Transition-state stabilization by a secondary substrate-ligand interaction: A new design principle for highly efficient transition-metal catalysis

Article abstract of DOI:10.1002/chem.200902553

A library of monodentate phosphane ligands, each bearing a guanidine receptor unit for carboxylates, was designed. Screening of the library gave some excellent catalysts for regioselective hydroformylation of ss,γ- unsaturated carboxylic acids. A terminal alkene, but-3-enoic acid, was hydroformylated with a linear/branched (l/b) regioselectivity up to 41. An internal alkene, pent-3-enoic acid was hydroformylated with regioselectivity up to 18:1. Further substrate selectivity (e.g., acid vs. methyl ester) and reaction site selectivity (monofunctionalization of 2- vinylhept-2-enoic acid) were also achieved. Exploration of the structure-activity relationship and a practical and theoretical mechanistic study gave us an insight into the nature of the supramolecular guanidinium-carboxylate interaction within the catalytic system. This allowed us to identify a selective transition-state stabilization by a secondary substrate-ligand interaction as the basis for catalyst activity and selectivity.

Full text of DOI:10.1002/chem.200902553

DOI: 10.1002/chem.200902553
Transition-State Stabilization by a Secondary Substrate–Ligand Interaction:
A New Design Principle for Highly Efficient Transition-Metal Catalysis
[a]
ˇ
Tomꢀsˇ Smejkal, Denis Gribkov, Jens Geier, Manfred Keller, and Bernhard Breit*
Abstract: A library of monodentate
phosphane ligands, each bearing a gua-
nidine receptor unit for carboxylates,
was designed. Screening of the library
gave some excellent catalysts for regio-
selective hydroformylation of b,g-unsa-
turated carboxylic acids. A terminal
alkene, but-3-enoic acid, was hydrofor-
mylated with a linear/branched (l/b) re-
gioselectivity up to 41. An internal
alkene, pent-3-enoic acid was hydrofor-
mylated with regioselectivity up to
18:1. Further substrate selectivity (e.g.,
acid vs. methyl ester) and reaction site
selectivity (monofunctionalization of 2-
vinylhept-2-enoic acid) were also ach-
ieved. Exploration of the structure–ac-
tivity relationship and a practical and
theoretical mechanistic study gave us
an insight into the nature of the supra-
molecular guanidinium–carboxylate in-
teraction within the catalytic system.
This allowed us to identify a selective
transition-state stabilization by a secon-
dary substrate–ligand interaction as the
basis for catalyst activity and selectivi-
ty.
Keywords: enzyme mimics · guani-
dine
·
homogeneous catalysis
·
hydroformylation
recognition
·
molecular
Introduction
design of this type are still relatively rare.[2] In our prelimi-
nary report, we recently described a new receptor-based
phosphane ligand 1 (Scheme 1a), which furnishes a highly
reactive and selective catalyst for regioselective hydroformy-
lation of b,g-unsaturated carboxylic acids (Scheme 1c).[2a]
The application of supramolecular chemistry to catalysis has
been a long-term objective of many research and develop-
ment groups, with the ultimate goal being to produce supra-
molecular systems capable of mimicking the catalytic ability
of natural enzymes. Pauling described enzymes as “mole-
cules that are complementary in structure to the activated
complex of the reaction that they catalyze” and therefore
stabilize the transition state with respect to the uncatalyzed
reaction.[1] The net result is a reaction rate enhancement
and energetic differentiation among competing reaction
pathways leading to isomeric products (selectivity).
A seemingly simple idea of how to make current synthetic
catalysts more efficient and selective is to equip them with
molecular recognition functionalities that can reversibly
bind and orientate the substrate through noncovalent or re-
versible covalent interactions. In spite of recent progress in
supramolecular catalysis, examples of successful catalyst
Scheme 1. a) Structure of ligand 1.[2a] b) Concept of a supramolecular hy-
droformylation catalyst (Do=donor; FG1,2=complementary functional
groups). c) Regioselective hydroformylation of but-3-enoic acid (2).[2a]
Herein, we present a full account of our research on gua-
nidine-based receptor ligands and their application in regio-
selective hydroformylation of b,g-unsaturated carboxylic
acids. Modifications of the ligand structure, a study of the
structure–activity relationship and a theoretical study of the
reaction mechanism are described. Recent applications of
these ligands in decarboxylative hydroformylation of a,b-un-
saturated carboxylic acids[2b] and activation of an aldehyde
ˇ
[a] T. Smejkal, D. Gribkov, J. Geier, M. Keller, B. Breit
Institut fꢀr Organische Chemie und Biochemie,
Freiburg Institute for Advanced Studies (FRIAS),
Albert-Ludwigs-Universitꢁt Freiburg,
Albertstrasse 21, 79104 Freiburg (Germany)
Fax : (+49)761-2038715
E-mail: bernhard.breit@organik.chemie.uni-freiburg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902553.
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FULL PAPER
substrate function[3] are not included, and will be reported in
full detail elsewhere.
Ligand synthesis: Synthesis of ligands is typically based on
several building blocks, in particular, triarylphosphanes con-
taining an amine or carboxylic acid function. Compounds
such as 1 and 6–8 (Schemes 1 and 3), containing various
core (pyridine, benzene, pyrrole) and binding site structures
(acyl guanidine, acyl aminopyridine), have already been de-
scribed.[2a,b,3]
Results and Discussion
Catalyst design: Our strategy was to combine the structural
features of phosphane ligands (catalyst binding unit) with a
guanidinium-based recognition site for carboxylates[4] in one
ligand molecule (Scheme 2). The recognition unit should
Scheme 3. Previously reported ligands 6,[2a] 7,[2a] and 8.[3]
By using a similar synthetic strategy, carboxylic acids 9[7]
and 11[8] were coupled with mono-Boc-protected (Boc=tert-
butyloxycarbonyl) guanidine. In the next step, the protecting
group was cleaved with trifluoroacetic acid to give, after
neutralization, ortho-substituted ligand 10 and an electroni-
cally modified pyridine derivative 12 (Scheme 4).
Scheme 2. Design of guanidine ligands for supramolecular catalysis, gen-
eralized structure of ligand (X=N, CH, NH; Y=CO, CH2, or no linker)
and substrate. Hypothetical structure of the hydrometalation transition
state.
allow for substrate binding and conformational orientation.
A further requirement of the design is that the ligand geom-
etry should exactly match the transition-state structure.
Only when the substrate–ligand interaction within the tran-
sition state is stronger than that in the catalyst–substrate
adduct will lowering of the activation energy barrier (rela-
tive to the nonrecognition catalyst) be expected. By employ-
ing molecular modeling, some ligand geometries could be
directly excluded, however, final tuning of the catalyst struc-
ture relied, to some extent, on trial and error. To lower the
risk of failure, we adopted a strategy that has been frequent-
ly employed in medicinal chemistry and prepared not only a
single ligand, but a small library of structurally diverse
ligand molecules based on the design principle depicted in
Scheme 2.
Scheme 4. Synthesis of ligands 10 and 12: 1) Boc-guanidine (Boc=tert-
butoxycarbonyl), N-methylmorpholine, 1-benzotriazolyloxytris(dimethyl-
AHCTUNGERTGaNNUN mino)phosphonium hexafluorophosphate, DMF, RT; 2) trifluoroacetic
acid, RT, then Na2CO3, H2O, CH2Cl2.
Introduction of the cyclic guanidine directing group was
achieved by reaction of 2-aminoimidazoline toluene-p-sulfo-
nate (15) with either the corresponding methyl picolinate 13
or methyl benzoate 14 precursors in methanol, in the pres-
ence of sodium methoxide as a base (Scheme 5).[9] While the
methyl picolinate reacted to give 16 in good yield (75%),
the yield of the methyl benzoate derivative 17 was lower
(40%), presumably due to reduced electrophilicity.
Hydroformylation of alkenes was selected as an ideal cat-
alytic reaction to test our supramolecular catalytic system.
Hydroformylation represents an example of an atom-eco-
ꢀ
nomic C C bond forming reaction that tolerates nearly all
additional functional groups in the substrate molecule. Fur-
thermore, this reaction constitutes the largest volume appli-
cation of homogeneous metal catalysis in industry.[5] One
possible drawback could be the multistep nature of the reac-
tion. However, extensive mechanistic studies on a number
of systems has revealed that, for rhodium triarylphosphane
complexes, alkene hydrometalation is typically the rate- and
selectivity-determining step.[6] Accordingly, control of this
early step in the catalytic cycle should result in a large over-
all supramolecular effect.
Scheme 5. Synthesis of ligands 16 and 17.
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B. Breit et al.
Ligands in which the guanidinium group is attached either
directly or through a CH2 bridge to the triarylphosphane
moiety were prepared by the reaction of the corresponding
amine with 1-carbomethoxy-2-methylthio-2-imidazoline (18;
Scheme 6).[10] Importantly, the methoxycarbonyl group was
already cleaved under the reaction conditions.
chart). When the reaction was conducted with unmodified
rhodium catalyst (no ligand added), moderate selectivity for
the formation of the branched regioisomer (l/b=0.6) was
observed. Ligands 10 and 22, which are equipped with a re-
ceptor moiety in the ortho-position relative to the phos-
phane moiety, inhibited the reaction completely. This may
be a possible consequence of rhodium chelation between
these two functionalities.
Activity and selectivity comparable to that with PPh3 was
observed for the majority of ligands tested (19, 16, 20, 17, 6,
21, and 7). However, three acylguanidine derivatives (1, 8,
and 12) gave catalysts with much higher activity. Pyridylacyl-
guanidinium ligand 1 gave an outstanding catalyst that oper-
ated with excellent activity (TOF=250 hꢀ1) and regioselec-
tivity (l/b=23). Interestingly, the activity and selectivity
could be further improved by fine-tuning of the electronic
properties of the ligand. Derivative 12, bearing two fluoro-
substituents, gave even higher regioselectivity (l/b=41) with
TOF>350 hꢀ1.[11] On the other hand, in the hydroformyla-
tion of but-3-enoic acid (2), although pyrrole derivative 8
provided one of the highest reaction rates (TOF=286 hꢀ1),
unfortunately, the regioselectivity was low (l/b=3.5). Appa-
rently, the formation of both regioisomers is promoted to
similar extents with this ligand. The most active catalysts
identified during the screening were applied in a more chal-
lenging reaction: the hydroformylation of internal alkene
(Z)-pent-3-enoic acid (23; Table 1). When using triphenyl-
phosphane as a ligand, hydroformylation proceeded slug-
gishly; under these conditions,
Scheme 6. Synthesis of ligands 19, 20, 21, and 22.
Hydroformylation of b,g-unsaturated carboxylic acids: With
the ligand library in hand, we started to evaluate its effec-
tiveness in hydroformylation. As the first test system, hydro-
formylation of vinylacetic acid (2) was studied (Figure 1).
The standard industrially applied catalyst, [RhACHTUNTGRNENG(U acac)(CO)2]/
PPh3 (acac=acetylacetone), displayed rather low activity
(turnover frequency (TOF)=30 hꢀ1, upper chart), and a typ-
ical linear/branched (l/b) regioselectivity (l/b=1.3, lower
the catalyst produced 5.5 equiv-
alents of aldehyde products in
68 h and formation of 25 over
24 was only slightly preferred
(Tabel 1, entry 1). In contrast,
an unprecedentedly high regio-
selectivity in the hydroformyla-
tion of an internal alkene was
achieved by using ligand 1; in
this case, branched aldehyde 24
was obtained as the major reac-
tion
product
(24/25=11:1;
Table 1, entry 2) together with
increased conversion (TON=
39). Applying more reactive
catalysts based on ligands 12
and 8 allowed lower catalyst
loadings (1 mol% [Rh]) to be
used and reduced the reaction
time (20 h). Ligand 12 also gave
the highest regioselectivity (24/
25=18.1:1; Table 1, entry 3).
Furthermore, the directed hy-
droformylation was applied in
selective monofunctionalization
of substrate 26, bearing two ter-
minal double bonds of similar
reactivity. Hydroformylation of
Figure 1. Hydroformylation of 2; [RhACHTNURGTENUNG(acac)(CO)2]/ligand/2=1:10:200 (acac=acetylacetonate); c0(2)=0.2m,
THF (2 mL), 10 bar CO/H2 (1:1), 408C, 4 h. TOF (mole aldehyde per mole catalyst per hour) determined
from the gas consumption curve. Regioselectivity, linear/branched (l/b) ratio, was determined by 1H NMR
spectroscopic analysis of the reaction mixture. n.d.=not determined.
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Secondary Substrate–Ligand Transition-State Stabilization
FULL PAPER
Table 1. Hydroformylation of (Z)-pent-3-enoic acid (23).
When using ligand 1, the remote alkene functional group
was hydroformylated at a similar rate and selectivity (l/b) to
that with PPh3. Conversely, the b,g-alkene group reacted ten
times faster (compared with PPh3) in a highly regioselective
manner, which is again indicative of a directed process (see
1
Time TON[a] Regioselectivity
[h]
Figure 3, which displays H NMR spectra of aliquots taken
Entry
1[b]
Ligand
PPh3
[24/25]
from the reaction mixture at different reaction times and
highlights the reaction-site selectivity). On a preparative
scale, aldehyde 27 could be isolated in 75% yield.[8]
68
5.5
1:1.7
2[b]
68
39
11:1
Hydroformylation of g,d-unsaturated carboxylic acids: Hy-
droformylation of the homologue pent-4-enoic acid (32),
which has the double bond one carbon further removed
from the carboxylate, was attempted (Figure 4). However,
most of the ligands tested showed reactivity comparable to
that of triphenylphosphane. Pyrrole derivative 8 was the
only ligand for which a significant supramolecular effect was
observed; in this case the rate enhancement was approxi-
mately fivefold higher than that with PPh3 (TOF=125 hꢀ1,
l/b=7.3:1).
3[c]
20
20
73
93
18.1:1
3.9:1
4[c]
The observed selectivity is surprising at first sight. Given
that addition of the formyl group occurred mainly at C-4 for
the b,g-unsaturated substrates 2 and 23, one would expect a
high selectivity for the formation of branched product 24.
However, although the identical alkyl rhodium intermediate
34 (see Scheme 8) could be formed from both substrates 23
and 32, the transition-state structures of the corresponding
hydrometalation steps leading to this common intermediate
are different. Clearly, the catalyst is not able to efficiently
accommodate any of the alternative hydrometalation transi-
tion states of the g,d-unsaturated substrate 32. Taken togeth-
er, these results provide evidence for hydrometalation being
the rate- and selectivity-determining step (see below).
[a] Turnover number=TON (mole of aldehydes per mole catalyst);
[b] [Rh(acac)(CO)2]/ligand/23=1:10:50, c0(23)=0.2m, THF (4 mL), 6 bar
CO/H2 (1:1), RT, 68 h; [c] [Rh(acac)(CO)2]/ligand/23=1:10:100, c0(23)=
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
0.2m, THF (2 mL), 10 bar CO/H2 (1:1), 408C, 20 h.
26 can potentially give up to four regioisomeric mono-alde-
hydes (27–30) and four bis-aldehydes (31) six of them as a
mixture of two or more diastereoisomers (Scheme 7).
When using triphenylphosphane as a ligand, the rates of
hydroformylation of the two alkene functions were very sim-
ilar (see Figure 2, which displays 1H NMR spectra of ali-
quots taken from the reaction mixture at different reaction
times and highlights the similar rates of alkene consump-
tion). Regardless of when the reaction was stopped, we ob-
tained an intractable mixture of several mono- and dihydro-
formylated products (27–31).
Control experiments: The proposed reaction mechanism, in-
cluding supramolecular ligand–substrate interaction, was
supported by a number of control experiments. No supra-
molecular effect was observed for ligand 35, which bears a
protected guanidine (Table 2, entry 2). Furthermore, when a
combination of acylguanidine
36 and triphenylphosphane was
used, neither the desired activi-
ty nor selectivity were obtained
(Table 2, entry 3). These find-
ings suggest that the molecular
recognition and catalytic units
must be an integral part of the
same molecule to achieve the
enhanced catalytic activity and
selectivity. Further evidence
came from the fact that methyl
ester 37, which lacks the com-
plementary acid functionality,
reacted slowly and with low se-
lectively (Table 2, entries 4 and
5).
Scheme 7. Hydroformylation of 26; [RhACHTNUGTRNEG(UN acac)(CO)2]/ligand/26=1:10:150; c0(26)=0.2m, THF (8 mL), 4 bar
CO/H2 (1:1), 258C.
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B. Breit et al.
Figure 2. Hydroformylation of 26 using PPh3 as a ligand. 1H NMR spectra
(400 MHz, CDCl3) of the double-bond region: a) 0 h; b) 9.5 h; c) 25.3 h.
Signals from H-2’ and H-7 are marked with empty and filled arrows, re-
spectively. Reaction-site selectivity and regioselectivity were determined
1
by H NMR spectroscopic analysis of the reaction mixture.
Figure 4. Hydroformylation of 32. [RhACHTNUGRTENUNG(acac)(CO)2]/ligand/32=1:10:200,
c0(32)=0.2m, THF (2 mL), 10 bar CO/H2 (1:1), 408C, 4 h. TOF (mole al-
dehyde per mole catalyst per hꢀ1) determined from the gas consumption
1
curve. Regioselectivity (33/24 ratio) was determined by H NMR spectro-
scopic analysis of the reaction mixture. n.d.=not determined.
Figure 3. Hydroformylation of 26 using ligand 1. 1H NMR spectra
(400 MHz, CDCl3) of the double-bond region: a) 0 h; b) 4 h; c) 8.5 h. Sig-
nals from H2’ and H7 are marked with empty and filled arrows, respec-
tively. Reaction-site selectivity and regioselectivity were determined by
1H NMR spectroscopic analysis of the reaction mixture.
Furthermore, using a catalyst containing a molecular rec-
ognition unit should make substrate differentiation possible,
which would be difficult to achieve with classical catalysts.
Thus, we carried out a competition experiment in which a
1:1 mixture of terminal olefins of similar reactivity was hy-
droformylated in the presence of [RhACTHUNTRGNEU(GN acac)(CO)2]/1 catalyst
(Table 3). The ratio of products at low conversion indicates
that the reaction rate of the hydroformylation of noncom-
plementary substrates was considerably slower and the cor-
responding aldehyde products were formed without any re-
gioselectivity (l/b ratio=2.3–3). Thus, our supramolecular
catalyst can carry out a chemical transformation selectively
on a specific target in a mixture of chemical substances.
If the interaction between the carboxylic acid and the
guanidine is important for catalyst performance, the addi-
tion of a second carboxylic acid to the reaction medium
should lead to competition for the recognition site. Indeed,
when acetic acid was added to the reaction mixture (1–
5 equiv relative to 2), we observed inhibition and decreased
selectivity (Figure 5).[12] These experimental results also ex-
clude the possibility that the carboxylic acid simply func-
Scheme 8. Substrate binding in the rate- and selectivity-determining hy-
drometalation step for substrates 23 and 32. The bold curve represents
the substrate binding site of ligand 1.
tions as a template for supramolecular bidentate ligand for-
mation, which could result in selectivity for the linear prod-
uct.
A mechanism in which the recognition event precedes the
catalytic reaction implies that, for high substrate concentra-
tions, saturation should be achieved. Hydroformylation of 2
was therefore conducted at various substrate concentrations
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Secondary Substrate–Ligand Transition-State Stabilization
Table 2. Control experiments.[a]
FULL PAPER
Entry
Ligand
Substrate
Conver- Regioselectivity TOF
sion [%] [l/b ratio]
[hꢀ1
N
]
1
2
3
1
35
2
2
2
100
77
20
23
1.4
1.5
1.1
1.4
250
50
12
29
34
PPh3/36 (1:1)
Figure 5. Hydroformylation of 2; [RhACHTNUGRTENUNG(acac)(CO)2]/1/2/AcOH=1:10:200:
4[b]
5
1
1
37
50
(0–1000), c0(2)=0.2m, THF (2 mL), 10 bar CO/H2 (1:1), 408C, 4 h. Gas
consumption curves for increasing amounts of inhibitor AcOH (0–
5 equiv relative to substrate 2). Regioselectivity (l/b ratio) was deter-
37/AcOH (1:1) 58
[a] [Rh
(acac)(CO)2]/ligand/substrate=1:10:200,
c0(substrate)=0.2m,
1
THF (2 mL), 10 bar CO/H2 (1:1), 408C, 4 h; [b] Suspension (ligand 1 is
practically insoluble in the reaction medium without a carboxylic acid);
all other runs were clear solutions.
mined by H NMR spectroscopic analysis of the reaction mixture.
tive rate of formation of the branched isomer 3b (vBACHTUNGTRENNUNG(rel)]
are minimal (Table 4). Accordingly, the energy of the
branched transition state does not seem to be particularly
affected by the secondary catalyst–ligand interaction. In
contrast, the relative rate of formation of the linear isomer
Table 3. Hydroformylation of a 1:1 mixture of two substrates.[a]
3l (vLACTHUNRTGNEUNG(rel)) is 14-times faster for the catalyst [Rh]/1 than for
[Rh]/PPh3; this acceleration is thus the source of the reac-
tion selectivity (Table 4).
Table 4. Effect of molecular recognition on the reaction rate.[a]
Entry
Substrate
Relative rate of
hydroformylation
Regioselectivity
[l/b ratio]
Ligand
v
G
vBACHTUNGTRENNUNG(rel)
PPh3
1
1
0.77
0.61
1
2
3
2
37
38
1
50
2.3
3
14.13
<0.1
<0.15
[a] Reagents and conditions, see Figure 1. vACTHNUTRGNE(NUG rel)=rate of hydroformyla-
tion (aldehyde formation) relative to vL(rel, PPh3).
[a] [RhACHTUNGTRENNUNG(acac)(CO)2]/1/2/37(38)=1:20:200:200, c0(2)=c0CAHTUNGTRENN(UGN 37 or 38)=
0.13m, THF (6 mL), 4 bar CO/H2 (1:1), RT.
Clearly, the supramolecular interaction matches the tran-
sition-state requirements for the formation of the linear re-
gioisomer and lowers the activation energy relative to the
nonrecognition catalyst. This is schematically demonstrated
in Figure 6, which shows selective lowering of the energy
barriers by an amount relating to the strength of the supra-
molecular ligand–substrate interaction.[14]
To gain a deeper understanding of the reaction, several
NMR spectroscopy experiments were undertaken with the
catalyst precursor [RhACHTUNTRGNEUNG(acac)(CO)2] and two equivalents of
(0.05–0.4m). Indeed, substrate saturation and even inhibition
was observed.[8]
All these results are consistent with a reaction mechanism
analogous to enzyme catalysis: 1) binding of the substrate to
the ligand(s) of the rhodium phosphane complex; 2) di-
rected catalytic reaction within the supramolecular sub-
strate–catalyst complex. However, the most important ques-
tions still remain to be answered: What does the catalyst–
substrate complex look like and what is the source of the re-
action selectivity? Hence, we decided to study the mecha-
nism of vinylacetic acid (2) hydroformylation in more detail.
ligand 1, suspended in CDCl3 under argon. After addition of
AcOH (1.0 equiv), dissolution of the compounds was ob-
served and the mixture was analyzed by NMR spectroscopy.
1
However, only very broad H and 31P NMR signals were ob-
Reaction mechanism: By using the activity and selectivity
data (Figure 1), the relative reaction rates for the formation
served and no signal assignments were possible. After addi-
tion of three further equivalents of AcOH, much clearer
spectra were observed. The spectra were interpreted as aris-
ing from the rhodium carboxylate complex 39
[Rh(1)2(CO)OAc] (Scheme 9) by analogy to the known tri-
of linear aldehyde 3l (v
(vBA(rel)) with either the [Rh]/1 catalyst or the [Rh]/PPh3 cat-
alyst were calculated (Figure 6).[13] Differences in the rela-
LACHTUNGTNER(NUNG rel)) and branched aldehyde 3b
CHTUNGTRENNUNG
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2475

B. Breit et al.
Scheme 10. NMR study of 1/AcOH interaction {[D6]DMSO, 300 MHz,
c0(1)=0.02–0.03m, RT}.[8]
AcOꢀ should be greater than 430mꢀ1 because of the addi-
tional attractive interaction between the opposite charges
(Scheme 10b). Titration of the free base 1 with acetic acid
(0–24 equiv) caused a significant downfield shift of various
Figure 6. Energy surfaces for the catalyst without (dashed) or with (full)
a molecular recognition system. Stabilization imparted by supramolecular
interaction marked with arrows, [C·S] or [C·P] represents catalyst–sub-
°
°
strate (product) adduct, [TS(L)] and [TS(B)] represent the corresponding
transition states. Selective lowering of the energy barrier is marked with
a black parenthesis.
1
proton signals of 1 in the H NMR spectrum. Interestingly,
comparison of these spectra with spectra obtained after the
addition of one equivalent of either CF3COOH or picric
acid revealed that signals of all protons of 1 gradually shift-
ed towards those of the protonated ligand 1+. This is inter-
preted as a gradual protonation of 1 (approximate equilibri-
um constant of this process is Keq =0.7mꢀ1, Scheme 10c).
In conclusion, these experiments suggest that, due to the
relatively low basicity of the acylguanidine 1, both protonat-
ed (1+) and neutral (1) ligands can coexist under the reac-
tion conditions of hydroformylation catalysis and, further-
more, that both ligand forms are able to efficiently bind to
carboxylates.
To get a better insight into the function of this catalyst
system, we undertook theoretical studies (DFT) on what is
considered to be the rate- and selectivity-determining step
of the rhodium/phosphane-catalyzed hydroformylation, that
is, the alkene hydrometalation[6] (Figure 7).[17] Interestingly,
the originally envisioned two-point guanidinium–carboxylate
interaction mode (Scheme 2) could not be localized as an
energy minimum, probably due to a severe repulsion be-
tween the lone electron pairs of the pyridine nitrogen and
the carboxylate oxygen.[18] However, the most stable cata-
lyst–substrate complex conformation (Figure 7a) was found
to involve the carboxylate complexed by four hydrogen
bonds from both guanidine ligands (one protonated, one
neutral). Interestingly, even for this intermediate, the calcu-
lated conformation predicts that the alkene should be signif-
Scheme 9.
phenylphosphane complex trans-[Rh(CO)OAc
Additionally, no signal was observed in the typical rhodium
N
1
hydride region of the H NMR (d=ꢀ9 to ꢀ10 ppm). When
high-pressure NMR spectroscopy was used to investigate
the effect of CO/H2 pressure (1:1; 10–40 bar) on this com-
plex, the formation of characteristic signals of rhodium hy-
dride species (1H NMR: d=ꢀ9.2 to ꢀ9.6 ppm) was ob-
served. However, the broad nature of the H and 31P NMR
1
signals did not enable unequivocal identification of the cor-
responding complexes. By analogy to known triphenylphos-
phane complexes,[16] formation of the rapidly equilibrating
trigonal bipyramidal isomers 40a and 40b is proposed
(Figure 6). Complexes 39 and 40 thus represent the resting
state of the active hydroformylation catalyst.
For solubility reasons, determination of the ligand–sub-
strate association constant had to be carried out in
[D6]DMSO. Nevertheless, based on H NMR spectroscopic
ꢀ
ꢀ
icantly turned from the P Rh P plane of the trigonal bipyr-
amidal complex towards that of the transition state leading
to the linear alkyl rhodium intermediate. On the way to the
transition state the alkene moiety rotates further out of the
equatorial plane and the hydride is transferred from the
metal center to the alkene moiety (Figure 7b). The calcula-
tion indicates an early transition state containing a nearly
1
titration experiments and spectroscopic studies of model sys-
tems (picrate, trifluoracetate), a complete association system
of acetic acid and 1 could be constructed (Scheme 10).[8]
Thus, a solution of the free base 1 was titrated with tetra-
methyl ammonium acetate (AcOꢀ) and the shift changes of
1
ꢀ
the H NMR signals associated with the ligand protons were
unperturbed rhodium–hydride bond (Rh H bond lengthens
monitored. Good fit of the measured data with the theoreti-
cal model for association constant Kass =430mꢀ1 with a 1:1
stoichiometry was obtained (Scheme 10a). Accordingly, the
hypothetical association constant of protonated ligand 1+/
by only 0.065 ꢃ). According to this analysis, most of the ac-
tivation energy for the hydrometalation can be attributed to
the rotation of the alkene from the equatorial in-plane ar-
rangement in the reactant to a nearly perpendicular orienta-
2476
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Chem. Eur. J. 2010, 16, 2470 – 2478

Secondary Substrate–Ligand Transition-State Stabilization
FULL PAPER
has enabled us to draw impor-
tant conclusions concerning
structure–activity relationships.
A mechanistic study of one par-
ticular case—regioselective hy-
droformylation of 2—revealed
that the experimentally ob-
served enhancement in activity
and selectivity brought about
by the ligand is a result of the
selective supramolecular transi-
tion-state stabilization within
our system. Furthermore, the
transition-state geometry and
the nature of the supramolec-
ular catalyst–substrate interac-
tion were identified by using
Figure 7. DFT calculations on the reaction mechanism of directed hydroformylation of 2. a) Catalyst–substrate
complex; b) transition state of hydrometalation; c) catalyst–product complex; d, e) alternative transition states.
E+ZPE=electronic energy+zero point energy (relative to structure a).
tion in the transition state. This movement is assisted by a
supramolecular interaction, which becomes optimal at the
transition state with hydrogen bonds pointing directly
DFT calculations. These calculations have led to a refine-
ment of our originally proposed supramolecular interaction
geometry and enabled a better understanding of the factors
involved in transition-state stabilization.
We hope that a detailed understanding of the reaction
mechanism will encourage future designs of supramolecular
and biomimetic catalysts for a broad variety of synthetically
relevant transformations.
ꢀ
toward the lone pairs of the carboxylate (d(N3 H···O5)=
ꢀ
ꢀ
2.012 ꢃ, d(N4 H···O5)=1.857 ꢃ, d(N5 H···O4)=1.569 ꢃ,
ꢀ
d(N6 H···O4)=1.583 ꢃ). This binding motif closely resem-
bles the so-called “oxanion hole” structures that are known
in enzymes and clearly stabilizes the formation of the car-
boxylate anion.[19] Additionally, this coordination mode min-
imizes repulsion between the lone pair of the pyridine nitro-
gen and the anionic carboxylate oxygen. For the hydrometa-
lation product (alkyl rhodium intermediate), the calculation
predicts a complex network of hydrogen bonding both be-
tween the ligand and the substrate and also between ligands
(Figure 7c). Additionally, a rhodium–carboxylate interaction
Experimental Section
General procedure for hydroformylation experiments: Experiments were
performed either in
a Premex stainless steel autoclave Medimex
(100 mL) equipped with a glass liner containing a magnetic stirring bar
(1000 rpm) or in an Argonaut Endeavour reactor system consisting of
eight parallel mechanically stirred (500 rpm) pressure reactors with indi-
vidual temperature and pressure controls. The hydroformylation solution
(dACHTUNGTRENNUNG(Rh···O)=2.463 ꢃ) was also identified. All attempts to
find an alternative catalyst–substrate interaction mode (e.g.,
one ligand bonding as shown in Figure 7d; or hydrogen
was prepared by charging a Schlenk flask with [RhACTHNUTRGEN(UNG acac)(CO)2], ligand,
1,3,5-trimethoxybenzene (internal standard 1H NMR) and solvent, under
argon. Then, the substrate was added and the mixture was stirred for
5 min under argon. The solution was transferred to the autoclave with a
syringe under an argon atmosphere. The autoclave was purged three
times with synthesis gas CO/H2 (1:1) and the reaction was conducted as
specified in the text. Runs were stopped by cooling the system (if appro-
priate), venting, and purging with argon. Reaction kinetics were moni-
bonding only as shown in Fig
higher activation energies.
ACHTUNGERTNuNUNG re 7e) resulted in much
Although the hydrometalation step is supposed to be
rate- and selectivity-determining, the catalytic cycle cannot
be reduced to this step only. The system based on the mono-
dentate receptor ligands is quite flexible and the binding ge-
ometry may vary during the catalytic cycle to accommodate
further reaction intermediates. The guanidine ligand might
also participate in CO dissociation (see Figure 7e), alkene
coordination or the hydrogenolysis of the acyl–rhodium in-
termediate.
1
tored either from the gas consumption curve or by H NMR spectroscop-
ic analysis of reaction samples.
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie, the
Deutsche Forschungsgemeinschaft (GRK 1038), and an Alfried Krupp
Award for young university teachers of the Krupp foundation (to B.B.).
Conclusion
A library of phosphane ligands bearing guanidine receptor
units for carboxylates was prepared and tested in the hydro-
formylation of unsaturated carboxylic acids. This study has
led to the identification of some new ligand structures that
could even surmount the activity and selectivity of the origi-
nally published supramolecular catalyst [Rh]/1. Notably, a
direct comparison of the performance of various catalysts
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2,
Catalyst
ð250ꢁ23Þ=24
ð30ꢁ1:3Þ=2:3
[Rh]/1:
TOF=250 hꢀ1
,
l/b=23:1.
ð250ꢁ1Þ=24
) vLðrel;1Þ ¼
¼ 14:13; vBðrel;1Þ ¼
¼ 0:61
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Received: September 16, 2009
Published online: January 14, 2010
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Chem. Eur. J. 2010, 16, 2470 – 2478