Iridium-catalyzed H/D exchange

Article abstract of DOI:10.1002/ejoc.200400669

The scope and limitation of an iridium-catalysed H/D exchange reaction has been investigated. Our results suggest a general mechanism for specific labelling at aromatic and non-aromatic double bonds by D₂O if an electron-donating group is in a 1,4-relation with the carbon where the H/D exchange takes place. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400669

FULL PAPER
Iridium-Catalyzed H/D Exchange
Jens Krüger,[a] Boripont Manmontri,[a] and Gregor Fels*[a]
Keywords: Isotopic labelling / Iridium / Deuterium exchange
The scope and limitation of an iridium-catalysed H/D ex-
change reaction has been investigated. Our results suggest
a general mechanism for specific labelling at aromatic and
non-aromatic double bonds by D2O if an electron-donating
group is in a 1,4-relation with the carbon where the H/D ex-
change takes place.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
more, it shows an excellent stability towards light, heat and
oxygen: even after three months storage it still retains its
full catalytic power. Its neutral form grants a good solubil-
ity in both polar and non-polar solvents, thereby making
exchange in nearly all possible substance classes possible.
Introduction
The potential usage of catalytic isotope-exchange reac-
tions varies from standards for NMR spectroscopy and
mass spectrometry to highly specific labelling of promising
drug candidates with tritium for physiological studies.
Furthermore it can give new hints about the mechanism of
catalytic processes and thus enable their improvement.
The ability of cyclooctadieneiridium(i) acetylacetonate
(1)[1] (Figure 1) to act as a catalyst for the exchange of hy-
drogen at aromatic and non-aromatic double bonds by deu-
terium has been reported previously. The isotopic hydrogen
is incorporated at a 1,4-position to a directing atom, where
it is not particularly susceptible towards loss by metabolism
or uncatalysed exchange (Scheme 1).
Results and Discussion
Acids
In aromatic systems a carboxylic acid functional group
has the ability to direct the H/D exchange in the ortho posi-
tion. 2-Methoxybenzoic acid (2), which was used as our
model substrate due to its high deuteration grade of 97.5%
and ease of handling, undergoes H/D exchange at the un-
blocked ortho position. On the other hand, 4-nitrobenzoic
acid (3) undergoes H/D exchange at both ortho positions
(2×99%), while 3-(dimethylamino)benzoic acid (4) shows
an exchange only in the unhindered C-6 position.
Figure 1. Cyclooctadieneiridium(i) acetylacetonate (1).
Carbonyls
Benzophenone (5) shows, as expected, an exchange in all
four ortho positions. 2-Hydroxy-4-methoxyacetophenone
(6) can tautomerise and have keto and enol forms. There-
fore, instead of having the H/D exchange that generally oc-
curs at the ortho position next to the carbonyl group, the
exchange occurs at the methyl group. Acetophenone oxime
(7), on the contrary, does not tautomerise; thus, the H/D
exchange occurs exclusively at the two ortho positions.
It was not possible to label 2-methoxybenzaldehyde (8).
A black precipitate was observed, which is presumably
caused by reduction of the catalyst to Ir0.
Scheme 1. General exchange pattern of a typical substrate.
Besides various carbonyl compounds it is possible to la-
bel acids, oximes and amines, with suitably high exchange
rates. Although high deuteration grades have also been re-
ported for specific systems with other catalysts, 1 is a good
all-round system[2–8] as it not only accepts a broad set of
functional groups as directors, but also tolerates coordinat-
ing substituents like methoxy and hydroxy groups. Further-
Amines and Alcohols
[a] Department of Chemistry, University of Paderborn,
Warburger Str. 100, 33098 Paderborn, Germany
Fax: +49-5251-603245
Benzylamines can be deuterated when catalysed by 1
whereas benzyl alcohols with similar structures cannot.
E-mail: fels@upb.de
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DOI: 10.1002/ejoc.200400669
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Iridium-Catalyzed H/D Exchange
FULL PAPER
Using 2-methoxybenzylamine (9) as a test substrate, the which can be deuterated at multiple points, while, in con-
deuteration grade obtained was above 50%. On the other trast, 3-benzoylacrylic acid (16) shows more than 75% of
hand, no deuteration of 2-methoxybenzyl alcohol (10) was deuteration, exclusively in the double bond at the β-position
observed. Following the HSAB concept, it is believed that relative to the acid functional group. The result in the latter
amines can interact much better with iridium in the first case indicates that the acid function is dominant over the
coordinating step (Scheme 2) than alcohols due to their carbonyl in directing the deuteration.
softer base character.
Chelate-Ring Size
With the assumption that 2 forms a five-membered
metallacyclic intermediate when reacted with 1,[10,11] further
investigation was made to see if the six- and seven-mem-
bered intermediates also show deuteration. 2-Methoxy-
phenylacetic acid (18) and 3,4-dimethoxyphenylacetic acid
(19) were used to study the six-membered metallacyclic in-
termediate system, whereas 3-(2-methoxyphenyl)propionic
acid (20) was used to study the seven-membered intermedi-
ate system. The results show that no deuteration was detect-
able for both the six- and seven-membered intermediate sys-
tems.
Temperature/Solvent
Figure 2 shows the deuteration grade of 2 − the model
substrate − at different temperatures when prepared in
DMA or CHCl3. Under similar conditions, the exchange
rate is proportional to the temperature. This statement is
clearly shown when DMA is used as a solvent. Under the
same conditions to that of DMA, the exchange rate when
CHCl3 is employed remains at approximately 5%, though
it increases to a small extent when temperature was raised.
These values indicate that the solvent plays an important
ide as the isotope source.
Scheme 2. Proposal of a simplified mechanism with deuterium ox-
role in the exchange mechanism and must have a certain
ligand characteristic, besides being polar and non-protic.
An exchange of solvent hydrogen by D2O can be ex-
Non-Aromatic Systems
cluded in the case of DMA, as we have found high deutera-
tion rates in our experiments. With CHCl3, however, this
could, in principle, be the reason for the low exchange rate
of less than 5%, although we assume that this is mainly
caused by the rather low coordination capability of CHCl3.
DMA is the solvent of choice amongst the solvents that
were examined. This could be due to the fact that it has a
suitable structure that ensures it can participate in the reac-
tion. The DMA molecule can act as a ligand and interact
with the iridium atom. This renders the correct electronic
environment that enables the exchange reaction.
DMF is another solvent of choice as, due to its structural
similarity to DMA, it can participate in the same way. In
any event, DMA is preferred due to its NMR spectrum as
the aromatic region is clear of solvent resonances that could
overlap with the product spectrum.[2]
Assuming that the double-bond system of a conjugated
carbonyl functional group could participate in deuteration
in the same manner as the aromatic ring in 2,[9] a number
of compounds were examined. Two of those were trans-cro-
tonic acid (11) and sorbic acid (12). Compound 11 can be
deuterated to a deuteration grade higher than 60% whereas
12, which has an extra conjugated double bond, cannot. It
appears that 12 coordinates to iridium in a different way,
thus suppressing the normal catalytic process. Further in-
vestigation was undertaken when the double bond is ad-
ditionally conjugated to an aromatic system, as in trans-
cinnamic acid (13) and trans-2,3-dimethoxycinnamic acid
(14). In this case, the substrate is exclusively deuterated at
the double bond in the β-position relative to the directing
group. The deuteration grades achieved were 17% and 87%,
respectively, thus demonstrating the electronic influence of
the substituents.
Reaction Time
As the α,β-unsaturated carbonyl group appeared to be as
a suitable group for H/D exchange, a number of compounds
The deuteration grade increases continuously with longer
that contain this system were screened. Some examples of reaction times. For 2 the equilibrium is reached after ap-
these compounds include trans-1,2-dibenzoylethylene (15), proximately two hours to yield 97 1% of labelling (Fig-
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J. Krüger, B. Manmontri, G. Fels
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Figure 2. Influence of temperature and solvent on the deuteration grade of 2-methoxybenzoic acid (2).
Figure 3. Influence of reaction time on the deuteration grade of 2-methoxybenzoic acid (2) at 90 °C.
ure 3). It appears that the achievable deuteration grade is vent molecules, for example DMA, to form the real catalyti-
only a function of time and isotopic dilution. In a few cally active compound. In addition, active IrI–DMA com-
exemplary tries, also with less active compounds, the reac- plexes are known from the literature and are generated in
tion time was increased, making practically quantitative situ as catalytic intermediates.[12] This is in good agreement
H/D exchange achievable. For example, after three hours 7 with reports of deuteration of cyclooctadiene when em-
showed only 2×12.5% exchange in the ortho position to ploying deuterium gas as the isotope source.[3]
the oxime, while after 48 h 2×82 5% was reached.
After the first coordination of the substrate, iridium is
inserted into the C–H bond. This can be formally described
as oxidative addition. Subsequently, with coordination of
Mechanism
The solvent influence on the overall exchange activity D2O, the exchange itself can take place. The reductive elimi-
gives strong evidence that cyclooctadiene is replaced by sol- nation then occurs and the deuterated substrate is released.
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Iridium-Catalyzed H/D Exchange
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This proposed mechanism reflects the preferred square- Analytics
planar coordination sphere for IrI and the octahedral coor-
dination for IrIII. The aforementioned scheme is in accord-
ance with the 16/18-valence-electron rule.
The term deuteration grade is used to describe the
amount of introduced deuterium atoms per possible posi-
Oxidative-addition reactions are typical for electron-rich, tion. It is given a value of 0% when there is no exchange,
low-valent complexes of “late” transition metals like Ir. In and 100% if the hydrogen has been completely replaced by
principle, however, as an alternative to the oxidative ad- deuterium. If multiple positions are present the results state
dition/reductive elimination sequence a σ-bond metathesis different values for each possible position (Table 1).
1
mechanism may also be reasonable, although this type of
For simple systems standard H NMR techniques were
reaction is more common for “early” transition metals, like used to assign the position and to calculate the deuteration
for instance Sc.[13]
grade from the corresponding integrals. It was very useful
Table 1. Deuterated products and their related data. Reactions were conducted at 90 °C for 2 h in DMA and D2O, with a catalyst-to-
substrate ratio of 1:25. Deviations from this standard procedure are given in the table.
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Table 1. (continued).
to employ substrates that contained, for example, a methyl Isotope Source
or methoxy group that can be used as internal standard.[4]
The results were occasionally verified by mass spectrometry,
which always showed a very good agreement.
Due to the inconvenience of handling D2 gas, nearly all
experiments were carried out with D2O as the isotope
For more complex systems inverse gated decoupled 13C source. To adapt this technique for tritium labelling of drug
NMR spectra were recorded. These carbon spectra, which candidates a suitable radioactive source is required. The
can be integrated, allow absolutely clear assignment of the high risk related to the usage of tritiated water prohibits its
deuteration position from the coupling pattern. A normal employment in standard methods.[10,14] Consequently, the
C–D coupling shows a triplet, whereas the C–H coupling catalyst system was tested with deuterium gas and 2 as
remains as a singlet (Figure 4). Their integration reflects the model compound. A deuteration grade of 45% was ob-
deuteration grade very precisely. These results can even be served, but surprisingly at the C-4 position, para to the acid
improved, because normally the neighbouring carbons split and meta to the methoxy group (Figure 5), thus indicating
up and also allow integration.
that a different mechanism from the one described above
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Iridium-Catalyzed H/D Exchange
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Conclusions
Screening a number of compounds has shown that the
iridium catalyst has the ability to catalyze H/D exchange in
an array of compounds. These include unsaturated carbox-
ylic acids, ketones and amines whose hydrogens at the
double-bond position can be exchanged. Complex 1 cata-
lyzes deuteration in a 1,4-relation relative to a directing
atom, via a five-membered metallacyclic intermediate, pro-
viding that there is no steric hindrance or blockage from
other functional groups.
Complex 1 is considered to be an all-round catalyst. It
can catalyze the H/D exchange at relatively low catalyst/
substrate molar ratios and in relatively short reaction times.
The standard conditions used throughout our experiment
employ a catalyst/substrate molar ratio of 1:25 and a reac-
tion time of two hours. Moreover, 1 catalyzes the reaction
at moderate reaction temperatures of 60–90 °C and it can
easily be prepared from its precursor [Ir(COD)Cl]2. Under
these conditions, H/D exchange varied between 5 and 99%
at a specific positions.
Figure 4. Representative C–D (left) and split up C–H (right) coup-
ling in trans-2,3-dimethoxycinnamic acid (14) with corresponding
integrals.
The mechanism presumably involves displacement of cy-
clooctadiene by a solvent molecule, which later on is re-
placed by a substrate, which in our case is an α,β-unsatu-
rated carbonyl group, or a benzylamine. In addition, the
solvent molecule presumably plays an important role in the
oxidation/reduction cycle of iridium on which the H/D ex-
change is based. The presence of a hetero atom in an unsat-
urated compound in a position that allows the formation
of a five-membered metallacycle with iridium is a prerequi-
site for a successful exchange reaction. With respect to the
heteroatom, softer bases coordinate more effectively to the
catalyst.
has taken place (Scheme 2). A similar experiment using 5
showed diverse exchange over the aromatic ring, although
not the expected ortho exchange: deuterium was mainly po-
sitioned meta and para to the carbonyl group, with an over-
all exchange rate of 30%.
The proposed mechanism is only applicable to the ex-
change of hydrogen by D2O. Employment of D2 as labelling
reagent yields, under identical conditions, isotopic exchange
in positions that can not be rationalised by the five-mem-
bered metallacyclic intermediate. This result will be the ob-
ject of further investigations in our laboratory.
Figure 5. With deuterium gas as the isotope source rather than
D2O, 2-methoxybenzoic acid (2) shows exchange para to the acid
and meta to the methoxy group, with no labelling ortho to the car-
boxylic acid.
Experimental Section
In contrast to our exchange reaction with D2O, we ob-
served precipitation of iridium when D2 was employed as
the isotope source. This finding parallels the experiments of
Hickey et al.,[15] in which 4-aminobenzoic acid was labelled
with D2 in the meta position rather than in the ortho posi-
tion In this case the results were explained by formation of
an iridium colloid cluster that is able to exchange in posi-
tions other than ortho.
Other recent reports have shown a similar exchange
pattern for naphthyl and phenyl substrates in the presence
of IrIII catalysts and deuterium gas.[16,17] We assume that
deuterium gas can reduce the acetylacetone and sub-
sequently form an active IrIII species, which enables ex-
change in positions other than those labelled with D2O. It
seems that only electronic effects in the aromatic ring are
relevant to this exchange reaction, and that there is no evi-
dence for an influence of directing groups in the substrate.
General Remarks: All solvents were purified by standard pro-
cedures and were distilled prior to use. Reagents obtained from
commercial sources were used without further purification. The
NMR spectra were measured with Bruker ARX 200 and Bruker
AV 500 instruments. Mass spectra were recorded with a Finnigan
MAT 8230 instrument.
Catalyst: To prepare cyclooctadieneiridium(i) acetylacetonate (1),
[Ir(COD)Cl]2 (250 mg, 0.372 mmol) was treated with degassed di-
ethyl ether (2 mL), and stirred under argon at room temperature
for 20 min until it had dissolved completely. Acetyl acetone (80 μL,
0.773 mmol) was added dropwise with a syringe to the reaction
mixture. After 5 min stirring 1 n KOH (1.25 mL) was added drop-
wise to the reaction mixture with a syringe. The reaction mixture
was stirred for an additional 10 min, then distilled water (2.0 mL)
was added dropwise with a syringe. The solution became darker as
distilled water was added and finally became dark brown. A yellow
solid could also be observed. The reaction mixture was stirred for
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J. Krüger, B. Manmontri, G. Fels
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an additional hour before diethyl ether was evaporated. The yellow
solid was filtered from the aqueous solution and washed three times
with portions of distilled water (3 mL). The crystals were dried
overnight to yield 215 mg (0.538 mmol, 73%) of fine, yellowish
Deuterium Gas: 2-Methoxybenzoic acid (2; 102 mg, 0.67 mmol)
and 1 (10.2 mg, 0.026 mmol) were placed in a 50-mL, round-bot-
tomed flask. The reaction vessel was evacuated and flushed with
argon to remove oxygen. DMA (7.6 mL) was added to the flask
crystals of 1. 1H NMR (CDCl3): δ = 1.66 (d, J = 7.6 Hz, 4 H), 2.04 and stirred until all the solid had dissolved. Then, a balloon con-
(s, 6 H), 2.28 (m, 4 H), 4.02 (s, 4 H), 5.55 (s, 1 H) ppm.[1,2]
taining roughly 50 mL of D2 was attached to the apparatus. The
gas phase consisted of approximately two parts deuterium to one
part argon. The reaction mixture was heated at 90 °C for 2 h,
changing colour from yellowish to dark brown and forming a black
precipitate. The mixture was then treated with 20 mL of H2O and
acidified with 5 mL of 1 n HCl before being extracted three times
with 20 mL of diethyl ether. The organic phase was dried with
MgSO4 and filtered. The solvent was removed and the deuterated
product was obtained. 1H and 13C NMR and mass spectra were
measured.
Reaction: The reactions were carried out mostly in the same man-
ner. This consists of stirring a mixture of substrate and 1 in the
solvent (DMA) under argon at 90 °C for 2 h. However, in some
cases, the reaction conditions were modified slightly. The modifica-
tions include the adjustment of the volume of solvent and D2O,
the use of D2 gas instead of D2O, alteration of the substrate to
catalyst ratio, omitting to use a condenser when the reaction was
carried out in a mini-reactor, and adjustment of temperature and
reaction time. The following paragraphs explain how the deutera-
tion reactions for sample compounds of each class were prepared.
Acknowledgments
Acids: 2-Methoxybenzoic acid (2; 102 mg, 0.67 mmol) and 1
(10.2 mg, 0.026 mmol) were placed in a 1-mL mini-reactor under
argon. DMA (0.65 mL) was added to the mini-reactor and stirred
until all the solid had dissolved. D2O (0.1 mL) was added dropwise
whilst stirring. The reaction mixture was heated at 90 °C for 2 h
and then left to cool. The mixture was then treated with 20 mL of
H2O and acidified with 5 mL of 1 n HCl before being extracted
three times with 20 mL of diethyl ether. The organic phase was
dried with MgSO4 and filtered. The solvent was removed and the
deuterated product was obtained. 1H and 13C NMR and mass spec-
tra were measured.
We thank Dr. Hans Egold, Prof. Birgit Drießen-Hölscher and Lars
Müller for their great support and invaluable counsel. This work
was supported by the International Isotope Society, Central Euro-
pean Division (IIS-CED).
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Neutral Compounds: Acetophenone oxime (7; 100.0 mg,
0.74 mmol) and 1 (11.6 mg, 0.029 mmol) were placed in a 50-mL,
round-bottomed flask. DMA (7.6 mL) was added to the flask and
stirred until all the solid had dissolved. D2O (2.4 mL) was added
dropwise whilst stirring. The reaction mixture was put under argon
gas and heated at 90 °C for 2 h and then left to cool. The mixture
was then treated with 20 mL of H2O before being extracted three
times with 15 mL of diethyl ether. The organic phase was dried
with MgSO4 and filtered. The solvent was removed and the deuter-
ated product was obtained. 1H and 13C NMR spectra were mea-
sured.
Amines and Alcohols: Complex 1 (10.1 mg, 0.025 mmol) was placed
in a 1-mL mini-reactor under argon. DMA (0.40 mL) was added
to the flask and stirred until all the solid had dissolved. 2-Methoxy-
benzylamine (9; 80 μL, 0.65 mmol) was added to the mini-reactor
and then D2O (0.1 mL) was added dropwise whilst stirring. The
reaction mixture was heated at 90 °C for 2 h and then left to cool.
The mixture was then treated with 20 mL of 12.5% NH3 before
being extracted three times with 20 mL of diethyl ether. The or-
ganic phase was dried with MgSO4 and filtered. The solvent was
removed and the deuterated product was obtained. A 1H NMR
spectrum was measured.
Allylic Systems: trans-Crotonic acid (11; 74.0 mg, 1.16 mmol) and
1 (13.5 mg, 0.034) were placed in a 10-mL, round-bottomed flask.
DMA (2.0 mL) was added to the flask and stirred until all the
solid had dissolved. Deuterium oxide (1.0 mL) was added dropwise
whilst stirring. The reaction mixture was put under argon gas,
heated at 90 °C for 4 h and then left to cool. The mixture was then
treated with 10 mL of 1 n HCl before being extracted three times
with 5 mL of 1-butanol. The organic phase was filtered, the solvent
was removed and the deuterated product was obtained after drying
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1
at high vacuum for 2 h. A H NMR spectrum was measured.
Received: September 03, 2004
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