Self-assembly of bidentate ligands for combinatorial homogeneous catalysis: Methanol-stable platforms analogous to the adenine-thymine base pair

Article abstract of DOI:10.1002/anie.200605202

(Chemical Equation Presented) Complementary partners: A combinatorial library of self-assembled ligand systems has been designed by analogy to the A-T base pair. When these ligand systems are applied in the rhodium-catalyzed hydroformylation of 1-octene (

Full text of DOI:10.1002/anie.200605202

Angewandte
Chemie
DOI: 10.1002/anie.200605202
Combinatorial Catalysis
Self-Assembly of Bidentate Ligands for Combinatorial Homogeneous
Catalysis: Methanol-Stable Platforms Analogous to the Adenine–
Thymine Base Pair**
Christoph Waloch, Jörg Wieland, Manfred Keller, and Bernhard Breit*
Tailor-made ligands are essential for efficient selectivity
control in homogeneous metal-complex catalysis. Since the
theoretical prediction of an optimal ligand for a given
reaction, substrate, and desired selectivity is impossible,
combinatorial approaches have emerged to accelerate cata-
lyst discovery.[1] However, these approaches still suffer from
limited access to structurally diverse and meaningful ligand
libraries. The problem is particularly acute for the important
class of bidentate ligands, for which the synthesis, in many
cases, involves nontrivial operations that are unsuited for
automation. Even more difficult is the synthesis of non-
symmetric bidentate ligands with two different donor sites.
As a solution to this problem, we recently introduced an
alternative to the classical bidentate-ligand synthesis, the self-
assembly of monodentate to bidentate ligands through
complementary hydrogen bonding.[2–4] Thus, on the basis of
a platform analogous to the A–T base pair, the amino-
pyridine–isoquinolone system, libraries of achiral and chiral
phosphine and phosphonite ligands were evaluated
(Scheme 1a). From these studies, excellent catalysts for
regioselective hydroformylation,[5] anti-Markovnikov hydra-
Scheme 1. a) A platform analogous to the A–T base pair for the self-
assembly of monodentate to bidentate ligands for hydroformylation
catalysts. b) A library of ligands with complementary hydrogen-bonding
motifs. rs=regioselectivity. FG=functional group. D=hydrogen-bond
tion of alkynes,[6] as well as asymmetric hydrogenation[7] have
emerged. In all cases, combinatorial ligand variations were
achieved by changing the donor site (Doa/b in Scheme 1a) on
donor. A=hydrogen-bond acceptor. Piv=pivaloyl.
the aminopyridine–isoquinolone platform. It was unclear
whether this approach would be restricted to the amino-
pyridine–isoquinolone self-assembly system, or whether,
indeed, a variation of the A–T base-pair analogous platform
would also be possible (Scheme 1b). It was reasonable to
expect that any change of the platform geometry or the
hydrogen-bonding system would have an immediate impact
on the ligand bite angle (q) and the coordination geometry at
the metal center, and thus, an important influence on the
catalyst performance.[8]
Herein, we report on the development of the first library
of self-assembled ligands based on new heterocyclic platforms
analogous to the A–T base pair. From a first evaluation of this
new library of self-assembled phosphine ligands, an extremely
regioselective hydroformylation catalyst emerged, in which
the ligandꢀs behavior was bidentate, even in protic solvents
such as methanol.
As A-analogous donor–acceptor ligands (LDA in
Scheme 1b), the heterocycle-functionalized phosphines 1–5
were chosen. As T-analogous acceptor–donor ligands (LAD in
Scheme 1b), we selected the known isoquinolone 6 and the
new 7-azaindole 7. The preparation of the ligands is described
in the Supporting Information.
[*] Dr. C. Waloch, Dipl.-Chem. J. Wieland, Dr. M. Keller, Prof. Dr. B. Breit
Institut für Organische Chemie und Biochemie
Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-8715
E-mail: bernhard.breit@organik.chemie.uni-freiburg.de
The coordination properties of all 10 possible ligand
combinations were studied through the NMR spectroscopic
investigation of the corresponding platinum complexes
[Cl2Pt(LDA)(LAD)] (Table 1). 31P NMR spectroscopy showed,
in all cases, the selective formation of a defined complex with
a heterodimeric ligand. In the 31P NMR spectra, an AB spin
[**] This work was supported by the Fonds der Chemischen Industrie,
the Krupp Foundation, through the Alfried Krupp Award for young
university teachers (to B.B.), and BASF. We thank A. Lutterer and G.
Leonhardt-Lutterbeck for technical assistance. C.W. is grateful to the
Fonds der Chemischen Industrie for a KekulØ Fellowship.
2
system with a J(P,P) coupling constant of 14.8–17.2 Hz was
detected, indicating that two non-equivalent phosphorus
atoms are bound to a single platinum nucleus. The J(P,Pt)
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
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Table 1: 31P and 1H NMR spectroscopic data for the cis-[Cl2Pt(LDA)(LAD)] complexes of the donor–
acceptor (LDA; 1–5) and acceptor–donor ligands (LAD; 6, 7).
system. If this notion is correct, it
should be interesting to see whether
the new platforms incorporating the
thiazole system remain intact in a
protic solvent environment (e.g.,
methanol). Indeed, previous studies
showed that the hydrogen-bonding
network of the first generation of
self-assembled ligands is inter-
rupted through interaction with
methanol,[2] which limits their ap-
plication range in homogeneous
catalysis.
LDA/LAD
31P NMR
1H NMR
d1 [ppm] 1J(P,Pt) [Hz] d2 [ppm] 1J(P,Pt) [Hz] 2J(P,P) [Hz] d(Ha) [ppm][a] d(Hb) [ppm][b]
1/6
2/6
3/6
4/6
5/6
1/7
2/7
3/7
4/7
5/7
11.3
8.7
10.4
10.6
10.3
2.9
4.8
2.1
2.3
3.3
3507
3463
3704
3512
3495
3667
3674
3687
3608
3608
13.0
16.0
13.3
11.5
13.0
9.3
7.2
10.9
5.9
3684
3691
3596
3770
3778
3537
3426
3613
3535
3539
14.8
14.8
14.8
14.8
14.8
14.8
14.8
14.8
14.8
17.2
10.4
12.5
10.7
10.7
11.1
11.0
11.7
12.1
12.6
12.1
10.3[c]
13.4[c]
10.8[c]
10.0[c]
13.2[c]
12.3[c]
12.6[c]
13.0[c]
12.4[c]
12.9[c]
5.6
Thus, the rhodium-catalyzed
[a] Ha is from the donor group of LDA; see Scheme 1a. [c] Hb is from the donor group of LAD; see
Scheme 1a. [c] The assignment of d(Ha)/d(Hb) is interchangeable.
hydroformylation
of
1-octene
employing the self-assembled plat-
forms was studied in methanol, and
coupling constants are all greater then 3000 Hz (Table 1), as is
typical for cis-diphosphine platinum(II) complexes.[9,10] The
1H NMR spectra revealed nuclear Overhauser effect (NOE)
contacts between the protons involved in hydrogen bonding.
Hence, in solution, all 10 ligand combinations form hydrogen-
bonding platforms analogous to the A–T base pair. Further-
more, the existence of defined cis-heteroleptic complexes in
the solid state was confirmed by the analysis of the crystal
structures of [Cl2Pt(4/6)] and [Cl2Pt(3/7)] by X-ray diffraction
(Figure 1).
the results were compared to those obtained in toluene
(Table 3). As expected, the first-generation platform 1/6
showed a significant drop in regioselectivity on going from
toluene (94:6) to methanol (82:18). The drop in regioselec-
tivity is indicative of a disruption of the hydrogen-bonding
To probe the influence of the self-assembled platforms on
the catalyst properties, we studied the rhodium-catalyzed
hydroformylation of terminal alkenes. We chose this reaction
because a strong chelating effect is well-established and is
indicative of the ligand binding properties of the kinetically
competent catalyst,[11] and because it has enormous industrial
importance.[12] 1-Octene was chosen as the test substrate.
In a first set of experiments, all the ligands were evaluated
independently. The regioselectivities were on the order of
75:25 to 81:19, which is the typical result for a monodentate
triarylphosphine rhodium catalyst.[13] Next, all 10 possible
ligand combinations were studied, and the results of these
hydroformylation experiments are given in Table 2. The
regioselectivies observed (89:11 to > 99:1) confirm that, in
all cases, bidentate-ligand catalysts are the kinetically com-
petent catalyst species.
Interestingly, in all of the relevant ligand combinations,
going from the pivaloyl substituent to a trifluoroacetyl group
led to an increase in regioselectivity (1/6 vs. 2/6, 1/7 vs. 2/7, 4/6
vs. 5/6, and 4/7 vs. 5/7). This trend is consistent with an
increase of hydrogen-bond strength, as reflected in the
downfield chemical shift of the amide proton Ha in the
1H NMR spectra of the corresponding cis-[Cl2Pt(LDA)(LAD)]
complexes (Table 1). Among all the ligand combinations, the
catalysts derived from the thiazole–isoquinolone (5/6) and
from the thiazole–7-azaindole (5/7) systems were the best. In
these cases, regioselectivities greater than 99:1 in favor of the
linear aldehyde were observed, even at a reaction temper-
ature of 808C. One explanation could be that going from the
six-membered aminopyridine systems 1–3 to the five-mem-
bered thiazole heterocycles 4 and 5 might result in stronger
hydrogen bonds and, hence, in a more rigid self-assembled
Figure 1. a) PLATON plot of the structure of cis-[Cl2Pt(3/7)] in the solid
ꢀ
state. Selected interatomic distances [Š] and angles [8]: Pt P1
ꢀ
2.2417(6), Pt P2 2.2517(6), N1···N3 2.910(3), N4···N2 2.987(3); P1-Pt-
ꢀ
ꢀ
P2 99.01(2), N1 H···N3 129.0, N4 H···N2 153.7. b) PLATON plot of
the structure of cis-[Cl2Pt(4/6)] in the solid state. Selected interatomic
ꢀ
ꢀ
distances [Š] and angles [8]: Pt P1 2.2609(5), Pt P2 2.2331(6), N1···N2
ꢀ
ꢀ
2.992(3), N3···O1 3.038(3); P1-Pt-P2 97.42(2), N1 H···N2 159.0, N3
H···O1 166.0. Pt green, C dark gray, H light gray, N blue, P orange,
O red, S pink, Cl yellow; H atoms bound to C atoms are omitted for
clarity.
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Chemie
Table 2: Turnover frequencies (TOF)[b] [hꢀ1] and linear:branched (l:b) regioselectivities[c] of the rhodium-
catalyzed hydroformylation of 1-octene for a 5ꢀ2 matrix of self-assembled bidentate ligands derived
from donor–acceptor (LDA; 1–5) and acceptor–donor ligands (LAD; 6, 7).[a]
[1] C. Gennari, U. Piarulli, Chem. Rev.
2003, 103, 3071 – 3100.
[2] B. Breit, W. Seiche, J. Am. Chem. Soc.
2003, 125, 6608 – 6609; W. Seiche, A.
Schuschkowski, B. Breit, Adv. Synth.
Catal. 2005, 347, 1488 – 1494; B. Breit,
W. Seiche, Pure Appl. Chem. 2006, 78,
249 – 256.
[3] For alternative approaches to self-
assembled ligand/catalyst libraries,
see: B. Breit, Angew. Chem. 2005,
117, 6976 – 6986; Angew. Chem. Int.
Ed. 2005, 44, 6816 – 6825; J. M.
Takacs, D. S. Reddy, S. A. Moteki, D.
Wu, H. Palencia, J. Am. Chem. Soc.
2004, 126, 4494 – 4495; V. F. Slagt, M.
Röder, P. C. J. Kamer, P. W. N. M. van
LDA
LAD
!
1
2
3
4
5
fl
TOF
l:b
TOF
l:b
TOF
l:b
TOF
l:b
TOF
l:b
6
7
2465
2713
94:6
89:11
3396
4356
96:4
96:4
2341
3205
95:5
95:5
3890
3233
98:2
95:5
3888
2318
>99:1
99:1
[a] Reaction conditions: [Rh(CO)2(acac)] (acac=acetylacetonato):LAD:LDA:1-octene=1:10:10:7500,
10 bar H2/CO (1:1), toluene, 808C, 5 h; catalyst preformation: 5 bar H2/CO (1:1), 30 min, RT!808C.
[b] Calculated as TOF [hꢀ1]=(mol aldehydes)ꢀ(mol catalyst)ꢀ1 ꢀ(time [h])ꢀ1 at a reaction time of
30 min; determined by GC. [c] The ratio of linear to branched aldehyde products; determined by GC.
Table 3: Linear:branched (l:b) regioselectivities of the rhodium-cata-
lyzed hydroformylation of 1-octene in toluene and in methanol for self-
assembled ligands derived from donor–acceptor (LDA; 1, 2, 4, 5) and
acceptor–donor ligands (LAD; 6, 7).[a]
Leeuwen, J. N. H. Reek, J. Am. Chem. Soc. 2004, 126, 4056 –
4057; V. F. Slagt, P. W. N. M. van Leeuwen, J. N. H. Reek,
Angew. Chem. 2003, 115, 5777 – 5781; Angew. Chem. Int. Ed.
2003, 42, 5619 – 5623; V. F. Slagt, P. W. N. M. van Leeuwen,
J. N. H. Reek, Chem. Commun. 2003, 2474 – 2475; K. Ding, H.
Du, Y. Yuan, J. Long, Chem. Eur. J. 2004, 10, 2872 – 2884.
[4] For the use of mixtures of monodentate ligands in combinatorial
homogeneous catalysis, see: M. T. Reetz, T. Sell, A. Meiswinkel,
G. Mehler, Angew. Chem. 2003, 115, 814 – 817; Angew. Chem.
Int. Ed. 2003, 42, 790 – 793; M. T. Reetz, Chim. Oggi 2003, 21, 5 –
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4596; M. T. Reetz, X. Li, Tetrahedron 2004, 60, 9709 – 9714; M. T.
Reetz, X. Li, Angew. Chem. 2005, 117, 3019 – 3021; Angew.
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Chem. 2005, 117, 3022 – 3024; Angew. Chem. Int. Ed. 2005, 44,
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de Vries, J. G. de Vries, B. L. Feringa, Org. Biomol. Chem. 2003,
1, 1087 – 1089; D. Pena, A. J. Minnaard, A. H. M. de Vries, J. G.
de Vries, B. L. Feringa, Org. Lett. 2003, 5, 475 – 478; D. Pena,
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de Vries, L. Lefort, Chem. Eur. J. 2005, 11, 6701 – 6717; C. Monti,
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[5] B. Breit, W. Seiche, Angew. Chem. 2005, 117, 1666 – 1669;
Angew. Chem. Int. Ed. 2005, 44, 1640 – 1643.
[6] F. Chevallier, B. Breit, Angew. Chem. 2006, 118, 1629 – 1632;
Angew. Chem. Int. Ed. 2006, 45, 1599 – 1602.
[7] M. Weis, C. Waloch, W. Seiche, B. Breit, J. Am. Chem. Soc. 2006,
128, 4188 – 4189.
[8] P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P.
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LDA/LAD
l:b[b]
in toluene
in MeOH
1/6
2/6
5/7
4/6
5/6
94:6
96:4
99:1
98:2
99:1
82:18
79:21
85:15
97:3
96:4
[a] Reaction
conditions:
[Rh(CO)2(acac)]:LDA:LAD:1-octene=
1:10:10:1000, 10 bar H2/CO (1:1), 808C 20 h. [b] The ratio of linear to
branched aldehyde products; determined by GC and 1H NMR spectros-
copy on crude reaction mixtures after a reaction time of 20 h; complete
conversion was reached in all cases.
network between ligands 1 and 6, which forces the system to
behave as a monodentate triarylphosphine rhodium cata-
lyst.[13] The same holds for the ligand combination 2/6 and 5/7.
However, for the thiazole systems 4/6 and 5/6, high regiose-
lectivities were observed in toluene and in methanol. Hence,
for the first time, we could identify complementary self-
assembled platforms that operate as bidentate ligands, even in
a protic solvent.
In conclusion, the combinatorial self-assembly of mono-
dentate to bidentate ligands for homogeneous catalysis is a
very promising approach to the development of new and
better catalysts. Herein, we have demonstrated that variation
of the heterocyclic self-assembly platform has an enormous
impact on the properties of the resulting catalyst. New
hydroformylation catalysts with excellent activities and out-
standing regioselectivities, even in protic solvents such as
methanol, were identified. This result is an important
extension of the application range of self-assembled catalysts
based on hydrogen bonding. New applications in homoge-
neous catalysis are expected to emerge soon.
Received: December 22, 2006
Published online: March 20, 2007
[13] Under identical conditions (Table 2), a turnover frequency of
1312 hꢀ1 and a linear:branched regioselectivity of 76:24 in the
rhodium-catalyzed hydroformylation of 1-octene were measured
for triphenylphosphine.
Keywords: combinatorial chemistry · homogeneous catalysis ·
hydroformylation · rhodium · self-assembly
.
Angew. Chem. Int. Ed. 2007, 46, 3037 –3039
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