 3 see: L. Lefort, J. A. F. Boogers,
A. H. M. de Vries, J. G. de Vries, Org. Lett. 2004, 6, 1733 – 1735.
[9] For related processes see: a) P. Maire, T. Bꢀttner, F. Breher, P.
Le Floch, H. Grꢀtzmacher, Angew. Chem. 2005, 117, 6477 –
6481; Angew. Chem. Int. Ed. 2005, 44, 6318 – 6323; b) P. Maire,
F. Breher, H. Schönberg, H. Grꢀtzmacher, Organometallics
2005, 24, 3207 – 3218; c) J. Zhang, G. Leitus, Y. Ben-David, D.
Milstein, Angew. Chem. 2006, 118, 1131 – 1133; Angew. Chem.
Int. Ed. 2006, 45, 1113 – 1115.
Keywords: hydrogen bonding · hydrogenation · rhodium ·
supramolecular ligands · tautomerism
.
[1] P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P.
Dierkes, Chem. Rev. 2000, 100, 2741 – 2769.
[2] For reviews see: a) M. J. Wilkinson, P. W. N. M. van Leeuwen,
J. N. H. Reek, Org. Biomol. Chem. 2005, 3, 2371 – 2383; b) B.
Breit, Angew. Chem. 2005, 117, 6976 – 6986; Angew. Chem. Int.
Ed. 2005, 44, 6816 – 6825; c) A. J. Sandee, J. N. H. Reek, Dalton
Trans. 2006, 3385 – 3391.
[10] Handbook of Homogeneous Hydrogenation (Eds.: J. G. de Vries,
C. J. Elsevier), Wiley-VCH, Weinheim, 2007.
[3] a) A. J. Sandee, A. M. van der Burg, J. N. H. Reek, Chem.
Commun. 2007, 864 – 866; b) B. Breit, W. Seiche, J. Am. Chem.
Angew. Chem. Int. Ed. 2008, 47, 3180 –3183
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3183