Orthopalladation of GFP-Like Fluorophores Through C–H Bond Activation: Scope and Photophysical Properties

Article abstract of DOI:10.1002/ejoc.201800966

The luminescence of oxazolones R₁-C₆H₄CH=CC(O)O-CN(R²) (1a–1j) and imidazolones R₁-C₆H₄CH=CC(O)NR₃CN(R²) (1k–1q) has been examined. The new GFP-like imidazo

Full text of DOI:10.1002/ejoc.201800966

A Journal of
Accepted Article
Title: Orthopalladation of GFP-like fluorophores through C-H bond
activation: scope and photophysical properties
Authors: Sandra Collado, Alejandro Pueyo, Christine Baudequin,
Laurent Bischoff, Ana Isabel Jimenez, Carlos Cativiela,
Christophe Hoarau, and Esteban Pablo Urriolabeitia
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800966
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10.1002/ejoc.201800966
European Journal of Organic Chemistry
FULL PAPER
Orthopalladation of GFP-like fluorophores through C-H bond
activation: scope and photophysical properties
Sandra Collado,[a] Alejandro Pueyo,[b] Christine Baudequin,[a] Laurent Bischoff,[a] Ana Isabel Jiménez,[b]
Carlos Cativiela,*[b] Christophe Hoarau,*[a] and Esteban P. Urriolabeitia*[b]
Dedication ((optional))
Abstract: The luminescence of oxazolones R1-C6H4CH=CC(O)O-
CN(R2) (1a-1j) and imidazolones R1-C6H4CH=CC(O)NR3CN(R2) (1k-
1q) has been examined. The new GFP-like imidazolones (GFP =
Green Fluorescent Protein) (1k-1q) have been prepared by reaction
diagnosis of many diseases, detected using fluorescent probes or
biological markers.[1-7] Despite the progress achieved in this area,
there are not large libraries of synthetic compounds that could be
used on the mentioned purposes, and continuous research is
of the oxazolones with amines H2NR3 and bis(trimethylsilyl)acetamide. needed. Sometimes, the nature provides bright solutions, and
The most intense fluorescence was found in push-pull systems
containing simultaneously strong electrondonating and electron-
withdrawing substituents. The incorporation of the Pd atom into the
molecular skeleton of oxazolones and imidazolones changes notably
their luminescence. The reaction of oxazolones (1a-1j) and
imidazolones (1k-1q) with Pd(OAc)2 (1:1 molar ratio) in carboxylic
acids gives the dinuclear [Pd(R1-C6H3CH=CC(O)OCN(R2))(-
carboxylate)]2 (2a-2j) and [Pd(R1-C6H3CH=CC(O)NR3CN(R2))(-
carboxylate)]2 (2k-2q) through regioselective C-H bond activation of
the ortho position of the respective 4-arylidene rings. Complexes 2a-
2q react with LiCl in MeOH to give the chloride-bridge derivatives
many natural compounds display luminescent properties. Among
them, GFP (Green Fluorescent Protein), and their mutations or
derivatives, offer very interesting possibilities.[8-21]
GFP is a protein that shows an intense and bright green emission
when it is irradiated with UV light. It shows widespread use in
scientific research, because it allows to see what happens into the
inner workings of cells, how the proteins are being made, and
even any movement of the proteins.[8-21] The way it works is
extremely simple, because it is just necessary to attach the GFP
to the target object (i.e., a virus): as the virus replicates and
disseminates, it is possible to see it just turning on the UV light
and watching the green glow. Due to all these facts it has been
named the microscope of the twenty-first century. The utility of the
GFP and its derivatives has been recognized with the chemistry
Nobel prize in 2008, that was awarded to Profs. Shimomura,
Chalfie and Tsien.[16-18]
However, the true responsible of the photophysical activity of the
GFP, the chromophore, is a small heterocyclic unit present in the
inner part of the protein, the 4-(p-hydroxybenzylidene)-5-(4H)-
imidazolone (Figure 1a), which is formed from residues of the
amino acids serine (Ser65), tyrosine (Tyr66) and glycine (Gly67),
although other combinations are also possible depending of the
type of GFP.[22,23]
[Pd(R1-C6H3CH=CC(O)OCN(R2))(-Cl)]2
(3a-3j)
and
[Pd(R1-
C6H3CH=CC(O)NR3CN(R2))(-Cl)]2 (3k-3q), which further react with
Tl(acac) (acac = acetylacetonate) to give the mononuclear species
[Pd(R1-C6H3CH=CC(O)OCN(R2)(acac)]
(4a-4j)
and
[Pd(R1-
C6H3CH=CC(O)NR3CN(R2)(acac)] (4k-4q). Complexes 4o and 4q,
having an orthopalladated push-pull imidazolone, are strongly
fluorescent, showing a notable increase of the quantum yield with
respect to the free ligands 1o and 1q up of one order of magnitude.
Introduction
The synthesis of compounds with photophysical properties of
interest (fluorescence, phosphorescence) is a research area
undergoing an increasing development due to their potential
applications and impact in our daily life. We find outstanding
applications of these compounds in optical devices and in the
[a]
[b]
S. Collado, Dr. C. Baudequin, Prof. Dr. L. Bischoff, Prof. Dr. C.
Hoarau
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000
Rouen, France
1 rue Tesnière, 76821 Mont Saint Aignan, France
E-mail: christophe.hoarau@insa-rouen.fr
A. Pueyo, Dr. A. I. Jiménez, Prof. Dr. C. Cativiela, Dr. E. P.
Urriolabeitia
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH)
CSIC-Universidad de Zaragoza
Figure 1. General structure of (a) the chromophore of GFP (Imidazolone) and
(b) its synthetic precursor (oxazolone)
This fact helps the synthetic chemists in the task of the
development of more efficient fluorophores, because it is
substantially easier the tuning of the heterocyclic core responsible
of the fluorescence (the imidazolone) than that of the whole
protein (GFP). In this respect, we have recently developed the
synthesis of a variety of 4-aryliden-2-alkenyl-imidazolones and 4-
aryliden-2-aryl-imidazolones through C-H bond alkenylation
and/or arylation of corresponding 2-H derivatives,[24,25] and also
Pedro Cerbuna 12, 50009 Zaragoza, Spain
webpage: www.isqch.unizar-csic.es/ISQCHportal/grupos.do?id=38
E-mail: esteban@unizar.es, cativiela@unizar.es
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800966
European Journal of Organic Chemistry
FULL PAPER
through direct reaction of the precursor oxazolones with amines
followed by cyclizative dehydration using bis(trimethylsilyl)-
acetamide.[26] Therefore, the synthetic access to a large library of
different imidazolones and oxazolones[27-44] is available. On the
other hand, imidazolones and their parent oxazolones show
notable photophysical properties, which are of high interest. For
instance, oxazolones are able to perform two-photons absorption
(TPA),[45-47] they interact with the light through Z-E isomerization
processes,[48-51] and are able to give [2+2]-photocycloaddition
reactions.[52-54] In addition, detailed studies have been devoted to
the improvement of the quantum yield of the luminescence of
imidazolones through rigidification, aiming to suppress as much
as possible the thermal deactivation pathways associated to
different internal rotations (hula-twist).[55-60] In this respect, the
introduction of a BF2 group in the molecular skeleton of the
imidazolones through N-H[61] or C-H[62-66] bond activation (Figure
2, left part) has shown to give rigid highly fluorescent compounds,
because radiationless decay has been minimized efficiently. Thus,
rigidification connecting both rings (arylidene and heterocycle)
seems to be an adequate tool to improve the photophysical
properties of these molecules.
Surprisingly, the use of transition metals for rigidification of
imidazolones has never been attempted and, in the case of
oxazolones, only some few cases using Pd as metal have been
reported.[53,79-82] Moreover, the photophysical properties of the
oxazolones once cyclopalladated remains totally unexplored. Due
to all of the abovementioned reasons, we have carried out a
systematic study of the orthopalladation through C-H bond
activation of different 2-aryl-4-aryliden-5(4H)-imidazolones and 4-
aryliden-5(4H)-oxazolones, and their luminescence studies. In
this contribution we present the obtained results.
Results and Discussion
1.- Synthesis of the precursors. We have selected a large
variety of oxazolones and imidazolones to screen different
possibilities (Chart 1).
Figure 2.General structure of (a) the chromophore of GFP (Imidazolone) and
(b) its synthetic precursor (oxazolone)
Chart1.Oxazolones1a-1jand imidazolones 1k-1q used in this work.
Following in this line, B is not the only atom able to be
incorporated to the oxazolone or imidazolone scaffolds. In
particular, the incorporation of transition metals forming C,N-
cyclometallated derivatives in highly advantageous due to several
reasons (Figure 2, right part).[67-75] This type of ligands provides
exceptional thermodynamic stability to the resulting complexes
and modifies the molecular orbital distribution, deactivating non-
radiative transitions centered in the metal orbitals. In addition, this
allows the harvesting of triplet states, this being highly desirable
when dealing with OLEDs applications.[76] At the same time, it
provides high rigidity to the metal-ligand environment, this also
quenching other non-radiative energy dissipation pathways, as
expected from our previous discussion.[77] The resulting molecule
can additionally be tuned through change of the ancillary ligands.
For all those reasons, cyclometallated derivatives are exceptional
candidates in the development of efficient luminescent systems.
Among different methods to make cyclometallated derivatives,
the C-H bond activation is a well-known synthetic tool.[78]
We have selected examples of oxazolones (1a-1j) containing one
or two substituents of electron-withdrawing or electron-donating
nature, located at different positions of the 4-arylidene ring to
cover all possibilities to tune the electron density and the steric
hindrance. We have also selected examples having an aryl group
(1a-1g) or a methyl group (1h-1j) at 2-position, aiming to change
the degree of delocalization of the electron density and the
bulkiness of the whole ligand. In the case of imidazolones we
have followed the same criteria in a reduced number of examples
(1k-1q), because we have focused in the push-pull systems (1o-
1q), those having a strong electron-releasing group at the 4-
arylidene ring and a strong electron-withdrawing group at the 2-
position of the imidazolone. The choice of the n-propyl group as
substituent for the N atom is due to their chemical inertness and
its role as 1H NMR probe (see below). The synthesis of the
oxazolones 1a-1j has been performed following basically the
Erlenmeyer method,[27-44] heating the hippuric or the aceturic acid
with NaOAc and with the corresponding aldehyde, using acetic
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10.1002/ejoc.201800966
European Journal of Organic Chemistry
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anhydride as reaction solvent. On the other hand, the synthesis
of the imidazolones 1k-1q has also been carried out by adaptation
of known procedures previously published by some of us.[24-26]
The reaction takes place in two steps from oxazolone precursors.
In the first step the oxazolone reacts with the amine opening the
heterocycle and giving the bis-amide derivative, which in the
second step undergoes dehydration by reaction with
bis(trimethylsilyl)-acetamide and ring closure (Figure 3).
successful for the three oxazolones, and the corresponding
dinuclear derivatives 2h-2j were obtained in moderated to
quantitative yields (see ESI for details). Probably, the reason of
the higher reactivity of 2-methyl-oxazolones 1h-1j compared with
the 2-phenyl counterparts is due to the higher electron density in
the aromatic ring in the former substrates. The characterization of
2h-2j shows that the palladation has taken place with full
regioselectivity at the ortho C-H bond of the 4-arylidene ring (2h,
2i) or at the 3-position of the 2-thiophene ring (2j), acting the N
atom of the oxazolone ring as directing group. In the case of 2i
two isomers are possible in principle, but only the less hindered
one is obtained, because Pd incorporation is produced at the 6-
position of the starting oxazolone 1i. The dinuclear nature of these
derivatives is inferred from the observation of a strong peak in the
mass spectrum of 2h (positive ESI) at 738.8475 a.m.u., which
agrees with the presence of the dimer [Pd(C^N)(O2CCH3)]2 which
has captured a Na+ cation. Taking into account the dinuclear
nature of 2h-2j, the observation of a single peak for the methyl
group of the bridging acetate strongly suggests that the relative
arrangement of the two cyclopalladated units [Pd(C^N)] is anti,
minimizing the steric interactions between the two palladium
environments. All these facts are reflected in the proposed
structures shown in Figure 4.
Figure 3. Synthetic pathways for the preparation of oxazolones 1a-1j and
imidazolones 1k-1q
2.- Orthopalladation of oxazolones and imidazolones. The
orthopalladation of (Z)-2-aryl-4-aryliden-5(4H)-oxazolones has
been reported by us some years ago, and these are up to date
the only reports about palladation through C-H bond activation on
oxazolones.[53,79-81] Despite its apparent simplicity, the reaction
shows some peculiarities. It takes place only in carboxylic acids
as solvents, which participate actively during the reaction
mechanism. In addition, the type of oxazolones to be activated
strongly depends of the pKa of the acid, in such a way that in weak
acids (for instance acetic acid) only very electron-rich substrates
undergo C-H bond activation, while in strong acids (trifluoroacetic
acid) even highly deactivated electron-deficient rings undergo C-
H bond activation.[53,80] Under these conditions, it is observed that
the palladation 2-aryl-4-aryliden-5(4H)-oxazolones is totally
regioselective towards the activation of the ortho C-H bond of the
4-arylidene ring, giving a six-membered ring palladacycle. Aiming
to check if these observations are general, we have attempted the
palladation of 2-methyl-4-aryliden-5(4H)-oxazolones (1h-1j) and
2-aryl-4-aryliden-5(4H)-imidazolones (1k-1q), shown in Figure 4.
We initially tried the orthopalladation of 2-methyl oxazolones 1h-
1j under the same reaction conditions as those reported for 2-
phenyl derivatives 1a-1g (CF3COOH, 25 to 75 °C). The reaction
failed in all attempted cases, because extensive decomposition
was observed even at room temperature, and no definite
compounds could be isolated at the end of the reaction.
Supposing that this could be due to the strength of the acid, we
carried out the reactions in the weaker acetic acid as solvent at
different temperatures. The reaction at the reflux temperature was
Figure 4. Orthopalladation of diverse oxazolones and imidazolones
On the other hand, the orthopalladation of 2-phenyl-4-aryliden-
5(4H)-imidazolones 1k-1q (Chart 1) takes place under
experimental conditions similar to those reported for the parent
oxazolones.[80] That is, the mixture of the imidazolone and
Pd(OAc)2 (1:1 molar ratio) has to be heated at 75 °C in
trifluoroacetic acid as solvent for 4 h to promote the reaction.
Under these conditions, the dimers 2k-2q are formed in moderate
to excellent yields (57-99%), as it is shown in Figure 4. Indeed,
the characterization of 2k-2q shows that the reaction occurs with
strictly the same regioselectivity than that observed previously in
oxazolones[80] or in complexes 2f-2j, and that only the 4-arylidene
ring has been palladated, despite the presence of other potential
directing groups, such as the pyridine fragment in 1q. In addition,
2k-2q are dinuclear as well, with a relative anti arrangement of
the cyclopalladated moieties, as it can be deduced from the
diastereotopic character of the NCH2 protons in the respective 1H
NMR spectra, and from the observation of a single peak in the 19
F
NMR spectra (meaning chemically equivalent bridging CF3
groups, see ESI). From the observed reactivity of oxazolones 1f-
1j and imidazolones 1k-1q, we can conclude that the selectivity
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10.1002/ejoc.201800966
European Journal of Organic Chemistry
FULL PAPER
observed in the cyclopalladation of 4-aryliden-5(4H)-oxazolones
and 4-aryliden-5(4H)-imidazolones is the same, and that the
process is general.
imidazolones (1o-1q), they have absorption wavelengths (abs) in
the purple to blue region. As expected, only push-pull systems
offering an important charge transfer permit to obtain interesting
photophysical properties both for oxazolones and imidazolones.
The first possibility consists to introduce the dimethylamino
(electron-donating group) in para-position on the arylidene ring
and the cyano group (electron-withdrawing part) on the C2
position on the oxazolone (1g) or the imidazolone core (1o or 1q).
A similar system but in the opposite site have been elaborated,
the 4-(dimethylaminp) phenyl was introduced on the C2 site and
the oxazolone or the imidazolone can be considered as the
electron-withdrawing part (1f and 1p).
We have already observed that the replacement of the
dimethylamino by a methoxy group, less electron-donor than
dialkylamino, resulted in decreased photophysical properties,
notably the quantum yield. As previously reported by Rodrigues
et al,[46] the better quantum yield concerning the oxazolone series
was obtained when the dimethylaniline is introduced at the C2
position. The comparison of compounds 1g, 1o and 1q that have
the 4-cyanophenyl and 4-(dimethylamino)phenyl groups as
external substituents allows to evaluate the influence of the core.
The incorporation of an imidazolone core instead of an oxazolone
led to a blueshift of the absorption maxima (abs) and emission
(em), a decrease of the molar extinction coefficient () and similar
quantum yield. When the oxazolones were orthopalladated,
similar values for the absorption and the emission wavelengths (
10 nm) were observed, however we noticed an important
decrease for both the quantum yield (1f vs 4f, 0.591 vs 0.018) and
the molar extinction coefficient  (55223 vs 19195 and 53534 vs
8024).The comparison between the push-pull imidazolones
(Table 1, 1o and 1q) and their orthopalladated analogs (Table 2,
4o and 4q) reveals a decrease of the molar extinction coefficient
(), but an important redshift for both absorption and emission
maxima as well as an important increase of the quantum yield (4.2
and 1% vs 0.3 and 0.2 %) are observed. Concerning compound
1p encompassing EWG and EDG at inverted positions compared
to classical fluorescent molecules of this family, i.e. “inverted
push-pull”, incorporating the 4-dimethylaminophenyl on the C2
ring and in this case, the imidazolone can be considered as the
electron-withdrawing part, the fluorescence is turned-off upon
ortho-palladation.
3.- Synthesis of the acetylacetonate derivatives. Even if the
dinuclear complexes 2a-2q could be potential candidates for the
study of their luminescent properties, it is clear that they are not
the best examples, due to several reasons. The main one is the
flexibility exhibited by these dimers in solution and, hence, the
concomitant loss of energy through non-radiative pathways.
Therefore, it is proposed the change of the bridging acetate
dimers in 2a-2q by other ligands aiming to obtain more rigid
systems. The acetylacetonate (acac) is the ideal candidate to
achieve this task, because it behaves as a strong chelate to the
Pd, providing additional stabilization to the resulting complexes,
and confers them good solubility properties. Moreover, acac-
complexes are often found in complexes with excellent optical
capabilities.[83-85] The synthesis of the corresponding acac-
derivatives was accomplished following standard methods, as
outlined in Figure 5. Briefly, the dimers with bridging carboxylate
ligands 2a-2q were reacted with excess of LiCl (1:4 molar ratio,
or higher) in MeOH, giving the corresponding planar dimers with
bridging chloride ligands 3a-3q, through a metathesis of anionic
ligands. Complexes 3a-3q are very insoluble in MeOH, and can
be isolated by simple filtration. Further reactivity of 3a-3q with
either Tlacac (1:2 molar ratio) in CH2Cl2, or with potassium
acetylacetonate (1:2 molar ratio) in MeOH, gives the acac-
derivatives 4a-4q as yellow or red solids in moderate to very good
yields. They are adequately soluble in the usual organic solvents
and are stable for months when exposed to the air and the
moisture. The characterization of 4a-4q has been carried out
following usual methods (HRMS, NMR) and is straightforward.
Table 1. Photophysical data for 4-arylidene oxazolones and imidazolones in
dichloromethane at 25 °C.
[b]
Compound[a]
abs,max
[nm]

em,max
[nm]
F
Stokes
shift [cm-1]
[M-1cm-1]
0.59[c]
0.008[d]
0.003[c]
0.054[d]
0.002[c]
3630
1979
3348
3895
4028
Figure 5. Synthesis pathway to the acetylacetonate complexes 4a-4q
1f
436
496
473
422
478
55223
53534
46742
15572
43942
518
550
562
505
592
1g
1o
1p
1q
4.- Photophysical properties of orthopalladated oxazolone
and imidazolone complexes. The optical properties of the 4-
arylidene oxazolones and imidazolones and their orthopalladated
analogs were recorded in CH2Cl2 at 25 °C by UV/Vis and
photoluminescence (PL) spectroscopy. The data of the
fluorescent compounds are summarized in Tables 1 and 2.
Unfortunately, the 4-arylidene oxazolones (1a-1e and 1h-1j) and
their corresponding orthopalladated compounds are not
fluorescent. Concerning the oxazolones (1f-1g) and the
[a] All spectra were recorded at 25 °C. [b] Quantum yield ( 10%) of
fluorescence determined by using : [c] Coumarine-153(F = 0.38 in EtOH,
exc = 430 or 450 nm); or [d] Rhodamine 6G (F = 0.94 in EtOH, exc = 488

nm) as standard.
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10.1002/ejoc.201800966
European Journal of Organic Chemistry
FULL PAPER
structures with carboxylate bridges. The metathesis of the
carboxylate ligands by chloride ligands afford dimeric planar
complexes, which in turn react with acetylacetonate affording rigid
neutral mononuclear complexes containing two chelating ligands,
one C,N-orthopalladated oxazolone or imidazolone and one O,O-
acac. The photophysical properties of these rigid mononuclear
complexes have been examined and confirm the importance of
rigidification of imidazolones. In addition, the high
regioselectivities of palladation reactions makes this reaction
interesting for future functionalizations. Development of a catalytic
version of the reaction for further rigidification upon palladium-
mediated cyclisations is currently underway in our laboratory.
1
0,8
0,6
0,4
0,2
0
1f
1g
1o
1p
1q
300
350
400
450
500
550
600
650
700
750
800
Wavelenght (nm)
Figure 6. Normalized absorption (dashed lines) and emission (solid lines)
spectra of oxazolones 2f-2g, and imidazolones 2o-2q in CH2Cl2 at 25 °C.
Experimental Section
1. General Remarks. Solvents were used as received from commercial
sources. They were not distilled nor subjected to additional purification.
Thin layer chromatographies (TLCs) were done on silica gel plates
DCFertigfolien Polygram® SIL G/UV254. Column liquid chromatography
was performed on aluminum oxide 90 neutral (50−200 μm) or silica gel
(70−230 μm) using the solvents specified on each case. Elemental
analyses (CHNS) were carried out on a Perkin Elmer 2400 Series II
microanalyser. 1H and 13C{1H} NMR spectra were recorded in CDCl3 or
CD2Cl2 solutions at 25 oC on Bruker AV300 or AV400 spectrometers ( in
ppm, J in Hz) at a 1H NMR operating frequency of 300.13 or 400.13 MHz,
Table 2. Photophysical data for the orthopalladated analogs in
dichloromethane at 25 °C.
abs,max
[nm]

em,max
[nm]
Stokes
shift [cm-1]
[b]
Compound[a]
F
[M-1cm-1]
4f
445
504
529
471
534
19195
8084
5405
8115
29749
524
555
597
-
0.018[c]
0.008[d]
0.042[d]
-
3387
1823
2153
-
4g
4o
4p
4q
1
respectively. H and 13C NMR spectra were referenced using the solvent
signal as an internal standard. The ESI (ESI+) mass spectra were recorded
using an Esquire 3000 ion-trap mass spectrometer (Bruker Daltonic
GmbH) equipped with a standard ESI/APCI source. HRMS and ESI (ESI+)
mass spectra were recorded using an MicroToF Q, API-Q-ToF ESI with a
mass range from 20 to 3000 m/z and mass resolution 15000 (FWHM).
610
0.010[e]
2333
[a] All spectra were recorded at 25 °C. [b] Quantum yield ( 10%) of
fluorescence determined by using : [c] Coumarine-153 (F = 0.38 in EtOH),
UV/Vis spectra were recorded with
a
Varian Can 50 scan
spectrophotometer by using a rectangular quartz cell (Varian, standard cell,
Open Top, light path 1010 mm, chamber volume: 3.5 mL). Fluorescence
spectroscopic studies (emission/excitation spectra) were performed with a

exc = 430 or 450 nm; or [d] Rhodamine 6G (F = 0.94 in EtOH),exc = 488
nm; or [e] Cresyl violet (F = 0.56in EtOH),exc = 550 nm as standard.
Varian Cary Eclipse spectrophotometer with
a semi-micro quartz
1
0,8
0,6
0,4
0,2
0
fluorescence cell (Hellma, 104F-QS, light path, 104 mm, chamber volume
1400 L, excitation filter: auto and emission filter: open, excitation and
emission slit: 5 nm). Fluorescence quantum yields were measured at 25
ºC by a relative method using Cresyl Violet (F = 56% in EtOH),
Coumarine 153 (F = 38% in EtOH), or Rhodamine 6G (F = 94% in EtOH),
as a standard. The following equation was used to determine the relative
fluorescence quantum yield:
4f
4g
4o
4q
2
퐴푠
퐴푥
퐹
푛푥
푥
( )
푥
퐹
=
×
× ( ) 퐹(푠)
퐹
푠
푛푠
300
350
400
450
500
550
600
650
700
750
800
Where A is the absorbance (in the range of 0.01 – 0.1 A. U.), F is the area
under the emission curve, n is the refractive index of the solvents (at 25
ºC) used in measurements, and the subscripts s and x represent standard
and unknown, respectively. The following refractive index values were
used: 1.361 for EtOH and 1.421 for CH2Cl2). The oxazolones containing
the phenyl ring at 2-position (1a-1e),[27-37] those containing the methyl
group at 2-position (1h-1j),[38-44] and the orthopalladated complexes 2a-
2e,[80] have been prepared by reported procedures. Compound 4a has
been reported by us elsewhere, but the method described here is slightly
different.[82]
Wavelenght (nm)
Figure 7. Normalized absorption (dashed lines) and emission (solid lines)
spectra of orthopalladated oxazolones 4f-4g and imidazolones 4o-4q in CH2Cl2
at 25 °C.
Conclusions
The orthopalladation of
a wide array of 4-aryliden-5(4H)-
oxazolones and -imidazolones with different substituents at the 4-
arylidene ring and at the 2-position of the heterocycle takes place
through C-H bond activation with full regioselectivity, because
only the ortho position of the 4-arylidene ring is activated. The
resulting orthopalladated complexes have dimeric open-book
2. General synthesis of the imidazolones 1k-1q. The synthesis of the
imidazolones 1k-1q has been carried out following previously reported
methods with some minor modifications.[26] Imidazolone 1q was prepared
via C-H arylation by reported procedures.[25] The yellow or orange starting
oxazolone (1.36 mmol) was suspended in pyridine (4 mL) and treated with
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10.1002/ejoc.201800966
European Journal of Organic Chemistry
FULL PAPER
n-propylamine (11.2 L, 1.36 mmol) with strong stirring for 20 minutes at
25 C. A white suspension is formed at this point. After this time,
bis(trimethylsilyl)acetamide (66.7 L, 2.73 mmol) was added, and the
resulting mixture was stirred while heated at 110 ºC for 15 h. After the
reaction time, the cool suspension was evaporated to dryness. The
remaining residue was redissolved in the minimal amount of CH2Cl2 (1-2
mL) and treated with n-hexane (10 mL). A cream-colored solid precipitated,
which was filtered, dried by suction, and characterized as the imidazolone
1k-1q. The characterization of 1k is shown here, that of imidazolones 1l-
1q is given as Supporting Information.
Synthesis of 2k. Method B. Pd(OAc)2 (691 mg, 3.1 mmol) was reacted
with 1k (1000 mg, 3.1 mmol) in CF3COOH (10 mL) to give 2k as a red
solid. Obtained: 1470 mg, 98 % yield. 1H NMR (300.13 MHz, CDCl3, r.t.):
3
 = 8.14 (s, 1H, =CH), 7.50 (t, 1H, Hp, C6H5, JHH = 7.5), 7.37 (t, 2H, Hm,
3
3
C6H5, JHH = 7.5), 7.31 (dd, 1H, C6H3, JHH = 8, 4JHH = 2), 7.10 (d, broad,
3
3
1H, C6H3, JHH = 7.5), 7.03 (dd, 1H, C6H3, JHH = 8), 6.95 (d, very broad,
2H, Ho, C6H5), 3.69 (ddd, 1H, NCH2, JHH = 15, JHH = 9, JHH = 6), 3.21
(ddd, 1H, NCH2, JHH = 15, JHH = 9, JHH = 6), 1.34-1.13 (m, 2H, CH2),
0.64 (t, 3H, Me, 3JHH = 7.5 Hz). 13C{1H} NMR (75.47 MHz, CDCl3, r.t.):  =
2
3
3
2
3
3
2
166.5 (C=N), 164.2 (CO), 164.1 (q, CF3CO2, JCF = 38.5), 137.8 (=C),
134.9 (C-Cl, C6H3), 133.1 (CH, C6H3), 132.5 (Cp, C6H5), 130.4 (C, C6H3),
129.5 (CH, C6H3), 129.2 (=CH), 128.7 (Cm, C6H5), 128.4 (Co, C6H5), 127.2
(C, C6H3), 126.7 (CH, C6H3), 126.2 (Ci, C6H5), 114.4 (q, CF3, 1JCF = 288),
43.5 (NCH2), 21.5 (CH2), 10.8 (CH3).19F NMR (282.40 MHz, CDCl3, r.t.):
= -74.35 (s). HRMS (ESI-TOF) m/z: [M+CF3CO2]- calcd for
C44H32Cl2F9N4O8Pd2 1194.9555, obtained 1194.9554.
1
Synthesis of 1k. Beige solid. Yield: 82%. H NMR (300.13 MHz, CDCl3,
r.t.):  = 8.96 (dd, 1H, C6H4Cl,3JHH = 7.5), 7.76 (dm, 2H, Ho, C6H5, 3JHH
7.8), 7.71 (s, 1H, =CH), 7.53-7.50 (m, broad, 3H, Hp + Hm (C6H5)), 7.38 (dd,
1H, C6H4Cl, JHH = 7.4), 7.27-7.23 (m, 2H, C6H4Cl), 3.73 (m, 2H, NCH2),
1.57 (tq, 2H, CH2, JHH = 7.5), 0.82 (t, 3H, Me, JHH = 7.4). 13C{1H} NMR
(75.47 MHz, CDCl3, r.t.):  = 171.5 (C=O), 164.0 (CN), 140.0 (C=), 136.4
(C-Cl, C6H4Cl), 133.8 (CH, C6H4Cl), 132.2 (C, C6H4Cl), 131.6 (Cp, C6H5),
131.0 (CH, C6H4Cl), 129.7 (CH, C6H4Cl), 129.6 (Ci, C6H5), 128.9 (Cm,
C6H5), 128.3 (Co, C6H5), 127.0 (CH, C6H4Cl), 123.2 (=CH), 43.4 (NCH2),
22.4 (CH2), 11.1 (CH3). HRMS (ESI-TOF): m/z calcd for C19H18ClN2O:
325.1108 [M+H]+; found 325.1114.
=
3
3
3
Synthesis of 2p. Method C. Pd(OAc)2 (172 mg, 0.89 mmol) was reacted
with 1p (300 mg, 0.89 mmol) in CF3COOH (6 mL) to give 2p as a yellow
solid. Obtained: 312 mg, 75 % yield. This compound was too insoluble in
usual deuterated solvents to perform a proper characterization by NMR
methods. Only IR and HRMS data could be obtained. IR (ν, cm-1): 1783 vs
(C=O).HRMS (ESI-TOF) m/z: [M+CF3CO2]- calcd for C48H42F9N6O8Pd2
1213.1178, obtained 1213.1191.
3. General synthesis of the orthopalladated derivatives 2h-2q through
C-H activation. Method A (compounds 2h-2j): To a suspension of
Pd(OAc)2 (100 mg, 0.44 mmol) in CH3CO2H (8 mL), the stoichiometric
amount of the oxazolones 1h-1j (0.44 mmol, 1:1 molar ratio) was added.
The resulting suspension was heated to 120 ºC for 1 h. During this time,
the suspension changes notably its aspect, from a brown color to a yellow
or yellowish-orange color. After the reaction time, the resulting suspension
was cooled to room temperature, and then treated with water (15 mL). The
amount of precipitated solid increases notably. This solid was filtered,
washed with additional water until the typical smell of acetic acid was not
detected (2×15 mL), dried by suction, and characterized as complexes 2h-
2j. Method B (compounds 2g, 2k-2q): To a suspension of Pd(OAc)2 (1
equiv.) in CF3CO2H, the stoichiometric amount of the oxazolone 1g or the
imidazolone 1k-1q (1:1 molar ratio) was added. The resulting suspension
was heated to 75 ºC for 4 h. During this time, the suspension changes
notably its aspect, from a brown color to a yellow or red color. After the
reaction time, the resulting suspension was cooled to room temperature,
and then treated with water (25 mL). The amount of precipitated solid
increased. This solid was filtered, washed with additional water until the
strong smell of CF3CO2H was not detected (2×25 mL), dried in vacuo, and
characterized as complexes 2g, or 2k-2q. Method C (Compounds 2f, 2p):
To a suspension of Pd(OAc)2 (1 equiv.) in CF3CO2H, the stoichiometric
amount of the imidazolone 1f or 1p (1:1 molar ratio) was added. The
resulting suspension was stirred at room temperature for 2 h. During this
time, the suspension changes notably its aspect, from a brown color to a
yellow or red color. After the reaction time, the resulting suspension was
treated with water (25 mL). The amount of precipitated solid increased.
This solid was filtered, washed with additional water until the strong smell
of CF3CO2H was not detected (2×25 mL), dried in vacuo, and
characterized as complexes 2f or 2p. The characterization of complexes
2j, 2k and 2p is shown here, that of the remaining orthopalladated
derivatives is given as Supporting Information.
4. General synthesis of the orthopalladated chloride-bridge
derivatives 3a-3q. The synthesis of 3a from 2a is detailed here. The
synthesis of 3b-3q has been carried using the same experimental method
from the respective starting materials 2b-2q, which are detailed in the
Supporting Information. To a suspension of 2a (475.2 mg, 0.51 mmol) in
methanol (20 mL) at room temperature, LiCl (86 mg, 2.03 mmol) was
added. The resulting suspension was stirred at room temperature for 24 h,
then filtered through a glass sintered funnel. The precipitated solid was
kept, and the solution was discarded. This solid was washed with cold
methanol (5 mL) and Et2O (20 mL), dried by suction, and characterized as
3a. Obtained: 266.6 mg (67.2% yield)
Synthesis of 3a. Deep yellow solid. Obtained: 266.6 mg (67.2 % yield).
IR (ν, cm-1): 1785 vs (C=O), 262 w (Pd2(-Cl)2). Elemental analysis found:
C, 49.15; H, 2.57; N, 3.82. Calculated for C32H20Cl2N2O4Pd2: C, 49.26; H,
2.58; N, 3.59.
5. General synthesis of the orthopalladated acetylacetonate
derivatives 4a-4q. The synthesis of 4a has been reported by us
elsewhere,[82] but using
a slightly different starting material. The
characterization of complex 4a here prepared is provided for comparative
purposes.[82] The synthesis of 4b is described here in detail. Method A. To
a suspension of 3b (463 mg, 0.545 mmol) in CH2Cl2 (15 mL) at room
temperature, Tl(acac) (331 mg, 1.09 mmol) was added. The resulting
suspension was stirred at room temperature for 4 h, then filtered through
celite to remove the solid TlCl formed during the reaction. The clear
solution was evaporated to dryness, and the solid residue was treated with
cold n-hexane (25 mL). Further stirring produced the formation of a solid,
which was filtered, washed with additional cold n-hexane (10 mL), dried by
suction and characterized as 4b. Other acetylacetonates obtained using
this method are given as Supporting Information.
Synthesis of 2j. Method A. Yellowish-orange solid, Obtained: 157 mg
(100 % yield). 1H NMR (400.13 MHz, CDCl3, 298 K): = 7.55 (d, 1H, SC4H2,
3JHH = 5.0), 7.31 (s, 1H, =CH), 7.04 (d, 1H, SC4H2, 3JHH = 5.0), 2.19 (s, 3H,
CH3C=N), 2.12 (s, 3H, CH3COO). 13C{1H} NMR (100.6 MHz, CDCl3, 298
K):  = 182.0 (AcO), 169.8 (C=O), 161.3 (C=N), 141.7 (C), 134.2 (CH),
132.8 (CH), 128.7 (CH), 127.3 (C), 118.7 (C), 24.4 (s, CH3COO), 15.6 (s,
CH3C=N). HRMS (ESI-TOF): m/z calcd for C22H18N2NaO8Pd2S2: 738.8478
[M+Na]+; found: 738.8475. IR (ν, cm-1): 1797, 1773 vs (C=O), 1626 vs
(C=N). Elemental analysis calcd for C22H18N2O8Pd2S2: C 36.94, H 2.54, N
3.92, S 8.96; found: C 37.15, H 2.77, N 3.80, S, 8.64.
Synthesis of 4b. Deep yellow solid. Obtained: 324.1 mg (60.8 % yield).
1H NMR (300.13 MHz, CDCl3, 298 K): = 8.43 (d, 2H, Ho, C6H5, 3JHH = 8),
8.26 (s, 1H, =CH), 7.68-7.63 (m, 2H, PdC6H3 (1H) + Hp, C6H5), 7.52 (t, 2H,
Hm, C6H5), 7.23-7.13 (m, 2H, PdC6H3), 5.22 (s, 1H, C3-H, acac), 2.03 (s,
3H, Me, acac), 1.23 (s, 3H, Me, acac). 13C{1H} NMR (75.47 MHz, CDCl3,
298 K):  = 187.1 (CO, acac), 186.0 (CO, acac), 167.0 (C=N), 161.5 (CO2),
148.7 (C, PdC6H3), 135.5 (=CH-), 135.4 (C, PdC6H3), 134.2 (Cp, C6H5),
133.6 (CH, PdC6H3), 130.9 (CH, PdC6H3), 130.7 (Co, C6H5), 129.8 (=C),
128.0 (Cm, C6H5), 126.5 (CH, PdC6H3), 124.9 (C, PdC6H3), 124.0 (Ci, C6H5),
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10.1002/ejoc.201800966
European Journal of Organic Chemistry
FULL PAPER
100.0 (C3H, acac), 27.4 (Me, acac), 26.4 (Me, acac). HRMS (ESI+) [m/z]:
Calc. for C21H16ClNO4Pd [M]+: 486.9803, obtained 486.9813.
[2]
[3]
A. Edgar, Luminescent Materials, in: S. Kasap and P. Capper, eds;
Springer Handbook of Electronic and Photonic Materials. Springer
Handbooks. 2017, Springer, Cham
A. Kitai, Luminescent Materials and Applications. 1st ed. Weinheim,
Germany: Wiley-VCH; 2008.
Synthesis of 4a. Complex 4a was obtained from 3a (458.4 mg, 0.587
mmol) and Tl(acac) (356.6 mg, 1.175 mmol) following the same
experimental method than that described for 4b. Yellow solid. Obtained:
[4]
[5]
[6]
I. S. Kandarakis, J. Luminescence, 2016, 169, 553-558.
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1
304.4 mg (57 % yield). H NMR (300.13 MHz, CDCl3, 298 K): = 8.44 (d,
3
3
4
2H, Ho, C6H5, JHH = 7.5), 7.81 (dd, 1H, PdC6H4, JHH = 8.0, JHH = 1.1),
3
4
7.64 (tt, 1H, Hp, C6H5, JHH = 7.8, JHH = 0.8), 7.61 (s, 1H, =CH), 7.51 (t,
3
[7]
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2H, Hm, C6H5), 7.33-7.29 (m, 2H, PdC6H4), 7.17 (td, 1H, PdC6H4, JHH
=
7.8, 4JHH = 1.2), 5.22 (s, 1H, C3-H, acac), 2.05 (s, 3H, Me, acac), 1.23 (s,
3H, Me, acac). 13C{1H} NMR (75.47 MHz, CDCl3, 298 K):  = 187.1 (CO,
acac), 186.1 (CO, acac), 166.3 (C=N), 161.8 (CO2), 145.9 (C, PdC6H4),
140.6 (=CH-), 134.8 (CH, PdC6H4), 133.9 (Cp, C6H5), 132.9 (CH, PdC6H4),
132.7 (=C), 131.0 (CH, PdC6H4), 130.6 (Co, C6H5), 127.9 (Cm, C6H5), 125.3
(CH, PdC6H4), 124.3 (C, PdC6H4), 123.4 (Ci, C6H5), 99.9 (C3H, acac), 27.5
(Me, acac), 26.5 (Me, acac). HRMS (ESI+) [m/z]: Calc. for C21H17NNaO4Pd
[M+Na]+: 476.0093, obtained 476.0076.
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Synthesis of 4k. The synthesis of 4k is described here in detail. Other
acetylacetonates obtained using this method are given as Supporting
Information. Method B. Acetylacetone (33 mg, 0.329 mmol) and KOH (18
mg, 0.329 mmol) in MeOH (10 mL) were stirred at room temperature
during 15 min. Then, 3k (139 mg, 0.149 mmol) was added and stirred at
room temperature during 2 hours. The solution was evaporated to dryness,
and the solid residue was washed with H2O. The remaining residue was
redissolved in the minimal amount of CH2Cl2 (1-2 mL) and treated with
petroleum ether (10 mL). A solid precipitated, which was filtered, dried by
suction, and identified as 4k. Orange solid. Obtained: 76 mg (97% yield).
1H NMR (300.13 MHz, CDCl3, 298 K): = 8.21 (s, 1H, =CH-), 7.90 (d, 2H,
Ho, C6H5, JHH = 7.5), 7.65 (d, 1H, C6H3Pd, JHH = 7.5), 7.59-7.54 (m, 3H,
Hm + Hp, C6H5), 7.18 (d, 1H, C6H3Pd, 3JHH = 7.5), 7.09 (t, 1H, C6H3Pd, 3JHH
= 7.7), 5.06 (s, 1H, C3-H, acac), 3.75 (t, 2H, NCH2, 3JHH = 6.7), 1.93 (s, 3H,
Me, acac), 1.53 (m, 2H, CH2, nPr), 1.18 (s, 3H, Me, acac), 0.79 (t, 3H, CH3,
nPr, 3JHH = 6.6). 13C{1H} NMR (75.47 MHz, CDCl3, 298 K): 187.0 (CO,
acac), 185.7 (CO, acac), 166.1 (C=O), 164.1 (C=N), 148.2 (C-Pd, C6H3),
135.4 (C-Cl, C6H3), 133.7 (CH, C6H3), 132.3 (=CH), 131.9 (Cp, C6H5),
130.7 (=C), 130.0 (CH, C6H3), 129.8 (Co, C6H5), 129.6 (C, C6H3), 128.6
(Cm, C6H5), 128.4 (Ci, C6H5), 126.4 (CH, C6H3), 99.7 (C3H, acac) , 44.0
(NCH2, nPr), 27.6 (Me, acac) , 26.2 (Me, acac), 22.3 (CH2, nPr), 11.1 (CH3,
nPr). HRMS (ESI+) [m/z]: Calc. for C25H26ClN2O4Pd [M+OMe]+: 559.0616,
obtained 559.0631.
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800966
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
The orthopalladation of 4-aryliden-
5(4H)-oxazolones and -imidazolones
through C-H bond activation is
regioselective and gives dimers where
only the ortho position of the 4-
GFP-orthopalladated fluorophores *
Sandra Collado, Alejandro Pueyo,
Christine Baudequin, Laurent Bischoff,
Ana Isabel Jiménez, Carlos Cativiela*,
Christophe Hoarau*, and Esteban P.
Urriolabeitia*
arylidene ring is activated. The
carboxylate ligands can be replaced
by acetylacetonate, affording rigid
neutral mononuclear complexes. The
photophysical properties of these rigid
mononuclear complexes have been
examined and confirm the importance
of rigidification of imidazolones.
Page No. – Page No.
Orthopalladation of GFP-like
fluorophores through C-H bond
activation: scope and photophysical
properties
This article is protected by copyright. All rights reserved.