Fluorophore tagged cross-coupling catalysts

Article abstract of DOI:10.1039/b820633c

Fluorophore tagged N-heterocyclic carbenes and the derived (NHC)Pd(allyl)Cl complexes were synthesized and the fluorescence signal was used to follow the course of a Suzuki coupling reaction. The Royal Society of Chemistry.

Full text of DOI:10.1039/b820633c

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Fluorophore tagged cross-coupling catalystsw
Volodymyr Sashuk, Dirk Schoeps and Herbert Plenio*
Received (in Cambridge, UK) 18th November 2008, Accepted 5th January 2009
First published as an Advance Article on the web 14th January 2009
DOI: 10.1039/b820633c
Fluorophore tagged N-heterocyclic carbenes and the derived
(NHC)Pd(allyl)Cl complexes were synthesized and the fluores-
cence signal was used to follow the course of a Suzuki coupling
reaction.
First the synthesis of a fluorophore tagged N-heterocyclic
carbene was undertaken (Scheme 1). According to a procedure
by Cooke et al.12 2,6-dimethylaniline 2a and 2,6-diisopropyl-
aniline 2b were aminomethylated to obtain up to 100 g of the
respective 4-morpholinomethyl-substituted anilines in excel-
lent yields. The anilines 3a and 3b were converted into the
imidazolium salt 6a and 6b in accordance with standard
procedures.13 Treatment of 3a or 3b with glyoxal gave the
respective diimines 4a and 4b, whose reduction with LiAlH4
resulted in the respective diamines 5a and 5b, followed by ring
closure with HC(OEt)3 and formation of 6a and 6b. The
CH2-N(morpholino) unit can be cleaved by prolonged treat-
ment with ClCOOEt in acetonitrile,14 to generate –CH2Cl-
substituted imidazolium salts 7a and 7b. These are the key
compounds for the work reported here, as the presence of two
–CH2Cl groups enables the facile introduction of various
nucleophiles onto the NHC precursor. The methyl-substituted
7a is produced in 52% yield after repeated treatment with
chloroformate. Due to the poor solubility of the imidazoli-
nium salt 6a in CH3CN (and in many other solvents suitable
for this reaction) the reaction proceeds slowly. However, the
starting material and the partially cleaved mono-morpholino
salt can be isolated and again exposed to the cleavage condi-
tions. The much better solubility of 6b in CH3CN enables the
synthesis of dekagram amounts of 7b in 84% yield. The facile
substitution of the –CH2Cl group with a variety of nucleo-
philes allows the introduction of numerous functional units. In
order to attach a dansyl-based fluorophore, the corresponding
nucleophile was required. A large excess of piperazine
(6 equiv.) was reacted with dansylsulfonylchloride and the
monosulfonated piperazine 1 isolated in 93% yield. Reaction
of the secondary amine 1 with the benzyl chloride 7 results in
the facile formation of a dansyl-tagged NHC precursors 8a
and 8b, respectively. The introduction of the fluorophore is
equally efficient for both 8a and 8b. However, for the
isopropyl-substituted species the difficult separation of 8b
and 1 results in a low yield of isolated 8b. According to
published procedures the carbenes resulting from 8a/8b were
converted to the Pd complexes 9a/9b. The (NHC)PdCl(allyl)
complex reported by Nolan et al. is useful in Suzuki cross-
coupling and Buchwald–Hartwig amination reactions.8,9
According to Nolan et al., the best catalytic conditions for
such catalyst are the use of KOtBu as a base and iPrOH as a
solvent. Unfortunately, due to the low solubility of our
Pd complex and the precipitation of inorganic salts during
reaction we were prompted to search for other solvents. In
polar solvents such as DMSO, DMF and DMA a very
low catalytic activity was observed. With a view to the
important role of iPrOH in the generation of active species,
DMA–iPrOH mixture (1 : 5) was found as an optimal choice.
The direct observation of catalyst complexes within the cata-
lytic cycle is desirable in order to obtain a better understanding
of homogeneous catalysis. Obviously, the amount of complex
required to initiate a catalytic transformation is small. Thus, it
is not surprising that the lack of selective and highly sensitive
spectroscopic techniques has precluded the direct observation
of homogeneous catalysts under real time conditions—unlike
the situation in heterogeneous catalysis.1
Fluorescence spectroscopy has the potential to allow the
detection of minute amounts of catalyst complexes. Fluorescence-
based approaches have been used in cross-coupling reactions,
but this has been limited mainly to examine product formation
with fluorophores attached to coupling partners.2–5 Tagging
with a fluorescent dye enables the detection of Pd complexes
down to the single molecule limit as demonstrated recently by
Blum et al. with fluorescence microscopy.6 Herten et al. have
shown that the formation and dissociation of individual
ligands from metal complexes can be monitored by single-
molecule fluorescence spectroscopy.7
We assume that direct information about species in the
catalytic cycle can be obtained when relevant ligands for
homogeneous catalysis are tagged with fluorophores.
A potential problem of such an approach is the occurrence
of fluorescent emissions unrelated to the catalytic event
following the dissociation of the fluorophore tagged ligands
from the transition metal complexes during the course of the
catalytic transformation. In this respect, N-heterocyclic
carbenes are very useful as they are tightly bound to the
metal center. Consequently, we report here on the synthesis
of fluorophore tagged N-heterocyclic carbenes and of
catalytically active (NHC)Pd complexes. We decided to
use complexes of the type (NHC)Pd(allyl)Cl as model
complexes, recently reported by Nolan et al.8,9 The dansyl
group appears to be suitable as a fluorophore since its
functional groups should not interfere with cross-coupling
chemistry.10,11 We report here on a preliminary investigation
of the fluorescence emission of the respective tagged complexes
during catalysis.
Anorganische Chemie im Zintl-Institut, Technische Universitat
¨
Darmstadt, Petersenstr., 18, 64287 Darmstadt, Germany.
E-mail: plenio@tu-darmstadt.de
w Electronic supplementary information (ESI) available: Full experi-
mental details, characterisation data, 1H and 13C NMR spectra. See
DOI: 10.1039/b820633c
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Scheme 1 Synthesis of fluorophore tagged Pd complex. Reagents and conditions: 2a (2,6-dimethylaniline), 2b (2,6-diisopropylaniline) (i) CH2O,
morpholine, EtOH, H2O, reflux; (ii) HCOOH, glyoxal, MeOH, rt; (iii) LiAlH4, THF, 0 1C, rt; (iv) NH4Cl, HC(OEt)3, 120 1C; (v) ClCOOEt,
MeCN, reflux; (vi) 1, DMF, rt (dansp-H = 1); (vii) [Pd(allyl)Cl]2, KOtBu, THF, rt.
Iodo- and bromoderivatives 10 and 11 were chosen as model
substrates. In this solvent medium the sterically less demanding
catalyst 9a is more active than 9b. The next step was to
establish the conditions needed for fluorescence monitoring
measurements in a cuvette to enable in situ fluorescence
measurements. Ideally all reagents and products should be
soluble in the reaction medium.
We studied the Suzuki coupling reaction of 3-trifluoro-
methyl-bromobenzene and 3-trifluoromethyl-iodobenzene
with phenyl boronic acid using 0.3 mol% (10À4 M) of the
fluorophore tagged Pd complex 9a at 40 1C in DMA–iPrOH
(1 : 5) (Scheme 2).
After excitation at 365 nm, the monitoring of the fluores-
cence signal at 532 nm during the coupling reaction (Fig. 1)
Fig. 1 Fluorescence vs. time curve of the Suzuki coupling of
reveals interesting features of the catalytic transformation.
During the first minutes the fluorescence signal of a mixture
of Pd2+ precatalyst 9a and phenylboronic acid is stable at
3100 a.u. According to Nolan et al., the addition of KOtBu
leads to the formation of the catalytically active Pd0 species.
This process results in an immediate drop in the fluorescence
intensity from 3100 to 2700 a.u. within a few seconds. We
believe that this drop in intensity is due to a change in the
fluorescence quenching behavior of Pd2+ vs. Pd0. It was
recently reported that Pd0 nanoparticles cause fluorescence
quenching in Alexa Fluor dyes.15 Again, the fluorescence
remains stable over the next ca. 20 min until the aryl halide
was added. This substrate induced a slower but much more
pronounced decrease in the fluorescent intensity from 2630 to
3-trifluoromethyl-iodobenzene and PhB(OH)2 using Pd complex 9a.
1100 a.u.. The exponential decay of the fluorescence intensity
corresponds to the shape of the GC derived conversion–time
curve of this Suzuki coupling reaction. This shows that
monitoring the fluorescence signal allows one to directly
follow the course of the coupling reaction. Since it is unlikely
that the organic coupling product formed is responsible for the
change in fluorescence intensity and since the distribution of
Pd complexes should be constant throughout the catalytic
transformation, other species must be responsible for the
decay of the fluorescence signal.
It is known that heavy atoms can quench the fluorescence
(heavy atom effect).16 A hint that iodide is responsible for this
in the cross-coupling experiments comes from the analogous
reaction of 11 with PhB(OH)2 from which qualitatively the
same curve was obtained. However, the slow exponential drop
in the fluorescence intensity is much less pronounced after the
addition of aryl bromide. This points to the formation of
iodide as being responsible for the strong decay of the
fluorescence signal during the coupling of 10. To confirm this,
Scheme 2 Suzuki coupling reactions of 10 and 11.
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Based on the NMR spectra the identity of 9c was not resolved,
but 9b and 9c are quite similar.
In conclusion, we have synthesized two imidazolinium salts
(7a, b) which possess functional groups (–CH2Cl) allowing the
facile introduction of various nucleophiles into N-heterocyclic
carbenes. A dansyl fluorophore was attached via a piperazine
linker and the corresponding (NHC)Pd(allyl)Cl complex was
prepared. The fluorescence signal of the dansyl group experi-
ences characteristic changes on forming the catalytically active
species from the precatalyst and during the actual cross-
coupling reaction. The presence of a fluorescent tag firmly
attached to Pd furthermore allows the detection of minute
amounts of (NHC)Pd species down to a concentration of ca.
2 Â 10À7 mol LÀ1. Future studies are aimed towards using
the variations in the fluorescent tag signal to learn more about
the nature and the concentration of the (NHC)Pd species
in the catalytic cycle. The tagging of various metal complexes
with the fluorophore NHC ligand should also enable the facile
detection of such complexes in trace amounts.
Fig. 2 Residual fluorescence of product solutions: after silica gel plug
filtration (left vial); after ethyl acetate chromatography (central vial);
after cyclohexane chromatography (right vial).
stoichiometric amounts of KI were added to the reaction
mixture. With solid KI, the fluorescence slowly decays due
to the slow dissolution of the salt; upon addition of a KI
solution an instant drop in the fluorescence intensity was
observed.
Another aspect of NHC fluorophore tagging is that it allows
the visual detection of palladium impurities in the cross-
coupling products. An example of the qualitative estimation
of palladium content using the precatalyst 9b in isopropanol is
shown below (Fig. 2). Initially, the reaction mixture was
passed over a short silica plug to remove salts, and all of the
(NHC)Pd species remain in the product solution. Next, chromato-
graphy with ethyl acetate led to a significant reduction in the
(NHC)Pd level, but only after cyclohexane chromato-
graphy were all of the (NHC)Pd species removed, as evidenced
by the absence of noticeable fluorescence. It is worth noting
that the smallest visually detectable concentration of 9b was
determined to be ca. 2 Â 10À7 mol LÀ1, which corresponds to
64 ng of Pd in 3 mL of solvent (volume of cuvette).
This work was supported by the DFG.
Notes and references
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It is important to confirm that the observed fluorescence
originates from the fluorophore tagged NHC ligand attached
to the metal and not from dissociated ligand. This was shown
by probing the reaction mixtures of the Suzuki coupling
reactions by TLC. Among the fluorescent products a primary
dominant fluorescent spot besides other more polar ones of
much lower intensity was observed. Based on fluorescence
intensity, the predominant portion of the fluorescence resides
in a single species denoted as 9c, which (according to TLC) is
not the initial Pd complex 9b. To learn more about the identity
of this fluorescent species, we did the following experiment: for
the coupling reaction of phenylboronic acid with 2,6-dimethyl-
chlorobenzene, 20 mol% of catalyst 9b and 1.4 equiv. of base
(KOtBu) were used. Again, the main fluorescent product is 9c,
which was purified by column chromatography and isolated.
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772 | Chem. Commun., 2009, 770–772