Conditions for deuterium exchange mediated by iridium complexes formed in situ

Article abstract of DOI:10.1016/S0040-4020(03)00422-8

A series of iridium-based complexes formed in situ, containing pyridine, phosphines, triphenylarsine, triphenylstibine, and triphenylamine as ligands, has been screened for ability to mediate ortho-exchange of hydrogen in a series of model substrates. Imp

Full text of DOI:10.1016/S0040-4020(03)00422-8

Tetrahedron 59 (2003) 3349–3358
Conditions for deuterium exchange mediated by iridium
complexes formed in situ
a
Paul W. C. Cross,a George J. Ellames,b Jennifer S. Gibson,b John M. Herbert,b William J. Kerr,
,
*
Alan H. McNeillb and Trevor W. Mathersa
aDepartment of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK
b
´
Department of Isotope Chemistry and Metabolite Synthesis, Sanofi-Synthelabo, Willowburn Avenue Alnwick,
Northumberland NE66 2JH, UK
Received 28 October 2002; revised 31 January 2003; accepted 13 March 2003
Abstract—A series of iridium-based complexes formed in situ, containing pyridine, phosphines, triphenylarsine, triphenylstibine, and
triphenylamine as ligands, has been screened for ability to mediate ortho-exchange of hydrogen in a series of model substrates. Improved
incorporation into a number of substrate classes has been achieved. The electronic properties and number of ligands at the metal centre are
instrumental in determining which catalysts are best suited to exchange in any given substrate. q 2003 Published by Elsevier Science Ltd.
1. Introduction
desirable and, at present, this level of incorporation is not
achievable by iridium-mediated exchange.
Over the past decade, a number of groups have reported
iridium complex-mediated hydrogen isotope exchange at
relatively unactivated carbon centres.1–5 Such methodology
is of considerable potential value for the preparation
of tritiated organic molecules in a minimal number of
radiolabelled steps, but the efficiency of exchange remains
insufficient for application to the preparation of deuterated
species. Where the latter are to be used as internal standards
for mass spectrometry, better than 99% exchange is
In a recent communication,6 we described the generation
of bis(phosphine)(cyclooctadiene)iridium(I) tetrafluoro-
borates, exemplified by the complexes formed with
triphenylphosphine and methyldiphenylphosphine, and the
in situ use of these pre-catalysts to mediate hydrogen
isotope exchange adjacent to a heteroatom-containing
functional group. More importantly, we demonstrated that
the results obtained upon deuterium exchange using
Scheme 1. Generalised form of isotopic exchange using complexes 1–3.
Keywords: iridium complexes; deuterium exchange; isotope exchange.
*
Corresponding author; e-mail: john.herbert@sanofi-synthelabo.com
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00422-8

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complexes generated and used without isolation were, at
worst, only slightly inferior to those obtained using the
isolated complexes. This approach has enabled us to
evaluate different ligands and stoichiometries (Scheme 1)
without isolating the pre-catalysts, and also gives us the
option of using catalysts whose isolation would be difficult.
cyclooctadiene)diiridium(I) dichloride with the phosphine
(4 M equiv.) and silver tetrafluoroborate (2 M equiv.).6
When complexation was carried out in CDCl3, within
5 min TLC and 1H NMR of the solution formed were
identical to those of the isolated complex.7
When the in situ catalyst generation technique was
employed and the resulting species used in labelling
reactions, in some cases it appeared that silver(I) was
reduced in parallel with the exchange process, forming a
silver mirror on the inside of the reaction flask.6 It was
therefore likely that sensitive substrates or more electron-
rich phosphines would be oxidised using this protocol.
Additionally, it was highly probable that deuterium was also
being oxidised. Importantly, any acid formed as part of
this latter process could promote degradation and inacti-
vation of the iridium catalyst,8 or alter the overall labelling
profile. Indeed, with regard to this latter point, acid-
mediated deuterium incorporation was observed in the
methyl group of acetophenone. As shown in Table 2, this
exchange could be suppressed by adding 1 equiv. of a mild
inorganic base, of which a number were tested. It can be
seen that sodium carbonate was the most satisfactory
additive, in that it allowed aryl exchange to continue to a
high level, whilst preventing any deuterium incorporation
on the methyl unit. With respect to the other basic additives
employed, the suppression of overall deuterium exchange
by excess pyridine was not surprising, since this will bind
competitively to the metal centre (while addition of more
than 25% of 1,8-bis(dimethylamino)naphthalene com-
pletely suppressed deuterium exchange). Triethylamine
removed all methyl exchange whilst still delivering
relatively good levels of arene labelling.
Altering the nature and number of ligands at a metal centre
can be expected to result in complexes with different
properties, which raises the prospect of altering the
characteristics of the iridium complex in order to optimise
isotopic exchange for any given substrate. In what follows,
we describe our initial attempts to explore the conditions
necessary for maximising exchange, using a series of
complexes 1–3 with a range of simple model substrates.
2. Discussion
2.1. Establishment of initial and optimised experimental
protocols
Before considering ligand effects, it was necessary to
establish robust experimental conditions. The effects of
reaction time, catalyst loading, and of the presence of acid
or base, were therefore examined using the readily available
isolated complex Ir(cod)(PPh3)þ2 .BF42 (1b). The first thing
to note is that variation of substrate/catalyst ratio (Table 1)
has a different effect depending on the substrate. The
process with acetophenone (entry 1) and 2-phenylpyridine
(entry 11), in particular, is unaffected by loading. In
contrast, where the directing group was a p-excessive
heterocycle (entries 8–10), deuteration was efficient with
less than 20% of catalyst, and an increased percentage of
catalyst actually resulted in less exchange. Where a 1:1 ratio
of catalyst to substrate was used, the recovery of such
substrates was generally poor. Having stated all of this, in
most cases deuteration became more efficient as the
catalyst/substrate ratio was increased up to approximately
1:2. This catalyst loading was used in the work that
followed, although just as this 1:2 ratio is by no means the
optimum for all substrates, it may not be ideal for all of the
complexes tested.
If complexation was carried out in the absence of a silver
salt, the resulting species had a different, and generally
poorer, range of activity. It was therefore not practical to
omit silver salts from the complexation step. Additionally
and despite the knowledge that the addition of sodium
carbonate could be advantageous, we felt that the overall
process should not be complicated by the addition of a base.
In this respect, we considered it preferable to filter off
insoluble silver salts from the solution of 1a before addition
of the substrate; this last method was used in all subsequent
work.
The most convenient means found for generation of 1b
in situ involved treatment of readily available bis(1,5-
We had established previously that deuterium exchange
mediated by Crabtree’s catalyst, [Ir(Py)(PCy3)cod]þ.PF62,
was not impeded by the presence of water.4 However, it is
worth noting that where wet silver tetrafluoroborate was
used to promote formation of 1b (and related complexes),
Table 1. Deuteration with different percentages of pre-formed 1b
Entry
Substrate
10%
20%
50%
1 equiv.
1
2
3
4
5
6
7
8
Acetophenone
Benzamide
N,N-Dimethylbenzamide
Benzylamine
N,N-Dimethylbenzylamine
Benzyl alcohol
Acetanilide
1-Phenylpyrazole
4-Phenylthiazol-2-amine
5-Acetyl-3-phenylisoxazole
2-Phenylpyridine
4-Phenylpyrimidine
Phenylpyrazine
1.8
0.1
0.6
0.0
0.4
–
0.2
1.4
1.7
1.9
1.7
0.1
0.0
1.8
0.1
–
–
–
0.4
–
–
0.4
–
–
1.8
0.3
1.4
0.1
0.5
0.3
0.7
1.0
0.3
1.7
1.7
0.1
0.1
1.8
0.4
1.8
0.1
0.3
0.9
0.7
0.7
–
1.0
1.7
0.4
0.6
Table 2. Effect of base upon the deuteration of acetophenone mediated by
1b
Base
Deuterium in arene ring
Deuterium in methyl group
9
None
NaHCO3
Na2CO3
Pyridine
Triethylamine
1.4
1.1
1.6
0.3
1.2
0.2
0.0
0.0
0.1
0.0
10
11
12
13
–
–
Figures quoted are the number of deuterium atoms per molecule of
substrate, as determined by mass spectrometry.
Figures quoted are the number of deuterium atoms per molecule of
substrate, as determined by mass spectrometry.

P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
3351
Table 3. Comparison of NMR and MS data for 3-substituted acetophenones after deuteration mediated by 1b
Acetophenone
Deuteration at C-2
Deuteration at C-6
Deuteration at C-4
Total (from NMR)
Total (from MS)
3-chloro-
3-bromo-
3-nitro-
3-methoxy-
3-methyl-
0.95
0.9
0.9
0.85
0.9
0.95
1.0
0.9
0.85
1.0
–
–
0.75
–
–
1.9
1.9
2.55
1.7
1.9
1.9
1.9
2.6
1.7
2.0
Figures quoted are the number of deuterium atoms incorporated per molecule of substrate.
there was a significant reduction of catalytic activity.
Presumably, hydration reduces the solubility of the silver
salt in dichloromethane. Since silver tetrafluoroborate is
deliquescent, the use of other silver salts was considered.
In this regard, silver hexafluorophosphate could be used in
place of silver tetrafluoroborate, but silver(I) carbonate,
methanesulfonate and trifluoroacetate all proved to be very
poor substitutes.
2.2. Analysis of the levels and rates of labelling
In view of the number of experiments we intended to
perform, it was of interest to compare the means by which
deuterium incorporation was evaluated. Although NMR
spectra were obtained for deuterated products, it was more
convenient, in many cases, to determine the degree of
deuteration simply by comparison of the averaged masses
of key peak clusters in the mass spectra of labelled and
unlabelled substrates. This method gives figures that agree
well with those obtained from NMR spectra of the same
deuterated products, as exemplified in Table 3 for a series of
3-substituted acetophenones.
At this stage it is also worth noting that, in contrast to
isolated complex, solutions of 1b retained the same
activity toward exchange with acetophenone, even after a
week of storage under nitrogen at room temperature
(despite the ruby red colour of the original solution
having faded significantly). The catalyst solution was
therefore suitably robust (and certainly more so than the
isolated complex), which augured well for the preparation
of potentially more sensitive complexes. Nevertheless,
the results presented here were obtained using freshly
prepared catalyst solutions and, where it was necessary
to store solutions, they were kept at 2208C under
nitrogen.
In order to ensure that sufficient time was allowed for
exchange runs to reach equilibrium, the kinetics of the
deuteration of acetophenone mediated by 1b, formed in
situ, were examined (Fig. 1). As observed previously with
[Ir(Py)(PCy3)cod]þ.PF624, there is an induction period of a
few minutes before any exchange is observed, correspond-
ing to the time required for removal of the cyclooctadiene
ligand from a significant proportion of the pre-catalyst (for
Figure 1. Deuterium incorporation into acetophenone, mediated by 1b, as a function of time.
Scheme 2. Partial scheme for exchange without added coordinating ligands.

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P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
Table 4. Deuterium incorporation in the presence of [Ir(cod)2]þ·BF42 (no
additional ligand)
additional coordinating ligand), each substrate was treated
with deuterium in the presence of half an equivalent of
bis(cyclooctadiene)iridium tetrafluoroborate. As shown in
Table 4, where a substrate contains an sp2 nitrogen (entries
10–14) capable of binding to the metal, some exchange is
observed, while the levels of deuterium incorporation
observed with amides are surprisingly high (entries 4 and
5). In these latter cases at least, lower levels of exchange
with phosphine-containing complexes (see Table 1; 50%
catalyst usage) could be interpreted as reflecting inhibition
of the process by phosphine ligands. However, from a
practical viewpoint, the significant drawback of self-
promoted exchange by substrates is that the recovery is
poor. More specifically, while substrate recovery in other
cases is typically better than 75%, the recovery of material
in the absence of added ligands is rarely better than 30%. In
all of these cases, varying quantities of a black precipitate,
assumed to be iridium(0), separated within the first 24 h; it
is therefore not surprising that exchange is observed
principally with substrates that could be expected to bind
efficiently to the metal centre.
Substrate
Deuterium incorporated
1
2
3
4
5
6
7
8
Acetophenone
Phenylacetone
Ethyl benzoate
N,N-Dimethylbenzamide
Acetanilide
Benzenesulfonamide
N-Phenyl-methanesulfonamide
Aniline
Methyl phenyl sulfone
Methyl phenyl sulfoxides
1-Phenylpyrazole
4-Phenylthiazole
5-Acetyl-3-phenylisoxazole
2-Phenylpyridine
Acetophenone O-methyl oxime
Nitrobenzene
0.4
0.0
0.0
1.9
1.7
0.0
0.0
0.9
0.0
0.0
1.2
0.2
1.4
0.2
1.4
0.0
9
10
11
12
13
14
15
16
Figures quoted are the number of deuterium atoms per molecule of
substrate, as determined by mass spectrometry; in all cases, 50% catalyst
loading was used.
example, formation of a mixture of deuterated cyclooctanes
was observed by GC/MS during this time). Subsequent
exchange is rapid, being more so where a greater quantity of
catalyst is used, then slows and reaches an equilibrium level
after 3–4 h.4 It should be noted that, even when using only
10% of catalyst, 1.8 atoms of deuterium per molecule were
eventually incorporated after 48 h. Accordingly, in practice,
deuteration runs were carried out over a period of at least
48 h to allow for the possibility that some complexes might
promote, or that some substrates might undergo, slower
exchange than others.
One implication of the results in Table 4 is that tertiary
amides or N-heterocycles could be suitable ligands for
iridium-mediated deuteration of, at least, some substrates. In
order to test this possibility, the same set of substrates was
exposed to deuterium in the presence of complexes prepared
from [Ir(cod)Cl]2 with one, 2 or 3 equiv. of dimethyl-
acetamide (DMA) or pyridine (Table 5). Once again, a
precipitate of what appeared to be iridium metal was
observed shortly after exposure to deuterium in all cases
(although the precipitate was only slight in the case of the
pyridine complexes). This suggests that the ligating power
of DMA and, to a lesser extent, pyridine is insufficient to
stabilise the reduced complex, with the result that the
iridium–dimethylacetamide complexes, irrespective of
stoichiometry, are essentially inactive as catalysts for
deuterium exchange. Nevertheless, for a few substrates,
amongst which methyl phenyl sulfoxide is the most notable,
the iridium–pyridine complexes were effective catalysts. In
fact, the bis-pyridine complex 1a is the most efficient
mediator found for exchange into methyl phenyl sulfoxide
and benzenesulfonamide. The latter observation is interest-
ing in view of the results obtained with less electron-rich
phosphine complexes (see later). However, the pyridine
2.3. Exploration of the scope and limitations of ligands in
IR-mediated exchange processes
One of the initial points for consideration is that, by
definition, if a substrate undergoes iridium-mediated
hydrogen isotope exchange, it must bind to iridium and
can be considered a ligand. Consequently, it seemed
perfectly possible that exchange might occur even if the
only species bound to the metal centre were the substrate,
solvent, and deuterium (Scheme 2). Therefore, in order to
establish a set of baseline figures (in the absence of any
Table 5. Deuterium-exchange mediated by iridium complexes of DMA and pyridine
Ligand
Dimethylacetamide (mol ligand/mol Irþ)
Pyridine (mol ligand/mol Irþ)
2
1
2
3
1
3
Substrate
N,N-Dimethylbenzamide
Benzenesulfonamide
Methyl phenyl sulfoxide
Acetophenone O-methyl oxime
2-Phenylpyridine
1-Phenylpyrazole
4-Phenylthiazole
Aniline
0.0
0.0
0.0
1.5
0.6
1.0
1.3
0.0
0.1
0.0
0.4
0.0
1.0
0.0
1.2
0.0
0.0
0.0
0.0
0.0
0.0
0.6
1.0
0.4
0.2
0.0
0.0
0.0
0.0
1.6
0.0
0.7
0.3
0.0
1.7
0.0
0.5
1.7
1.8
0.0
0.7
0.3
0.0
0.0
0.5
0.0
0.0
1.3
0.7
1.7
0.0
0.6
1.5
0.0
Acetanilide
Figures quoted are the number of deuterium atoms per molecule of substrate, as determined by mass spectrometry. Acetophenone, ethyl benzoate, and 5-acetyl-
3-phenylisoxazole were not deuterated under any of these conditions.

P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
3353
Table 6. Results from deuterium-exchange mediated by iridium complexes of triphenylphosphine (b) and methyldiphenylphosphine (c)
Complex no.
3b (mol liþgand/
3c (mol liþgand/
1ba (mol lþigand/
1ca (mol ligand/
2b (mol liþgand/
2c (mol liþgand/
mol Ir )
mol Ir )
mol Ir )
mol Irþ)
mol Ir )
mol Ir )
1
2
3
Substrate
Acetophenone
Phenylacetone
Ethyl benzoate
Dimethylbenzamide
Benzenesulfonamide
Methyl phenyl
sulfoxide
1.5
0.3
0.0
1.7
0.1
0.0
1.5
0.9
0.0
1.6 (1.8)
0.0
1.2 (1.2)
1.1 (1.4)
0.1
1.5 (1.8)
0.2
1.1 (1.8)
1.5 (1.5)
0.0
2.0
0.2
0.0
0.2
0.3
0.0
1.7
0.5
0.6
0.8
1.3
0.4
0.4
0.2
0.2
0.3 (0.4)
Acetophenone
O-methyl oxime
2-Phenylpyridine
1-Phenylpyrazole
5-Acetyl-3-phenyl-
isoxazole
1.7
0.8
1.7
1.6
1.7
1.4
1.3
1.0
1.5
0.6
0.6
0.8
1.4 (1.8)
1.0
1.7 (1.7)
0.8 (1.1)
0.7 (0.9)
1.6 (1.8)
0.4
0.9
1.0
0.2
0.5
1.0
4-Phenylthiazole
Acetanilide
1.2
0.4
0.8
2.0
1.7 (1.2)
0.6
1.3 (1.5)
1.6 (1.6)
0.3
0.4
0.6
1.0
Figures quoted are the number of deuterium atoms per molecule of substrate, as determined by mass spectrometry.
a
Figures obtained using pre-formed complex are shown in parentheses.
complexes were of limited value in mediating exchange into
2-phenylpyridine, by comparison with results obtained
previously.5,6
with the involvement of different active intermediates in
each case.
In many cases, the level of exchange achieved approaches
90% of the theoretical maximum (or better). For example,
complete ortho-exchange was observed in the case of
acetophenone, using catalyst 2b and in acetanilide, using
catalyst 3c. Additionally, ethyl benzoate, acetophenone
O-methyl oxime, 2-phenylpyridine, 5-acetyl-3-phenylisoxa-
zole, and acetanilide are all labelled very effectively with
various complex types. On the other hand, benzenesulfon-
amide and methyl phenyl sulfoxide are both exchanged
more efficiently using iridium-pyridine complexes (see
Table 5), while dimethylbenzamide and phenylazoles in
general are exchanged much more efficiently using
[Ir(Py)(PCy3)cod]þ.PF62.4 At this point, why particular
complexes are efficacious in specific cases is unclear.
Nonetheless, use of the in situ catalyst preparation methods
has allowed us to (i) rapidly assess how a series of substrates
perform with iridium–phosphine complexes of varying
stoichiometries, and (ii) move towards choosing the most
effective complex type for a given substrate class.
To date, the majority of iridium complexes reported to
mediate deuterium exchange have borne either two
phosphine ligands, or one phosphine and one pyridine
ligand. However, in view of our earlier findings,6 we were
interested in the possibility that phosphine complexes with
different stoichiometries might have different activities as
pre-catalysts. As has been reported already,6 addition of
4 mol of phosphine ligand per mole of iridium generated a
catalytically inactive complex, but reducing the ratio of
phosphine to iridium to as little as 1:1 still gave an active
exchange catalyst. The results obtained by treatment of a
panel of substrates with complexes formed in situ from
[Ir(cod)Cl]2 with triphenylphosphine and methyldiphenyl-
phosphine are summarised in Table 6; the results from
exchange mediated by the isolated complexes 1b and 1c are
included for comparison. From these results, complexes
containing 1, 2 and 3 M equiv. of phosphine ligand per
iridium do have substantially different properties, consistent
Table 7. Results from deuterium-exchange mediated by iridium complexes of tris(pentafluorophenyl)phosphine (d) and tris(2-furyl)phosphine (e)
Complex
3d (mol liþgand/
3e (mol liþgand/
1d (mol liþgand/
1e (mol liþgand/
2d (mol liþgand/
2e (mol liþgand/
mol Ir )
mol Ir )
mol Ir )
mol Ir )
mol Ir )
mol Ir )
1
2
3
Substrate
Acetophenone
Phenylacetone
Ethyl benzoate
Dimethylbenzamide
Benzenesulfonamide
2-Phenylpyridine
1-Phenylpyrazole
5-Acetyl-3-phenyl-
isoxazole
0.5
1.0
0.0
0.3
0.5
1.5
0.3
0.0
0.5
0.3
0.0
0.8
0.7
0.8
1.1
1.3
0.4
0.0
0.0
0.2
1.1
1.4
1.5
1.7
1.6
0.0
0.0
1.5
0.1
0.6
0.8
1.4
0.7
0.5
0.3
0.3
0.7
0.5
1.2
1.5
0.3
0.0
0.3
0.4
0.9
1.5
1.1
4-Phenylthiazole
Acetanilide
0.3
0.4
1.2
0.3
0.2
0.0
1.2
0.5
1.3
0.8
1.5
1.0
Figures quoted are the number of deuterium atoms per molecule of substrate, as determined by mass spectrometry.

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P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
Table 8. Results from deuterium-exchange mediated by iridium complexes of tricyclohexylphosphine (f) and HMPT (g)
Complex
3f (mol liþgand/
3g (mol liþgand/
1f (mol liþgand/
1g (mol liþgand/
2f (mol liþgand/
2g (mol liþgand/
mol Ir )
mol Ir )
mol Ir )
mol Ir )
mol Ir )
mol Ir )
1
2
3
Substrate
Acetophenone
Phenylacetone
Ethyl benzoate
Dimethylbenzamide
Benzenesulfonamide
2-Phenylpyridine
1-Phenylpyrazole
5-Acetyl-3-phenyl-
isoxazole
1.8
0.0
0.0
1.3
0.5
1.6
1.3
1.4
0.1
0.0
0.0
0.5
0.0
0.7
0.8
1.7
0.0
0.1
0.5
0.6
0.0
0.2
0.7
0.0
0.0
0.1
0.0
0.6
1.3
0.0
0.3
0.0
0.0
0.3
0.0
0.7
0.8
1.3
0.0
0.0
0.0
0.0
0.6
a
–
a
4-Phenylthiazole
Acetanilide
–
1.0
0.5
0.4
0.5
1.2
0.2
0.5
0.3
1.2
0.4
Figures quoted are the number of deuterium atoms per molecule of substrate, as determined by mass spectrometry.
a
Substrate not recovered.
Additionally, from these observations one can envisage how
minor changes to the electronic properties of the phosphines
might also be expected to enable optimisation of exchange
within certain substrates.
even less generally useful complexes. Therefore, for
substrates such as ketones and amides, there appears to be
an optimum range of s-donicity, into which triphenyl-
phosphine and dimethylphenylphosphine both fall.
In an effort to extend the range of usable ligands, we
examined deuterium labelling of a similar range of
substrates with complexes formed using the relatively
electron-poor tris(pentafluorophenyl)phosphine and tris(2-
furyl)phosphine (Table 7), and the more electron-rich
tricyclohexylphosphine and hexamethylphosphorous tria-
mide (HMPT) (Table 8). We also examined the activity
profiles of analogous complexes containing triphenylarsine,
triphenylstibine, and triphenylamine (Table 9). In all cases,
with the exceptions of 1-phenylpyrazole and (in one
example) phenylacetone, complexes with these ligands are
poorer mediators of deuteration than those described above.
Moving down group V, the organic derivatives are expected
to become poorer s-donors, and it appears that, in most
cases, phosphines represent an optimum s-donicity. In view
of the similar poor s-donicity of tri-2-furylphosphine and
tris(pentafluorophenyl)phosphine, it appears that, for the
majority of substrates, poorer s-donor ligands significantly
reduce the efficiency of the complex. On the other hand, the
very electron-rich tricyclohexylphosphine and HMPT form
Beyond the general observations just made, there are some
definite trends in the efficiencies of complexes containing
different phosphines. The exchange of acetophenone
appears comparatively robust and, for complexes 1 at
least, the electronic character of the phosphine seems to
have little general influence upon the degree of exchange.
However, acetophenone is unique in this respect. 2-Phenyl-
pyridine and the phenylazoles appear to be most poorly
deuterated by complexes of the most electron-rich phos-
phines and, in general, phosphine complexes are less
efficient mediators of the deuteration of this group of
substrates than is [Ir(Py)(PCy3)cod]þ.PF62.4 The highest
level of exchange into phenylacetone (albeit only 50% of
the theoretical maximum) is observed using complex 3d. It
may be that a single tris(pentafluorophenyl)phosphine
provides a balance of limited s-donicity as well as limited
steric demand, so that the complex is able to accommodate
a six-membered metallacycle.9 However, much more work
remains to be done in order to develop an efficient system
for exchange in this type of substrate.
Table 9. Results from deuterium-exchange mediated by iridium complexes with triphenylarsine (h), triphenylstibine (i) and triphenylamine (j)
Complex
3h (mol liþgand/
3i (mol liþgand/
1h (mol liþgand/
1i (mol ligand/
mol Irþ)
1j (mol liþgand/
2h (mol liþgand/
2i (mol ligand/
mol Irþ)
mol Ir )
mol Ir )
mol Ir )
mol Ir )
mol Ir )
1
2
3
Substrate
Acetophenone
Phenylacetone
Ethyl benzoate
Dimethylbenzamide
Benzenesulfonamide
2-Phenylpyridine
1-Phenylpyrazole
5-Acetyl-3-phenyl-
isoxazole
1.1
0.0
0.7
1.6
0.6
1.2
0.7
0.8
0.0
0.0
0.0
0.0
0.0
0.0
0.0
1.3
0.2
0.4
1.1
1.2
0.7
0.9
0.6
1.3
0.0
1.4
0.1
0.0
0.5
0.8
0.0
0.0
0.0
0.2
0.0
0.0
0.0
0.0
0.3
0.0
0.0
0.2
0.4
0.2
1.3
0.2
0.6
0.0
0.0
0.2
0.0
0.0
0.0
0.0
4-Phenylthiazolea
Acetanilide
1.2
1.7
0.1
1.1
0.6
0.8
0.2
0.8
0.3
0.0
0.4
0.0
Figures quoted are the number of deuterium atoms per molecule of substrate, as determined by mass spectrometry.
a
10% catalyst.

P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
3355
Deuteration of benzenesulfonamide in the presence of 1d or
1h occurs at a level comparable to that mediated by 2c.
However, all of these are inferior to the bis-pyridine
complex 1a (Table 5, column 5) which, at this point, is the
best lead candidate complex for mediating exchange in
sulfonamides. None of the phosphine complexes were at all
effective in mediating isotopic exchange into methyl phenyl
sulfoxides, although up to 90% ortho-deuteration was
achieved with this substrate with this substrate by use of
1a (Table 5, column 5); 3a (column 4) and 2a (column 6)
also perform well with methyl phenyl sulfoxide. The data at
this point are insufficient to draw any definite conclusion,
but it is possible that this is a consequence of hard/soft
interactions between the complex and substrate. The
nitrogen centre in pyridine is likely to be a harder s-donor
than a phosphine or an arsine, although the absence of
exchange using 1j is unexpected on this basis. Nevertheless,
it would be reasonable to expect binding of the electron-rich
(but very hard) oxygen of a sulfoxide to be promoted by
hard ligands at the metal centre, whereas softer ligands,
even where their s-donicity is poor, may not perform the
same function.
[IrL3(cod)]þ·BF42 in line with previous reports.11,16 Inter-
estingly, 31P NMR of this latter type of species contains only
one signal, with a shift very similar to that for the bound
phosphines in 1b and 1c. The phosphine ligands in 2b and
1
2c are therefore magnetically equivalent. Nevertheless, H
NMR signals due to the phosphine-methyl group in 2c are
split, with only a 3H doublet observed clear of the aliphatic
multiplet. It appears that rotation around Ir–P bonds in this
complex is severely restricted, even by comparison to 2b,
reflecting the very congested nature of the metal centre in
complexes 2 generally.
Complexes 3b and 3c, formed from a 1:1 ratio of phosphine
to iridium, can be formulated nominally as [Ir(cod)L]þ.
1
However, both H and 31P NMR data for 3b suggest the
presence of more than one species in solution, while the
spectra of 3c are more complex still. In the former case,
the multiplets due to the aliphatic protons of the cyclo-
octadiene moiety are very much broadened by comparison
to the corresponding signals in the spectrum of 1b or 2b; 31P
NMR data for 3b are consistent with the presence of two
closely related complexes in a ratio of approximately 9:1.
The more complex situation with 3c is most apparent in the
presence, in the 1H NMR spectrum, of four different signals
due to the phosphine methyl group, with two markedly
2.4. NMR analysis of complexes prepared in situ
2
We considered it important to examine the nature of the
complexes present either as pre-catalysts or as active species
in the exchange process. Complex 1b is well-character-
ised;7,10 1H and 31P NMR spectra of the species formed in
situ are identical to those of the isolated complex, and the
two have comparable activities as exchange catalysts.
The same applies in the case of 1c,10,11 while the 1H
NMR spectra of 1e and that of the known complex 1h12
follow the same pattern. In the case of 1e, however, the
signal due to the vinylic protons of cyclooctadiene is shifted
downfield by ca. 0.6 ppm, relative to the corresponding
signal in 1b. Tri-2-furylphosphine is known to be a strong
p-acceptor,13 and this deshielding of the vinylic protons
reflects a significant reduction in electron density at the
metal centre. There is no such downfield shift of the
different values for JPH. Meanwhile, the 31P NMR
spectrum contains three different resonances in a ratio of
approximately 8:1:1. Nevertheless, 31P NMR shifts for the
ligands in pre-catalysts 3b and 3c are in environments that
are electronically similar to those in the corresponding
complexes 1 and 2. In addition, vinylic resonances in
complexes 3b and 3c are observed around d 4.2 in accord
with expectations.
An additional consideration is that it is possible that, at
the point of preparation, complexes 3b and 3c contain
adventitious water as an additional ligand, and that the
multiplicity of NMR signals reflects the presence of
isomeric hydrates. The similarity of the 31P NMR shifts to
those for complexes 1b–c and 2b–c suggests that the major
species present are monomeric, but we have not character-
ised these species any further. In the presence of a suitable
substrate, it is expected that any of complexes 3 could be
converted into a complex of general form [Ir(PR3)(cod)L]þ,
which would have different catalytic activity from
the complexes discussed already. Indeed, although the
activity of putative pre-catalyst [Ir(MePPh2)(cod)]þ 3c
toward most substrates is poorer than that of 1c, it is
unexpectedly effective in the deuteration of acetanilide, as
mentioned above, and both 2c and 3c are significantly
more effective than 1c in the exchange of benzenesulfon-
amide. In contrast, 3b has an activity profile similar to that
of 1b.
1
corresponding signal in the H NMR spectrum of known
complex 1h; triphenylarsine is expected to be a poorer
s-donor than triphenylphosphine but, considering reported
Ir–As bond lengths,12 it is not expected to be a strong
p-acceptor.
Deshielding (or downfield shifts) of the vinylic protons
in these cases, therefore, appears to be indicative of a
particularly electron-deficient metal centre. In the case of
1d, the vinylic resonances are completely split, with the
furthest downfield signal being observed at d 5.24. Since
tris(pentafluorophenyl)phosphine is again reported not to
have significant p-acceptor character,14 it is possible that
the steric bulk of the ligand (cone angle 1848)15 results in
distortion of the complex with, for example, the Ir–P bond
lengths being different. As a result, the vinylic protons
would be shielded to different extents. In this context, it is
worth noting that tri-tert-butylphosphine (cone angle
Overall, the electronic environment of phosphorus in
cationic complexes 1–3 appears to change very little
whether the complex contains one, two or three bound
phosphines. The phosphines are therefore likely to be in
electronically very similar environments across this range of
complexes, and so it is to be expected that the iridium centre
should become considerably more electron-rich (and by
implication less electrophilic) as the number of phosphine
ligands increases.
1
1828)15 gives a complex (1k) whose H NMR spectrum
indicates no such distortion.
Addition of a third equivalent of phosphine results in
complexes 2 which, from NMR data, can be formulated as

3356
P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
3. Conclusion
appropriate. The extract was evaporated to give crude
deuterated substrate; where readily exchangeable protons
were present, the product was redissolved in methanol
and evaporated, and this last process repeated before
analysis.
The establishment and investigation of methods for the
formation of iridium-based catalysts, and their use to
mediate exchange in situ, has allowed a series of complexes
to be screened rapidly. Consequently, we have identified
potential avenues for improving incorporation into a
number of substrate classes. Moreover, we have found
evidence that the electronic properties and number of
ligands at the metal centre are instrumental in determining
which catalysts are best suited to exchange in any given
substrate. Depending upon the substrate concerned,
hydrogen isotope exchange may be promoted most
efficiently by a pre-catalyst containing 2 or 3 mol of
pyridine, phosphine or arsine ligand per mole of iridium.
Complexes containing a single ligand were of generally
lesser value; although the observation that complex 3c
mediates essentially quantitative exchange into acetanilide
is worthy of further investigation. At this point, tertiary
amine and stibine complexes do not appear to mediate
exchange to any useful extent. Further investigations into
the effect of ligand stereoelectronic properties will be
reported in due course.
Data obtained in the best case with each substrate are
summarised below.
Exchange of acetophenone (2.4 ml, 20 mmol) in the
presence of 2b (10 mmol) gave [2,6-2H2]-acetophenone,
m/z 122 (Mþz), 107 (PhCOþ; average fragment mass 107.06,
vs. 105.08 for unlabelled material).
Exchange of 3-bromoacetophenone (8.5 ml, 64 mmol) in the
presence of 1b (32 mmol) gave [2-2H0.6,6-2H0.9]-3-bromo-
acetophenone (13 mg). dH (270 MHz, CDCl3) 2.58 (3H, s),
7.35 (1H, d, J¼9 Hz, H5), 7.65–7.7 (1.1H, m, H2/4);
m/z(EI) 202, 201, 200, 199 (Mþz), 187, 186, 185, 184
([M2CH3]þ).
Exchange of 3-chloroacetophenone (8.3 ml, 64 mmol) in the
presence of 1b (32 mmol) gave [2-2H0.9,6-2H]-3-chloro-
acetophenone (13 mg). dH (270 MHz, CDCl3) 2.56 (3H, s),
7.37 (1H, d, J¼8 Hz, H5), 7.50 (1H, d, J¼8 Hz, H4), 7.79
(0.05H, d, J¼8 Hz, H6), 7.89 (0.05H, s, H2); m/z(EI) 154,
156 (Mþz), 139, 141 ([M2CH3]þ).
4. Experimental
4.1. General
Exchange of 3-methoxyacetophenone (8.8 ml, 64 mmol) in
the presence of 1b (32 mmol) gave [2,6-2H1.7]-3-methoxy-
acetophenone (7 mg). dH (270 MHz, CDCl3) 2.57 (3H, s),
3.84 (3H, d, s), 7.09 (1H, d, J¼9 Hz, H4), 7.3–7.4 (1H, m,
H5), 7.47 (0.l5H, s, H2), 7.52 (0.15H, d, J¼7.5 Hz, H6);
m/z(EI) 152, 151 (Mþz), 147, 146 ([M2CH3]þ).
Gas chromatography was performed using a Hewlett–
Packard chromatograph (HP 5890) fitted with a mass-
selective detector (HP 5972MSD) on a capillary column
(HP1, 30 m£0.25 mm; 0.25 mm layer); the injector tem-
perature was 2508C and the oven temperature was
increased, after an initial 2 min delay, either from an initial
70 to 2008C at 58C/min, or from an initial 100 to 2408C at
108C/min. 1H NMR spectra were recorded using Jeol
GSX-270 and Bruker 500 instruments; all spectra reported
were recorded of solutions in deuterochloroform. Bis(1,5-
cyclooctadiene)diiridium(I) dichloride was obtained from
Strem and Fluka; 1c was obtained from Aldrich Chemicals,
and 1b was prepared according to the published procedure.7
Substrates were obtained commercially, or were prepared as
described previously.4 Key spectrometric data which
permitted the determination of deuteration levels have
been reported already.4
Exchange of 3-methylacetophenone (7.1 ml, 64 mmol) in
the presence of 1b (32 mmol) gave [2-2H0.9,6-2H]-3-
methylacetophenone (7 mg). dH (270 MHz, CDCl3) 2.39
(3H, s), 2.56 (3H, s), 7.3–7.4 (2H, m), 7.75 (0.lH, s, H2);
m/z(EI) 136, 135 (Mþz), 121, 120 ([M2CH3]þ).
Exchange of 3-nitroacetophenone (9.0 mg, 64 mmol) in the
presence of 1b (32 mmol) gave [2-2H0.9,6-2H]-3-methyl-
acetophenone (9 mg). dH (270 MHz, CDCl3) 2.68 (3H, s),
7.67 (1H, m, H5), 8.27 (0.05H, d, J¼7 Hz, H6), 8.41 (0.25H,
d, J¼9 Hz, H4), 8.77 (0.1H, s, H2); m/z(EI) 165 (Mþz), 150
([M2CH3]þ).
4.1.1. Typical exchange procedure. Bis(1,5-cycloocta-
diene)diiridium(I) dichloride (67 mg, 0.1 mmol) was
weighed into a 25 ml flask. To this was added the phosphine
(0.2/0.4/0.6 mmol), followed by silver tetrafluoroborate
(39–43 mg, 0.20–0.22 mmol). DCM (10 ml) was added, a
nitrogen atmosphere was established, and the mixture was
stirred for 20–30 min, giving a dark brown/black suspen-
sion. This solution was filtered through Celite and the pad
was washed through with DCM until the filtrates became
clear. The filtrate was made up to a total of 20 ml with
DCM, to give a 10 mmol/ml solution of the iridium
complex. This solution (1 ml/20 mmol) was added to the
substrate; the system was degassed and flushed with
deuterium, then sealed and stirred, typically for 48–72 h.
After this time volatiles were evaporated and the residue
was extracted with ether or ethyl acetate (5 ml) as
Exchange of phenylacetone (7.2 ml, 50 mmol) in the
presence of 2b (25 mmol) gave [2,6-2H0.5]-phenylacetone
(6 mg) as a colourless oil. dH (CDCl3) 2.14 (3H, s), 3.69
(2H, s), 7.19 (1.5H, br d, J¼7.0 Hz, H2/6), 7.25–7.28 (1H,
m, H4), 7.30–7.36 (2H, m, H3/5). m/z 135, 134 (Mþz), 92,
91 (100%).
Exchange of ethyl benzoate (3.0 ml, 20 mmol) in the
presence of 2b (isolated complex; 9.1 mg, 10 mmol) gave
[benzoic acid-2,6-2H1.8]-ethyl benzoate, m/z 152, 151
(Mþz), 107, 106 (PhCOþ; average fragment mass 106.89,
vs 105.08 for unlabelled material).
Exchange ofN,N-dimethylbenzamide(12 mg,80 mmol)inthe
presence of bis(cyclooctadiene)iridium(I) tetrafluoroborate

P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
3357
(28 mg, 40 mmol) gave [2,6-2H1.9]-N,N-dimethylbenzamide
(2 mg), dH (500 MHz, 708C, CD3SOCD3) 2.94 (6H, s),
7.36–7.39 (2H, m), 7.40–7.43 (1.1H, m); m/z 152, 151, 150,
149 (Mþz/[M2H]þ), 107, 106 (PhCOþ; average fragment
mass 106.99, vs 105.08 for unlabelled material).
deuterochloroform (0.5 ml) containing bis(1,5-cycloocta-
diene)diiridium(I) dichloride (6.5 mg, 10 mmol) and tri-
phenylphosphine (5.3 mg, 20 mmol) was stirred for
20 min, then filtered through Celite. The filter cake was
washed through with a little additional deuterochloro-
form, and the yellow filtrate was transferred to an NMR
tube. dH (CDCl3) 1.9–2.0 (4H, m), 2.2–2.6 (4H, m), 4.19
(4H, br s), 7.3–7.75 (15H, m); dP (CDCl3) 18.55, 20.51 (ca.
9:1).
Exchange of benzenesulfonamide (12 mg, 76 mmol) in the
presence of 1a (40 mmol) gave [2,6-2H1.7]-benzenesulfona-
mide (8 mg). dH (500 MHz, 708C, CD3SOCD3) 7.28–7.34
(3H, m, H4/NH2), 7.53–7.60 (2H, m, H3/5), 7.82 (0.3H, br
d, J¼8.0 Hz, H2/6); m/z 157 (Mþz), 77 (C6H5þ).
This general technique, with appropriate changes in ligand
stoichiometry, was also used to prepare: Ir(cod)(MePPh2)þ.
BF24 (3c) as a yellow solution. dH (CDCl3) 1.70 (1H, d,
J¼6.2 Hz, P–CH3), 1.8–2.5 (8H, m), 2.00 (0.5H, d, J¼
6.2 Hz, P–CH3), 2.06 (1H, d, J¼12.5 Hz, P–CH3), 2.37
(0.5H, d, J¼12.5 Hz, P–CH3), 3.46 (2H, br s), 4.23 (2H, br
s), 7.15–7.75 (10H, m); dP (CDCl3) 3.07, 37.37, 51.93 (ca.
8:1:1).
Exchange of methyl phenyl sulfoxide (6 mg, 43 mmol) in
the presence of 1a (20 mmol) gave [2,6-2H1.8]-methyl
phenyl sulfoxide. dH (500 MHz, 708C, CD3SOCD3) 3.70
(3H, s), 7.45–7.53 (3H, m), 7.63 (0.2H, br d, J¼7.3 Hz); m/z
142, 141 (Mþz), 127, 126 ([M2CH3]þ).
Exchange of acetophenone O-methyl oxime (12 mg,
80 mmol) in the presence of 1b, (40 mmol) gave
[2,6-2H1.7]-acetophenone O-methyl oxime (10 mg). dH
(270 MHz, CDCl3) 2.25 (3H, s), 4.01 (3H, s), 7.35–7.40
(3H, m, H3/4/5), 7.60–7.70 (0.3H, m, H2/6); m/z 151, 150
(Mþz).
Ir(cod)(PPh3)2þ.BF42 (1b) as a ruby red solution.8,9 dH
(CDCl3) 1.55–2.12 (4H, m), 2.30–2.54 (4H, m), 4.19 (4H,
br s), 7.25–7.70 (30H, m); dP (CDCl3) 18.58.
Ir(cod)(MePPh2)2þ.BF42 (1c) as a ruby red solution.9,10 dH
(CDCl3) 1.70 (6H, d, J¼6.2 Hz, P–CH3), 1.95–2.05 (4H,
m), 2.25–2.35 (4H, m), 4.21 (4H, br s), 7.30–7.60 (20H,
m); dP (CDCl3) 3.05.
Exchange of 2-phenylpyridine (3.1 mg, 20 mmol) in the
presence of 2b (isolated complex; 9.1 mg, 10 mmol)
gave [2,6-2H1.8]-2-phenylpyridine (3 mg). dH (500 MHz,
CD3SOCD3) 7.34 (1H, ddd, J¼7.4, 4.9, 1.2 Hz, H5), 7.42
(1H, m, H40), 7.46–7.50 (2H, m, H30/50), 7.86 (1H, ddd, J¼
8.0, 7.4, 1.8 Hz, H4), 7.94 (1H, d0dd, J¼8.0, 1.2, 1.1 Hz,
H3), 8.07 (0.2H, d, J¼8.0 Hz, H20/6 ), 8.66 (1H, ddd, J¼4.9,
1.8, 0.9 Hz, H6); m/z(EI) 157, 156 (Mþz), 129, 128
([M2HCN]þ).
Ir(cod)[P(C6F5)3]2þ.BF42 (1d) as a ruby red solution. dH
(CDCl3) 1.86 (4H, m), 2.34 (4H, m), 3.48 (1H, m), 3.74 (1H,
m), 4.03 (1H, br s), 5.24 (1H, m).
Ir(cod)(P-2-furyl3)2þ.BF42 (1e) as a ruby red solution. dH
(CDCl3) 1.56–1.67 (4H, m), 2.28–2.37 (4H, m), 4.81 (4H,
br s), 6.47–6.49 (6H, m), 6.69–6.71 (6H, m), 7.59 (6H, br
s).
Exchange of 1-phenylpyrazole (5.6 mg, 40 mmol) in the
presence of 1d (20 mmol) gave [2,6-2H1.5]-1-phenylpyra-
zole (4 mg). dH (500 MHz, CD3SOCD3) 6.53 (1H, dd,
J¼2.3, 2.0 Hz, H4), 7.29 (1H, m, H40), 7.46–7.51 (2H, m,
H30/50), 7.73 (1H, dd, J¼2.0, 0.6 Hz, H5), 7.83 (0.5H, br d,
J¼8.6 Hz, H20/60), 8.47 (1H, dd, J¼2.3, 0.6 Hz, H3); m/z
146, 145, 144 (Mþz), 118, 117, 116 ([M2HCN]þ).
Ir(cod)[P(c-C6H11)3]2þ.BF42 (1f) as a ruby red solution. dH
(CDCl3) 1.10–2.05 (66H, m), 2.10–2.30 (4H, m), 4.24 (2H,
br s), 4.80–4.85 (2H, m).
Ir(cod)(AsPh3)2þ.BF42 (1h) as a ruby red solution.11 dH
(CDCl3) 1.50–1.90 (4H, m), 2.15–2.45 (4H, m), 3.55 (2H,
br s), 4.36 (2H, br s), 7.25–7.35 (12H, m), 7.35–7.50 (18H,
m).
Exchange of 5-acetyl-3-phenylisoxazole (3.7 mg, 20 mmol)
in the presence of 1c (10 mmol) gave [2,6-2H1.8]-5-acetyl-3-
phenylisoxazole, m/z 189, 188, 187 (Mþz), 146, 145, 144
([M2CH3CO]þ; average fragment mass 94.98, vs 144.16
for unlabelled material).
Ir(cod)(P-t-Bu3)2þ.BF42 (1k) as a ruby red solution. dH
(CDCl3) 1.46 (54H, s), 1.60–1.64 (4H, m), 2.20–2.30 (4H,
m), 4.25 (4H, br s).
Exchange of 4-phenylthiazole (3.2 mg, 20 mmol) in the
presence of 1b (10 mmol) gave [2,6-2H1.7]-4-phenylthia-
zole, m/z 163, 162 (Mþz; average molecular ion mass
162.87, vs. 161.19 for unlabelled material), 136, 135
(average fragment ion mass 135.85, vs 134.17 for unlabelled
material).
Ir(cod)(PPh3)þ3 .BF42 (2b) as a ruby red solution. dH (CDCl3)
1.90–1.95 (4H, m), 2.3–2.4 (4H, m), 4.03 (2H, br s), 4.19
(2H, br s), 7.25–7.70 (45H, m); dP (CDCl3) 18.56.
Ir(cod)(MePPh2)þ3 .BF42 (2c) as a ruby red solution. dH
(CDCl3) 1.71 (3H, d, J¼6.2 Hz), 1.60–2.50 (14H, m), 4.22
(4H, br s), 7.20–7.60 (30H, m); dP (CDCl3) 3.04.
Exchange of acetanilide (2.7 mg, 20 mmol) in the presence
of 3c (10 mmol) gave [2,6-2H2]-acetanilide, m/z 137 (Mþz),
95 (PhNHþ2 z; average fragment ion mass 94.98, vs 92.99 for
unlabelled material).
Acknowledgements
4.1.2. NMR experiment. Preparation of Ir(cod)(PPh3)1.
BF24 (3b). A suspension of silver tetrafluoroborate (5 mg) in
The authors wish to thank Dr S. J. Byard for NMR spectra.

3358
P. W. C. Cross et al. / Tetrahedron 59 (2003) 3349–3358
7. Ashworth, T. V.; Ashworth, V.; Singleton, J. E.; de Waal, D. J.
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