Iridium-catalyzed H/D exchange into organic compounds in water

Article abstract of DOI:10.1021/ja017219d

The air-stable complex Cp*(PMe₃)IrCl₂ efficiently catalyzes the exchange of deuterium from D₂O into both activated and unactivated C-H bonds of organic molecules without added acid or stabilizers. Selectivity is observed in many cases, with activation of primary C-H bonds occurring preferentially. A number of new stoichiometric transformations involving the iridiym catalyst precursor are also presented, including an ozidation-decarbonylation reaction with primary alcohols. Copyright

Full text of DOI:10.1021/ja017219d

Published on Web 02/14/2002
Iridium-Catalyzed H/D Exchange into Organic Compounds in Water
Steven R. Klei, Jeffrey T. Golden, T. Don Tilley,* and Robert G. Bergman*
Department of Chemistry and Center for New Directions in Organic Synthesis (CNDOS), UniVersity of California,
and DiVision of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720-1460
Received October 2, 2001
a
Table 1. H/D Exchange Results with 5 Mol % Cp*(PMe3)IrCl2
Deuterium- and tritium-labeled compounds have a number of
important uses, from solvents for NMR spectroscopy to reagents
for mechanistic investigations.1 Deuterium oxide (D2O) is the most
attractive isotopic source for the preparation of these materials due
to its combined low cost and low toxicity. However, general
procedures for the incorporation of deuterium into the C-H bonds
of organic compounds which utilize D2O are often limited to
activated positions of the molecules.2,3
An exception to this is the pioneering work of Garnett4-6 and
Shilov,7,8 which showed that K2PtCl4 is a competent catalyst for
homogeneous H/D exchange between D2O and arenes or alkanes.
It was found that the platinum-catalyzed process required the
addition of several additives to proceed efficiently. First, a strong
inorganic acid was used to prevent disproportionation of the catalyst
to Pt(0) and Pt(IV). Additionally, an aromatic compound such as
pyrene acted as an “olefin stabilizer” for Pt(II). Furthermore, the
inclusion of an organic acid such as CH3CO2H was necessary to
maintain homogeneity. For statistical reasons, the presence of these
additives necessarily leads to a lower maximum deuterium exchange
percentage. Reactions with halide salts of iridium9 and rhodium10
suffered from similar limitations. We report here that Cp*(PMe3)-
IrCl2 (1) efficiently catalyzes the exchange of deuterium from D2O
into organic molecules without added acid or stabilizers, and we
discuss decomposition pathways of the catalyst that suggest future
catalyst improvements.
We recently reported that the Ir complex [Cp*(PMe3)IrH-
(CH2Cl2)][B(C6F5)3Me] (2) catalyzes low-temperature H/D ex-
change between C6D6 and a variety of organic substrates.11 In search
of an air-stable Ir(III) catalyst that could make use of D2O as the
deuterium source, we elected to study the aqueous H/D exchange
behavior of Cp*(PMe3)IrCl2 (1). We believed that the aqueous
medium would render the chloride ligands labile and lead to a
catalytically active 16-e Ir fragment. Similar to the manner in which
Periana and co-workers found that organic ligands altered the course
of Pt(II) halide-catalyzed methane oxidation,12 we were hopeful
that a well-defined ancillary ligand set would lead to H/D exchange
results better than those of the Ir(III) or Pt(II) systems studied
previously.
a All reactions were performed with complex 3 in sealed glass containers
containing 0.5 mL of D2O at 135 °C for 40 h. For % D, 1H NMR
spectroscopy was used for analysis.
in those systems containing more than one type of C-H bond. For
example, the internal methylene position of n-propanol is the least
rapidly deuterated of the three positions available. When ibuprofen
(entry 6 in Table 1) was used as the substrate, exchange into
unactivated secondary and tertiary C-H bond positions was not
observed. Similarly, sodium octanoate showed surprisingly high
selectivity for the terminal position. Some preferential reaction at
terminal sites has been seen previously in C-H activation/
functionalization reactions and has been attributed to steric ef-
fects.8,16 We do not yet understand the physical basis of these
selectivities, but the activation of stronger, primary C-H bonds is
persuasive evidence against an exchange mechanism involving
radicals. Exchange reactions using substrates which lack polar
substituents, such as amylbenzene and naphthalene, led to low levels
of deuterium incorporation (<10% overall) with use of the reaction
conditions in Table 1.
Deuterium incorporation into ethereal substrates, such as diethyl
ether and tetrahydrofuran (THF), is also a facile process with the
dichloride catalyst 1. Monitoring the reactions by 1H NMR
spectroscopy reveals a preference for activation of the â-position
in diethyl ether (presumably because these are primary hydrogens),
whereas the R-position is attacked first in THF. Selective C-H
activation of THF at the R-position had been previously observed
in exchange reactions catalyzed by [Cp*(PMe3)Ir(H)(CH2Cl2)]-
[B(C6F5)3Me]11 and in stoichiometric C-H activation reactions of
Ir(III).17 Carmona and co-workers have reported that TpMe IrH4
Heating a variety of organic substrates with a catalytic amount
(5 mol %) of the dichloride complex 1 in D2O leads to extensive
H/D exchange; Table 1 presents typical results.13 Emphasis was
placed on substrates that had high water solubility, so that the
reactions could be monitored by 1H NMR spectroscopy.14 Choosing
substrates with differently substituted carbon centers allowed issues
of selectivity to be addressed. EI-MS was also used to confirm
deuterium incorporation, although fragmentation of the parent ion
of many of the substrates prevented this from being a definitive
method for measuring deuterium content.15Although 1 catalyzed
extensive deuterium incorporation into many different types of
unactivated C-H bond positions, some selectivity was observed
2
mediates H/D exchange between THF and D2O by heating to 90
°C for 7 days. However, the levels of incorporation were very low
and no selectivity for either the R- or â-positions was observed.18
The deuteration of sodium benzoate is significantly slower than
that of benzoic acid (Table 1) because it leads to the formation of
the less reactive Ir complex, Cp*(PMe3)Ir(O2CPh)2 (3).
Exchange with all substrates was observed to stop after heating
at 135 °C for 40 h, with concomitant formation of a new Ir-con-
taining material, observed by 31P NMR spectroscopy.19 The same
species was found to be produced by heating Cp*(PMe3)IrCl2 in
D2O at 135 °C in the absence of organic substrate. Comparison
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C O M M U N I C A T I O N S
with authentic samples verified that the products were [Cp*(PMe3)2-
IrCl][Cl] (4) and [Cp*IrCl2]2 (5) (eq 1).20,21 The equilibrium constant
for this reaction is Keq ) 0.6 ( 0.1 L1/2 mol-1/2. Production of the
Ir ion pair 4 is presumably the driving force for the disproportion-
ation in the polar medium; no such disproportionation of 1 was
observed by NMR spectroscopy in CD2Cl2 solution.
reaction with primary alcohols were observed when heating Cp*-
(PMe3)IrCl2 under otherwise identical conditions in CD2Cl2. This
is most likely due to the fact that the chloride ligands of 1 are not
labile in CD2Cl2.28 We are currently investigating ways to prevent
the disproportionation of 2 and better understand the intimate
mechanism of the H/D exchange reaction.
It was important to establish the catalytic properties of the
disproproportion mixture of 4 and 5 toward the H/D exchange
reaction. Bis(phosphine) complex 4 was shown to be completely
inactive, and dimer 5 was shown to be moderately active (although
substantially less active than dichloride 1). More importantly, a 1:1
mixture of 4 and 5 was inactive. We therefore believe that 4 is an
effective inhibitor of 5 by serving as a source of free chloride ion
(vide infra).
Another decomposition route of dichloride complex 1 was
encountered when primary alcohols were used as substrates in the
exchange reactions. Although extensive H/D exchange was evident
with n-propanol, complete formation of a new Ir species was
observed after heating to 135 °C for 40 h. This new complex was
Acknowledgment. This work was supported by the Director,
Office of Energy Research, Office of Basic Energy Sciences,
Chemical Sciences Division, of the U.S. Department of Energy
under Contract No. DE-AC03-7600098, and also by a National
Science Foundation Predoctoral Fellowship to S.R.K.. We thank
Dr. Ulla Andersen and Professor Julie Leary for informative
discussions concerning mass spectrometry. CNDOS is supported
by Bristol-Myers as a founding member.
Supporting Information Available: Synthetic procedures, char-
acterization data for 3 and 6a-c, and information about measurement
of deuterium incorporation and equilibrium constant (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(2) Kadam, A. J.; Desai, U. V.; Mane, R. B. J. Labeled Cpd. Radiopharm.
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shown to be [Cp*(PMe3)Ir(CO)(Et)][Cl] (6a) after subsequent
isolation (61% yield) and characterization. Similarly, deuteration
of benzyl and ethyl alcohol led to the isolation of [Cp*(PMe3)Ir-
(CO)(Ph)][Cl] (6b, 72% yield) and [Cp*(PMe3)Ir(CO)(Me)][Cl] (6c,
57% yield), respectively (eq 2).22 We believe that the production
(3) Tashiro, M.; Tsuzuki, H.; Isobe, S.; Goto, H.; Ogasahara, S.; Mataka, S.;
Yonemitsu, T. J. Labeled Cpd. Radiopharm. 1991, 29, 405.
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of these carbonyl complexes is initiated by oxidation of the alcohol
to form the corresponding aldehyde. Activation of the weak
aldehydic C-H bond results in formation of an acyl complex, which
undergoes facile decarbonylation to give the observed products.23,24
Further studies indicated that 2-propanol and phenol undergo H/D
exchange, but catalyst decomposition leads to disproportionation
products 4 and 5 because a decarbonylation pathway is not expected
to be accessible.
(13) Results for 2-propanol used (CH3)2C(H)OD as the starting material; all
other starting organics were unlabeled. Deuterium incorporation data
collected at earlier times can be found in the Supporting Information.
(14) For an example of NMR spectroscopy as a method of determining
deuterium incorporation, see: Lenges, C. P.; White, P. S.; Brookhart, M.
J. Am. Chem. Soc. 1999, 121, 4385.
(15) For a discussion concerning the limitations of using mass spectroscopy
to determine levels of deuterium incorporation, see the Supporting
Information.
(16) Chen, H. Y.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995.
(17) Luecke, H. F.; Arndtsen, B. A.; Burger, P.; Bergman, R. G. J. Am. Chem.
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(19) A small amount of starting complex 1 is also observable, and both 31P
NMR signals show a number of isotopomers. This indicates that H/D
exchange with the catalyst ligands is possible. This result was confirmed
by EI-MS analysis of dichloride 2, which was isolated after heating it to
135 °C for 40 h.
(20) Gilbert, T. M.; Bergman, R. G. J. Am. Chem. Soc. 1985, 107, 3502.
(21) White, C.; Oliver, A. J.; Maitlis, P. M. J. Chem. Soc., Dalton Trans. 1973,
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(22) The reaction stoichiometry mandates that 1 equiv of both H2 and HCl be
released in this reaction.
We speculate that the mechanism of H/D exchange in this system
is similar to the one observed by Shilov and Garnett.8 Dissociation
of chloride from the Ir center produces a cationic 16-e fragment
capable of C-H activation. Consistent with this, it was observed
that added sodium chloride (10 equiv) completely inhibited the
reaction. Because heterogeneous Rd and Pt catalysts have been
shown to catalyze H/D exchange,1 we considered the possibility
of catalytically competent Ir colloids in our system. However, the
addition of elemental mercury25,26 had no effect on the deuteration
of n-propanol, providing evidence against this possibility.
These preliminary H/D exchange data involving dichloride 1 are
very promising and in some cases even surpass the performance
of the Pt(II) and Ir(III) halide salts mentioned earlier. We made
our comparison using identical conditions to those in Table 1,
meaning that 5 mol % of the catalyst was heated to 135 °C for 40
h with the substrate in D2O and without any additives. Using those
conditions, deuteration of Et2O with 1 leads to a total incorporation
level of 36%, whereas K2PtCl4 affords 7% and Na3IrCl6 yields
15%.27 The results presented here are unique to aqueous chemistry.
Neither the disproportionation nor the oxidation-decarbonylation
(23) Tandem C-H activation/decarbonylation of aldehydes has been previously
observed with methyliridium(III) species: Alaimo, P. J.; Arndtsen, B. A.;
Bergman, R. G. Organometallics 2000, 2130.
(24) For a recent example of alcohol oxidation by an iridium complex as part
of a catalyzed transfer hydrogenation, see: Hiller, A. C.; Lee, H. M.;
Stevens, E. D.; Nolan, S. P. Organometallics 2001, 20, 4246.
(25) Anton, D. R.; Crabtree, R. H. Organometallics 1983, 2, 855.
(26) Whitesides, G. M.; Hackett, M.; Brainard, R. L.; Lavalleye, J. P.; Sowinski,
A. F.; Izumi, A. N.; More, S. S.; Brown, D. W.; Staudt, E. M.
Organometallics 1985, 4, 1819.
(27) A small amount (<10%) of unidentified decomposition product derived
from Et2O is formed in the case of Na3IrCl6.
(28) Burger, P.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 10462.
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