Meta-substituent effects on organoiridium-catalyzed ortho-hydrogen isotope exchange

Article abstract of DOI:10.1002/jlcr.1588

Reports in the literature appear to differ on the effects of some C3 substituents on the relative efficiencies of isotope exchange in the nonidentical C2- and C6-positions catalyzed by organoiridium complexes. Controlled experiments were conducted using a

Full text of DOI:10.1002/jlcr.1588

Research Article
Received 13 November 2008,
Revised 13 January 2009,
Accepted 20 January 2009
Published online 23 March 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1588
Meta-substituent effects on organoiridium-
catalyzed ortho-hydrogen isotope exchange
Ã
J. Richard Heys, and Charles S. Elmore
Reports in the literature appear to differ on the effects of some C3 substituents on the relative efficiencies of isotope
exchange in the nonidentical C2- and C6-positions catalyzed by organoiridium complexes. Controlled experiments were
conducted using a set of model substrates in attempts to clarify these effects. The results clearly showed that, in common
with most previous findings, alkyl substituents at C3 reduced the rate of isotope incorporation into C2 relative to C6, as
expected on steric grounds. In contrast, all substituents possessing electron lone pairs resulted in a lessening of the
inhibition of C2-vs-C6 labeling or promoted C2 labeling to such a degree that it became faster than that at C6. NMR
measurements on equimolar mixtures of active iridium complex with selected substrates revealed that the ratios of C2- and
C6-iridacycles present in solution correlated with the relative rates of ortho-deuteration in the rate studies. The results of
the two studies, taken together, suggest that conventional explanations for the origin of the positive meta-effect may not
be adequate for the present system. An alternative hypothesis is advanced.
Keywords: Ir-catalyzed ortho-hydrogen exchange; deuteration; directing effect
substituents at C3 are labeled to a greater extent at C2 than at
C6, but others7 indicate greater labeling at C6, while yet others8
Introduction
Heteroatom-directed intramolecular aryl C–H activation (ortho-
metallation) by transition metal complexes has been widely
investigated in organometallic chemistry, developed for new
selective C–C bond-forming reactions in synthetic chemistry,
and applied to hydrogen isotope labeling. For the last, the
report of the Crabtree group that the hydrogens of the methyl
group of 8-methylquinoline and the N3-methyl group of
caffeine are rapidly exchanged with deuterium gas in the
suggest a lack of discrimination between C2 and C6 labeling in
such substrates.
As the abovementioned isotope labeling studies differed from
one another in their objectives, experimental designs and in the
ways the data were interpreted, the reasons for the differing
conclusions are obscure. Our objective was to clarify the issue by
investigating the effects of a range of meta (C3)-substituents on
the exchange of the nonequivalent ortho-positions (C2 and C6)
in a selected set of substrates, under conditions where
confounding variables were excluded to the extent practicable.
Two experimental protocols were used: One was designed to
permit direct measurement of the relative rates of C2 and C6
deuteration in substrates with different substituents at C3; the
other was to permit observation of the relative amounts of the
two isomeric iridacycle intermediates that are obligatory
intermediates in the isotope exchange at C2 and C6, respec-
tively.
1
presence of [Ir(H)2(acetone)2(PPh3)2]BF4 inspired us2,3 and
others4 to investigate this and related iridium complexes for
their ability to catalyze regioselective isotopic exchange labeling
of compounds from deuterium or tritium gas sources. Since
then, a variety of complexes have been found to be effective in
different compound types, and organoiridium-catalyzed
heteroatom-directed hydrogen isotope exchange (HDE) has
become a commonly used method for the preparation of a wide
variety of tritium- and deuterium-labeled compounds, especially
for use as tracers in the life sciences.5
In aromatic compounds, this labeling method introduces
isotopic hydrogen into positions ortho to the directing group,
probably via an iridacyclic intermediate formed by coordination
of the iridium center with the directing group and oxidative
addition to the ortho C–H bond.6 In meta-substituted substrates,
the two ortho-positions are nonequivalent, and literature reports
of the labeling of such compounds are not entirely in agreement
as to the influence of these substituents on labeling. Although
all reports are consistent in showing that meta-substituents of
the alkyl and aryl types are associated with lower or no labeling
at C2 relative to C6, results reported for compounds whose
meta-substituents possess electron lone pairs are not. Some
reports2,6 indicate that compounds possessing alkoxyl and halo
Results
In the first series of experiments, we determined the deuterium
content of C2 and C6 in each substrate at various time points
during deuteration reactions by mixing the substrate and a
catalytic amount (0.2–5%) iridium complex in an NMR tube,
purging the solution for a few seconds with deuterium gas, then
Isotope Chemistry, CNS Chemistry, AstraZeneca Pharmaceuticals LP, Wilmington,
DE 19350, USA
*Correspondence to: J. Richard Heys, PO Box 576, Litchfield, CT 06759, USA.
E-mail: rheys@optonline.net
J. Label Compd. Radiopharm 2009, 52 189–200
Copyright r 2009 John Wiley & Sons, Ltd.

J. R. Heys and C. S. Elmore
1
measuring the diminution of the H NMR signals of C2 and C6
The results are collected below in a set of graphs in which the
extent of deuteration at C2 is plotted against the degree of
deuteration at C6 at the same time point. In this way of presenting
the data, identical rates of labeling C2 and C6 would give points
along a straight line with slope = 1 (diagonal black line, added for
reference). Faster labeling at C2 gives data points beneath the
diagonal, and faster labeling at C6 above it. Curves were fitted to
each substrate’s data points using origin to calculate a curve using
the non-linear best fit method. The farther a curve deviates from
the diagonal and toward the corners, the greater the difference
in the rate of exchange at the two sites. Thus, this mode of
presentation gives a clear qualitative view of the results. The
experimental procedure allows measurements of the progress of
exchange in real time, and removes the effects of variables such as
overall reaction rates, interexperimental differences in catalyst
loading or quantity of deuterium gas and any confounding effects
caused by ancillary sources of exchangeable hydrogen.
These graphs are immediately informative in several ways:
First, it is clear that in all three series, substrates with meta-
CH3 and -CF3 undergo exchange at C2 much slower than at C6,
and CF3 has a stronger effect than CH3. This behavior is
consistent with expectations based on steric factors alone.
Examination of the slopes of the curves from both substituents
at early reaction stages shows that the rate of C6 deuteration is
at least an order of magnitude faster than C2 deuteration.
with time. As dichloromethane is the solvent of choice for such
HDE reactions, we used CD2Cl2 as the solvent in most
experiments in order to facilitate the NMR measurements.
It has already been shown that, at least over the reaction times
used here, hydrogen/deuterium from this solvent is not
exchanged.1,2 In cases where the NMR signals of interest
were not resolved in CD2Cl2, reactions were run in CH2Cl2 and
aliquots were withdrawn for NMR analysis (usually in CDCl3 or
D6-DMSO). The complexes used in our study were the two most
commonly used for HDE: [(cod)IrI(PPh3)2]BF4 (1) and
[(cod)IrI(PCy3)(py)]PF6 (2); they are reduced rapidly in situ by
deuterium gas to produce the active catalyst forms [Ir-
III(D)
2S2(PPh3)2]BF4 and [IrIII(D)2S2(PCy3)(py)]PF6, respectively
(S = loosely bound ligand such as solvent, substrate or
adventitious water). Three substrate classes, typical of those
commonly used as model substrates for HDE, were used:
acetophenones, N,N-dimethylbenzamides and acetanilides. The
meta-substituents included F, Cl, Br, I, CH3 (or for acetophenone
3,4-dimethyl), CF3, OCH3, OH (for acetophenone and acetanilide)
and OCF3 (acetophenone only). In most cases, results from
multiple experiments with the same substrate–catalyst combi-
nation were combined in order to give an adequate number of
data points, as the rapid rate of exchange often permitted the
acquisition of only a limited number of NMR measurements on a
single sample.
3-Halo-acetophenones
3-Halo-dimethylbenzamides
1.0
1.0
O
zero
Br
aceFluroride
1to1ratio
AceChloride
0.8
AceBromide
O
NMe2
Fluoride
Bromide
Chloride
Iodide
0.8
0.6
0.4
0.2
0.0
AceIodide
O
I
I
0.6
Dichloride
NMe2
O
NMe2
NMe2
0.4
Cl
O
O
Cl
F
Br
O
NMe2
0.2
0.0
O
O
F
Cl
Cl
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
C-2 deuterium incorporation
C-2 Deuterium incorporation
1to1ratio
Fluoride
Chloride
Bromide
Iodide
Ac 3-Halo-acetamides
HN
1.0
0.8
0.6
0.4
0.2
I
Ac
HN
Cl
Ac
HN
Br
Ac
HN
F
0.0
0.0
0.2
0.4
0.6
0.8
1.0
C-2 Deuterium Incorporation
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Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 189–200

J. R. Heys and C. S. Elmore
Acetophenones
Dimethylbenzamides
O
1.0
0.8
0.6
0.4
0.2
0.0
1.0
CF3
NMe2
NMe2
O
O
O
O
CH3
CH3
0.8
0.6
0.4
0.2
0.0
OCF3
CH3
CF3
NMe2
O
O
OH
OMe
1to1ratio
Methoxy
Methyl
Trifluoromethyl
O
OMe
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
C-2 Deuterium Incorporation
C-2 Deuterium Incorporation
Acetamides
1.0
Ac
HN
Ac
HN
CH3
0.8
0.6
0.4
0.2
0.0
CF3
Ac
HN
Ac
HN
OH
OMe
1to1ratio
hydroxy
Methoxy
Methyl
Trifluoromethyl
0.0
0.2
0.4
0.6
0.8
1.0
C-2 Deuterium Incorporation
Second, within each class of substrate, those with meta-
In the second set of experiments, the fully deuterated
substituents possessing electron lone pairs either undergo precursor complex [(cod)IrfPðC6D5Þ3g2]BF4 (3) was used in order
labeling at C2 faster than at C6, or the labeling at C2 is less to permit unencumbered observation of the substrate-derived
retarded relative to that at C6 compared with those substituted 1H NMR signals in the aromatic region. Reaction mixtures
with CH3 and CF3. This suggests the influence of a meta-effect consisting of 1:1 molar ratios of complex 3 and 3-fluoro-,
opposing the steric effect.
3-trifluoromethoxy-, 3-chloro- or 3-trifluoromethylacetophenone
Third, the positive effects of meta-substituents effects are were stirred briefly under hydrogen gas to convert 3 into the
most pronounced in the acetophenone series, less so in the active complex [Ir(H)2S2fP(C6D5)3g2]BF4. 1H and 19F NMR
dimethylbenzamide series and weakest in the acetanilide series. analyses of reaction mixtures at this point showed only the
Fourth, the rank order of substituent effects is similar for all signals of the intact meta-substituted acetophenone in the
three substrate classes. Their potency in facilitating C2 exchange aromatic region. That is, the substrate was present as free
increases in the order IoBroOCH3 (OCF3)ECloOHEF. Where compound or only coordinated to iridium at the carbonyl
tested, OCF3 is only slightly less potent than OCH3. The effects of oxygen; all four ring-C–H signals were present and integrated as
OH and F substituents are so strong that, as indicated by the 1.0H in the spectra. The reaction mixtures were then briefly
slopes of the curves at early reaction stages, the rates of C2 purged with nitrogen to remove H2 and then heated at 801C
deuteration are faster than those at C6 by at least an order of under a nitrogen atmosphere for 12 h. 1H and 19F NMR analyses
magnitude in the acetophenone and dimethylbenzamide series, of the crude reaction mixtures at this stage showed the
and by a factor of at least five in the acetanilide series.
presence of new signals, along with those of varying amounts
Data points acquired in comparable experiments with of remaining intact meta-substituted acetophenone. In each
[(cod)Ir(PPh3)2]BF4 (1) or [(cod)Ir(PCy3)(py)]PF6 (2) and acetophenone case, complete assignments were made of the new NMR signals
substrates possessing Cl, Br, I, OCH3 and CF3 fall nearly along the through the use of proton–proton couplings, Heteronuclear
same curves: the two curves for 3-bromo-, 3-iodo- and Multiple Quantum Coherence (HMQC) experiments and by
3-trifluoromethylacetophenone were indistinguishable from one comparison with the chemical shifts reported for the parent
another; those for 3-chloroacetophenone suggested that the effect acetophenone iridacycle prepared by a similar method recently
with catalyst 2 was slightly greater than that with catalyst 1, but those reported.9 This allowed unambiguous identification of two
for 3-methoxyacetophenone were just the reverse. Therefore, data iridacycles for each substrate, one fused to the acetophenone
obtained with both catalysts are combined in the respective graphs. ring at C2 and the other at C6. A small peak at 7.5 ppm grew in
J. Label Compd. Radiopharm 2009, 52 189–200
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

J. R. Heys and C. S. Elmore
slowly with increasing reaction times but did not hinder data
evaluation; this peak is attributed to slow exchange of H into the
ortho-positions of the deuterated phosphine phenyl rings. The
relative quantities of isomeric iridacycles obtained in these
reactions are given in Table 1. These ratios of isomeric
iridacycles correlate with the relative rates of C2-vs-C6 deutera-
tion found for the same substrates in the first set of experiments.
Reexposure of solutions of these iridacycle mixtures to
hydrogen and stirring for 10–90 min at room temperature (rt)
converted them entirely, within the limits of NMR detection,
back to the intact meta-substituted acetophenone form(s) (see
also Reference 5).
Discussion
The competing pathways to deuterium labeling at C2 and C6
can be depicted as shown in Figure 1. First, the carbonyl oxygen
of the directing function (acetyl, dimethylaminocarbonyl or
benzoyl) of the substrate (4) coordinates to the iridium center
(step 1) to form intermediate 5. Then, iridium oxidatively adds to
the C2–H or the C6–H bond, cleaving it to form either an ZO2 ;C2
metallacycle (6a) or an ZO2 ;C6 metallacycle (6b). Subsequent
ligand isomerization around the Ir(III) center rotates the C2- or
C6-derived H out of the orientation cis to the Ir–C bond and
replaces it with a D (7a,b). Finally, reductive elimination of
iridium forms a C2–D or a C6–D bond, thence eventually free
deuterium-labeled substrate [2-2H]4 or [6-2H]4. Except for the
presence of the isotope, steps 4a and 4b are the same in reverse
as 2a and 2b, respectively, and decoordination steps 5a and 5b
are the same in reverse as the first step.
Table 1. Ratio of Iridacycles formed with metasubstituted
acetophenones
m-X-acetophenone
Ratio of C2/C6 iridacycles
The findings here of the retardation of C2 labeling in
substrates with C3-methyl and -trifluoromethyl substituents
are consistent with a large number of published observations,
both in HDE and in related organometallic reactions, and are
generally agreed to occur because the steric bulk of these
Fluoro
5:1
Trifluoromethoxy
Chloro
Trifluoromethyl
1.3:1
1.6:1
1:410
R
O
4
= direct bond
or -NH-
X
+ [IrLm]+
1
Path b
Path a
+
R
O
IrLm
2a
2b
+
R
O
+
R
O
X
IrLn
H
IrLn
H
5
X
6a
X
6b
3a
3b
+
+
R
O
R
O
7b
IrLn
IrLn
D
7a
D
X
X
+
+
R
O
R
O
IrLm
IrLm
4a
4b
D
D
X
X
[2-2H]5
[6-2H]5
- [IrLm]+
- [IrLm]+
5b
5a
R
O
R
O
D
D
[2-2H]4
[6-2H]4
X
X
Figure 1. Proposed mechanistic routes leading to 2- and 6- deuterated products
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Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 189–200

J. R. Heys and C. S. Elmore
substituents increases the congestion that occurs with the step is the carbon–carbon bond formation between the olefin
approach of the iridium center to the C2–H bond, thereby and the aryl ring,11 and cyclometallation is fast. Therefore, if it is
raising the activation energy of the metallacyclization. In the true that electronic interaction between ruthenium and the
present system this diverts the labeling process from Path a to meta-substituent facilitates substitution at C2, it must do so
Path b of Figure 1 to give mainly C6-labeled product. Our data either by lowering the activation energy for the Calkyl–C2aryl
further show that the C3 halo and oxygen-containing sub- bond-formation step (relative to Calkyl–C6aryl bond formation) or
stituents exert an opposite effect, partially or entirely offsetting by providing thermodynamic stabilization of the Z2O;C2 ruthena-
the steric effect and toward Path a, and in some cases cycle (7) (relative to the Z2O;C6 ruthenacycle, 6) in a rapid
overriding it to make Path a predominant.
Positive meta-substituent effects such as these have been
preequilibrium.
The Orito group12 revealed that some coordinating meta-
observed in a few other systems but have not been thoroughly functions exert moderate positive effects in the palladium-
investigated mechanistically.10 A further example that is some- catalyzed carbonylation–cyclization of N-substituted benzyla-
what related to the present HDE system is the Murai mines and phenethylamines (Pd(OAc)2, Cu(OAc)2, CO; Figure 3).
chemistry,11 in which silylolefins add to aromatic ketone The 3,4-methylenedioxy substituent was the most effective and
substrates to give exclusively ortho-(silyl)alkyl products. This is the only substituent that gave predominately C2 products. This
illustrated in Figure 2 for a typical reaction between acetophe- positive effect was stronger in the phenethylamine case
none and triethoxysilylethene catalyzed by RuH2(CO)(PPh3)3. (Y = –CH2CH2–, where the palladacyclic intermediate is a six-
Most meta-substituents tested give addition only at C6, in membered ring) than in the benzylamine case (Y = –CH2–; five-
accordance with expected effect of the higher steric congestion membered palladacycle); this is the reverse of our findings,
around C2. However, 3-fluoroacetophenone is preferentially where the positive meta-effects in the acetanilide series (six-
alkylated at C2 (77:3 vs C6) and so is 3-methoxyacetophenone membered iridacycles) are weaker than in the other two series
(83:10). No other halo derivatives were reported on. The (five-membered iridacycles). The explanation offered by the
rationale tentatively advanced was that this phenomenon Orito group is that chelation occurs between the C3-oxygen of
results from (undefined) electronic interactions between ruthe- 3,4-methylenedioxy group and the palladium(II) center during
nium and the lone pair of electrons on the methoxy oxygen or the transition state of the metallacycle ring closure at C2 (i.e.
the fluorine atom. In the Murai chemistry the rate-determining 8-9). The fact that the 3-methoxy group of the 3,4-dimethoxy
Me
O
Me
O
Me
O
X
X
X
C6 Product
C2 Product
Ru
Ru
Ru
Me
6
H
Si(OEt)3
O
Si(OEt)3
Me
Me
O
Me
O
O
Ru
Ru
Ru
H
X
X
X
Si(OEt)3
7
Si(OEt)3
X = F, OCH3
Figure 2. Murai ortho-substitution of 3-substituted acetophenones catalyzed by RuH2(CO)(PPh3)3
Y
Y
H
Y
NHR
NHR
NHR
PdLn
PdLn
O
O
O
O
H
O
O
8
9
Y = -CH2- or -CH2CH2-
Y
Y
Y
NHR
NR
NHR
PdLn
PdLn
O
O
O
O
O
O
O
O
O
10
Figure 3. Meta effect on the palladiumcatalyzed carbonylation-cyclization of N-substituted benzylamines and phenethylamines with Pd(OAc)2, Cu(OAc)2, and CO
J. Label Compd. Radiopharm 2009, 52 189–200
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

J. R. Heys and C. S. Elmore
analog was not as effective in this role was attributed to its (labeled as 5a,b-labeled as 4a,b) is very unlikely to be the rate-
greater steric demand relative to methylenedioxy. However, in a determining step as it is rapid and reversible. The ligand
separate set of experiments with the dimethoxy substrate, the isomerization step (6a,6b-7a,7b) is also unlikely to be rate-
rank order of C2/C6 product ratios obtained by varying the determining, as such rearrangements have been shown16 to
added ligand was in the order PPh34Cu(OAc)24none. This have low activation energies (o5 kcal/mol). Our second set of
trend is the reverse of that predicted by the explanation based experiments shows that the metallacycle forms (6a,b and 7a,b)
on steric congestion. As no mechanistic analysis was presented are thermodynamically less stable than the ring-opened forms
for the overall transformation, the meta-effect in the Orito (5). This conclusion comes from the fact that in the presence of
system may in reality be expressed in a different way or in H2 the ring-opened forms predominate, and only upon removal
another step. One possibility would be by assisting the of hydrogen and heating do the ring-closed forms predominate
migratory insertion of the carbonyl (electronic interaction (Figure 5; see also Reference5). Therefore, it is likely that the ring
indicated by the dotted line in structure 10).
closure (5a-6a and 5b-6b in Figure 1) is rate-determining,
Recent reports that are highly relevant to our mechanistic and is the step through which the influence of meta-
speculations, but that highlight a more fundamental problem, substituents is exerted on the relative rates of C2 and C6
are the selective ortho C–H activation of haloarenes and anisole deuteration. Once the 6a,b structures are reached, either they
by an iridium(I) complex.13 In this chemistry, complex 11 reacts revert to 5a,b or proceed rapidly to isotopically labeled
directly with the substrates to give the aryl hydrido complexes products.
12 (Figure 4).
How do OH, OCH3, OCF3, F, Cl, Br and I functions at C3
After 1-h reaction times, mixtures of ortho-, meta- and para- facilitate the iridacyclization of 5 to 6? No conventional
halo or -methoxy complexes are observed, and after 24–48 h, explanations seem to be able to account for our findings. If
most of the mixtures equilibrate toward the ortho isomer, whose the effect involves coordination of the substituent lone electron
substituent is coordinated to the iridium center (13). Table 2 pairs to the iridium center during iridacyclization, the order of
summarizes the Milstein results.
potency should be very different from that observed, as
These results clearly establish that the Kinetically preferred discussed above. If it instead involves an inductive influence
products are determined by the coordinative affinity of the of the substituent, OCF3 and CF3 would be expected to produce
iridium center with the aryl substituent. The order of affinity is C2/C6 deuteration ratios greater than OCH3 and CH3, respec-
OCH34Br4Cl4F. This trend is in agreement with the earlier tively, but the opposite is found. Nor does an examination of
reported stability of ortho-haloaryl ligands of iridium complexes.14 mesomeric forms provide a credible explanation.
It is also consistent with predictions, based on C-halogen bond
An alternative and novel possibility is that the influence of the
polarizabilities and s-donor capacity, that the order of decreasing coordinating meta-substituents might be exerted through
coordinative avidity toward a low-valent, late transition metal intermediary atoms. Likely candidates for such a role are water
center such as Ir(I) should be I4Br4Cl4F.15
and (isotopic) dihydrogen. Water (small amounts of which are
This is the opposite of the order of the power of halogens to always present adventitiously) is known to be a ligand in
facilitate C2-deuterium exchange in our studies, a serious organoiridium complexes such as these.17 The Crabtree group
problem for the hypothesis that direct coordination between has reported18 on new types of intramolecular hydrogen bonds
meta-substituents and the iridium center can explain the in iridium complexes and associated hydrogen transfers invol-
positive meta-effects of these substituents.
ving such intermediaries, i.e. Irdþ ꢀ ꢀ ꢀ Hdꢁ ꢀ ꢀ ꢀ Hdþ ꢀ ꢀ ꢀ Xdꢁ, where X
The rate-determining step in our HDE sequence can be is N or O. Either water or (isotopic) dihydrogen could play such a
proposed with some degree of confidence. Initial coordination role in our system, as illustrated in Figure 6. Supporting these
of substrates’ directing atoms to iridium (4-5 in Figure 1) is possibilities for indirect electronic interaction is the fact that
common to both Paths a and b, and the decoordination H ꢀ ꢀ ꢀhalogen bond strengths increase in the order IoBroCloF.
t-Bu2
t-Bu2
t-Bu2
P
P
P
X
H
H
N Ir
N
Ir
+
N Ir
X
X
P
P
t-Bu2
P
t-Bu2
t-Bu2
12
13
11
Figure 4. Insertion of Ir-complex 13 into Aryl C-H bond
Table 2.
+
+
R
X
O
R
O
1 h
24–48 h
Ir(nH)2SL2
- nH2
+ nH2
IrnHSL2
nH
Ortho
Meta
Para
Ortho
Meta
Para
OCH3
Br
Cl
28
7
4.6
2
ꢂ1
2
2
ꢂ1
1
1
All
All
All
1.8
—
—
—
—
—
—
—
1
X
n = 1,2
6a,b;7a,b
[2/6-nH]5
F
2
1
Figure 5. Proposed rate determining step in the HDE reaction
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Copyright r 2009 John Wiley & Sons, Ltd.
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J. R. Heys and C. S. Elmore
H3C
H3C
residue. To the bulk material was added 0.206 mg (0.256mmol) of
Crabtree’s catalyst and the solution purged with D2 for approx.
15s. The vial was capped and gently rocked back and forth 5
times. After standing for 15min, 0.5 mL was removed, concen-
trated to near dryness and a 1H NMR was acquired on the residue.
This procedure was repeated with additions of 0.412 mg
O
O
O
H3C
Ln
Y
Ln
Y
Ln
Y
Ir
H
Ir
Ir
H
H
H
H
X
H
X
X
1
(0.512mmol) and 0.825 mg (1.024mmol) of Crabtree’s catalyst. H
Y = H or O-H
X = F, Cl, Br, I, OH, OCH3, OCF3
NMR (500MHz, D6-DMSO) d ppm 2.01 (s, 3H), 6.41 (dd, J = 7.9,
1.8 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H),
7.17(s, 1H), 9.73 (br. s., 1H), 9.27 (br. s., 1H).
Figure 6. Proposed hydrogen bonding effect leading to a preference of ortho
exchange in some substrates.
Run A
3
Run B
3
This is the only parameter that trends in the same direction as
the observed effects of the substituents.
ppm
1
2
4
5
1
2
4
5
H-2 7.17 0.88 0.57 0.38 0.24 0.26 1.0 0.81 0.55 0.33 0.21
H-6 6.91 1.0 0.94 0.74 0.6 0.32 1.0 1.0 0.97 0.86 0.60
Experimental
General: N-(3-methylphenyl)acetamide, N-(3-trifluoromethylphenyl)-
acetamide, N-(3-chlorophenyl)acetamide, N-(3-methoxyphenyl)aceta-
mide, N-(3-bromophenyl)acetamide and N-(3-iodophenyl)acetamide
were prepared in one step from the corresponding anilines.
[(cod)Ir(PCy3)(py)]PF6 (Crabtree’s catalyst) was obtained from
Strem Chemical Company. [(cod)IrI(PPh3)2]BF4 was prepared from
[(cod)IrICl]2 by treatment with PPh3 as reported by Singleton.19
Dichloromethane was obtained from Fisher Scientific and was used
directly in reactions. Deuterium gas (ultrahigh purity, 99.95% D2) was
obtained from GT&S gas. The aromatic proton chemical shifts were
assigned using a combination of NOESY and COSY. 1H NMR spectra
were recorded on an Avance 500 spectrometer and were referenced
to residual solvent peak (7.26 for CDCl3, 5.32 for CH2Cl2, 2.49 for D6-
DMSO and 7.20 for D6-benzene). 19F NMR were recorded on an
Avance 500 spectrometer and were referenced externally to CFCl3
(0 ppm).
N-(3-fluorophenyl)acetamide: A total of 11.96 mg (0.0781mmol)
of N-(3-fluorophenyl)acetamide in 6 mL of CH2Cl2 was treated as
described in method B with 0.206, 0.206, 1.24 and 1.24mg of
Crabtree’s catalyst for run A and with 0.206, 0.412, 0.825, 1.65 and
2.27mg of Crabtree’s catalyst for run B. 1H NMR (500MHz,
D6-DMSO) d ppm 2.05 (s, 3H), 6.84 (dt, J = 1.8, 8.2 Hz, 1H), 7.26 (d,
J = 7.9 Hz, 1H), 7.31 (dt, J = 8.2, 6.7 Hz, 1H), 7.58 (d, J = 11.9Hz, 1H),
10.10 (br. s., 1H).
Run A
Run B
3
ppm
0
1
2
3
4
5
1
2
4
5
H-2 7.58 1.00 0.97 0.90 0.82 0.67 0.35 0.96 0.88 0.68 0.56 0.26
H-6 7.26 1.00 1.00 0.97 0.97 0.93 0.80 1.01 1.01 0.90 0.85 0.65
Method A: N, N-dimethyl 3-fluorobenzamide: To a solution of
1.01 mg (6.0 mmol) of N, N-dimethyl 3-fluorobenzamide in 1 mL of
CD2Cl2 in an NMR tube was added 16 mg (0.020 mmol) of Crabtree’s
catalyst in 20 mL of CD2Cl2. The solution was gently purged with D2
for approx. 10 s, and the NMR tube capped. The tube was rocked
back and forth 5 times and the 1H NMR was taken immediately. A
solution of 33 mg of Crabtree’s catalyst in 40mL of CD2Cl2 was
added to the NMR tube and the solution purged with D2 for
approx. 10 s. The NMR tube was rocked gently back and forth and
the 1H NMR taken immediately. Additional aliquots of 50 and
67 mg in 60 and 80 mL of CD2Cl2, respectively, were added and the
procedure repeated. For run B, 2.70mg (16.3mmol) of N, N-
dimethyl 3-fluorobenzamide was treated as described above with
four aliquots of Crabtree’s catalyst (0.640, 1.4, 1.0 and 6.7mg). 1H
NMR (500 MHz, CD2Cl2) d ppm 2.97 (br. s., 3H), 3.09 (br. s., 3H), 7.12
(m, 2H), 7.19 (d, J= 7.6 Hz, 1H), 7.37 (td, J= 7.9, 5.6Hz, 1H).
N-(3-methylphenyl)acetamide: A total of 9.84 mg (0.066 mmol) of
N-(3-methylphenyl)acetamide in 6 mL of CH2Cl2 was treated as
described in method B with 0.197, 0.295, 0.590 and 0.982 mg of
Crabtree’s catalyst for run A and 0.532, 1.064, 2.128, 4.256 and
15.623 mg of Crabtree’s catalyst for run B. H NMR (500 MHz, D6-
DMSO) dppm 2.02 (s, 3H), 2.26 (s, 3H), 6.83 (d, J= 7.6 Hz, 1H), 7.15 (t,
J= 7.8 Hz, 1H), 7.35 (d, J=7.9Hz, 1H), 7.40 (s, 1H), 9.79 (br. s., 1H).
1
Run A
Run B
ppm
0
1
2
3
4
5
1
2
3
4
5
6
H-2 7.40 1.00 1.03 1.03 1.04 1.03 1.03 0.99 1.02 1.06 1.09 1.06 0.72
H-6 7.35 1.00 0.95 0.94 0.85 0.72 0.55 0.86 0.72 0.60 0.32 0.14 0.10
N-(3-trifluoromethylphenyl)acetamide: A total of 11.003 mg
(0.054 mmol) of N-(3-trifluoromethylphenyl)acetamide in 6 mL
of CH2Cl2 was treated as described in method B with 0.197,
0.295, 0.295, 0.590 and 0.982 mg of Crabtree’s catalyst for run A
and 0.532, 1.064, 2.128, 4.256 and 10.3 mg of Crabtree’s catalyst
Run A
Run B
ppm
1
2
3
4
1
2
3
4
1
for run B. H NMR (500 MHz, D6-DMSO) d ppm 2.08 (s, 3H), 7.37
(d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H),
8.07 (s, 1H), 10.23 (br. s., 1H).
H-2
H-6
7.12
7.19
0.93
0.99
0.84
0.96
0.6
0.93
0.27
0.88
0.58
0.96
0.18
0.84
0.03
0.83
0
0.1
Method B: N-(3-hydroxyphenyl)acetamide: A solution of 8.74mg
(57.8 mmol) of N-(3-hydroxyphenyl)acetamide and 0.206 mg
(0.256mmol) of Crabtree’s catalyst in 9 mL of CH2Cl2 was purged
with D2 for approx. 15s and the vial was capped and rocked back
and forth 5 times. After standing for 15min, 0.5 mL was removed,
concentrated to near dryness and a 1H NMR was acquired on the
Run A
3
Run B
3
ppm
1
2
4
5
1
2
4
5
H-2 8.07 0.98 0.99 1.00 1.01 1.03 1.00 1.01 1.03 1.03 1.03
H-6 7.76 0.98 0.93 0.85 0.76 0.65 0.89 0.76 0.57 0.32 0.10
J. Label Compd. Radiopharm 2009, 52 189–200
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

J. R. Heys and C. S. Elmore
N-(3-chlorophenyl)acetamide: A total of 10.05 mg (0.059 mmol) Crabtree’s catalyst for run A and five 0.862 mg additions of
1
of N-(3-chlorophenyl)acetamide in 6 mL of CH2Cl2 was treated as Crabtree’s catalyst for run B. H NMR (500MHz, DMSO-d6)d ppm
described in method B with 0.197, 0.295, 0.590 and 0.982 mg of 2.88 (br. s., 3H), 2.96 (br. s., 3H), 7.24 (t, J = 7.8 Hz, 1H), 7.41
Crabtree’s catalyst for run A and 0.532, 1.064, 2.128 and 4.256 mg (d, J = 7.6 Hz, 1H ), 7.73 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H).
of Crabtree’s catalyst for run B. 1H NMR (500MHz, D6-DMSO)
d ppm 2.05 (s, 3H), 7.07 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H),
7.41 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 10.08 (br. s., 1H).
Run A
Run B
ppm
1
2
3
4
5
6
1
2
3
4
5
Run A
3
Run B
H-2 7.73 0.91 0.86 0.82 0.76 0.66 0.48 0.8 0.53 0.42 0.20 0.16
H-6 7.41 1.0 0.98 0.92 0.85 0.77 0.59 0.89 0.61 0.43 0.30 0.24
ppm
1
2
4
5
1
2
3
4
5
H-2 7.80 0.98 0.98 0.98 0.96 0.90 1.00 0.98 0.96 0.88 0.43
H-6 7.41 0.94 0.92 0.86 0.79 0.65 0.89 0.78 0.70 0.41 0.23
N, N-dimethyl 3-trifluoromethylbenzamide: A total of 11.05 mg
(50.9 mmol) of N, N-dimethyl 3-trifluoromethylbenzamide in 6 mL
of CH2Cl2 was treated as described in method B with 0.090, 0.18,
N-(3-methoxyphenyl)acetamide: A total of 8.35 mg (0.051 mmol) of 0.18, 0.54, 0.90 and 0.90 mg of Crabtree’s catalyst for run A and
N-(3-methoxyphenyl)acetamide in 6 mL of CH2Cl2 was treated as des- 0.045, 0.090, 0.090, 0.18, 0.18 and 1.8 mg of Crabtree’s catalyst
1
cribed in method B with 0.197, 0.298, 0.590 and 0.982 mg of Crab- for run B. H NMR (500 MHz, CDCl3) d ppm 2.98 (br. s., 3H), 3.13
tree’s catalyst for run A and 0.197, 1.064, 1.064, 2.128 and 4.312 mg of (br. s., 3H), 7.54 (t, J = 7.8 Hz, 1H), 7.61(d, J = 7.8 Hz, 1H), 7.67
1
Crabtree’s catalyst for run B. H NMR (500 MHz, D6-DMSO) dppm (d, J = 8.2 Hz, 1H), 7.69 (s, 1H).
2.03 (s, 3H), 3.72 (s, 3H), 6.60 (dd, J=8.2, 1.8Hz, 1H), 7.10 (d, J=8.2Hz,
1H ), 7.18 (t, J=8.1Hz, 1H), 7.28 (s, 1H), 9.86 (br. s., 1H).
Run A
Run B
3
ppm
1
2
3
4
5
6
1
2
4
5
6
Run A
3
Run B
H-2 7.69 1.00 1.00 1.00 1.00 1.00 0.96 1.00 1.00 1.00 1.00 1.00 0.89
H-6 7.61 0.99 0.96 0.86 0.75 0.61 0.18 0.99 0.98 0.96 0.89 0.67 0.20
ppm
1
2
4
5
1
2
3
4
5
6
H-2 7.28 0.98 0.98 0.98 0.96 0.85 0.99 0.98 0.93 0.89 0.79 0.35
H-6 7.10 0.97 0.87 0.84 0.68 0.37 0.96 0.79 0.62 0.49 0.33 0.09
N, N-dimethyl 3-methylbenzamide:
A total of 7.10 mg
(43.5 mmol) of N, N-dimethyl 3-methylbenzamide in 6 mL of
CH2Cl2 was treated as described in method B with four aliquots
of 0.433 mg of Crabtree’s catalyst for run A and three aliquots of
N-(3-bromophenyl)acetamide:
A total of 7.7 mg of N-(3-
bromophenyl)acetamide in 6 mL of CH2Cl2 was treated as
described in method B with 0.187, 0.374, 0.748, 1.496, 1.87
1
and 2.9 mg of Crabtree’s catalyst. H NMR (500 MHz, D6-DMSO)
d ppm 2.05 (s, 3H), 7.23 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 8.1 Hz, 1H),
7.45 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 10.06 (br. s., 1H).
1
0.862 mg and one of 1.72 mg of Crabtree’s catalyst for run B. H
NMR (500 MHz, CDCl3) d ppm 2.33 (s, 3H), 2.89 (br. s., 3H), 2.96
(br. s., 3H), 7.16 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 7.24 (d, J = 7.3 Hz,
1H), 7.31 (t, J = 7.6 Hz, 1H).
Run A
Run B
Run A
Run B
ppm
1
2
3
4
5
6
1
2
3
4
ppm
1
2
3
4
5
6
1
2
3
4
5
6
H-2 7.19 0.99 0.98 0.97 0.95 0.88 0.76 0.98 0.84 0.74 0.50
H-6 7.16 0.98 0.91 0.89 0.83 0.70 0.48 0.94 0.55 0.46 0.27
H-2 7.93 0.96 0.96 0.98 0.95 0.88 0.33 0.99 0.98 0.96 0.95 0.94 0.76
H-6 7.45 0.98 0.95 0.84 0.64 0.32 0.13 0.99 0.95 0.85 0.70 0.46 0.23
N, N-dimethyl 3-methoxybenzamide: A total of 1.703 mg
N-(3-iodophenyl)acetamide: A total of 8.30 mg (31.7 mmol) of (9.5 mmol) of N, N-dimethyl 3-methoxybenzamide in 0.75 mL of
N-(3-iodophenyl)acetamide in 6 mL of CH2Cl2 was treated as CD2Cl2 was treated as described in method B with 0.108, 0.138,
described in method B with 0.187, 0.374, 0.748, 1.496, 1.87 and 0.110, 0.087 and 0.119 mg of Crabtree’s catalyst for run A and
5.2 mg (10.1 mg for run B) of Crabtree’s catalyst. 1H NMR 2.188 mg (12.2 mmol) of N, N-dimethyl 3-methoxylbenzamide
(500 MHz, D6-DMSO) d ppm 2.03 (s, 3H), 7.09 (t, J = 7.9 Hz, 1H), with 0.250, 0.375, 0.500, 0.750 and 1.0 mg of Crabtree’s catalyst.
7.38 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 8.08 (s, 1H), 9.98 1H NMR (500 MHz, D6-DMSO) d ppm 2.89 (br. s., 3H), 2.98 (br. s.,
(br. s., 1H).
3H), 3.77 (s, 3H), 6.92 (d, J = 2.1 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H),
6.96 (dd, J = 8.2, 2.4 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H).
Run A
Run B
Run A
Run B
ppm
1
2
3
4
5
6
1
2
3
4
5
6
ppm
1
2
3
4
5
1
2
3
4
5
H-2 8.08 0.99 0.98 0.99 1.00 1.02 0.79 0.98 0.98 1.00 1.01 0.99 0.82
H-6 7.49 0.94 0.84 0.65 0.81 0.32 0.19 0.97 0.85 0.69 0.53 0.33 0.27
H-2 6.92 0.87 0.92 0.74 0.68 0.46 0.84 0.66 0.41 0.25 0.09
H-6 6.93 1.0 0.97 0.84 0.71 0.64 0.90 0.75 0.57 0.33 0.13
N, N-dimethyl 3-bromobenzamide: A total of 2.23 mg (9.8 mmol)
of N, N-dimethyl 3-bromobenzamide and 0.826 mg (3.5 mmol) of
2, 6-di-t-butylmethoxyphenol in 0.75 mL of CD2Cl2 were treated
N, N-dimethyl 3-iodobenzamide: A total of 10.95 mg (39.8 mmol)
of N, N-dimethyl 3-iodobenzamide in 6 mL of CH2Cl2 was treated
as described in method B with five 0.433 mg additions of
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 189–200

J. R. Heys and C. S. Elmore
as described in method A with 0.517, 0.471 and 0.953 mg of
Crabtree’s catalyst for run A and 2.26 mg (9.9 mmol) of N, N-
dimethyl 3-bromobenzamide and 0.971 mg (4.1 mmol)of 2, 6-di-
t-butylmethoxyphenol with 0.423, 0.517, 0.634 and 1.52 mg of
Crabtree’s catalyst. 1H NMR (500 MHz, CD2Cl2) d ppm 2.97 (br. s.,
3H), 3.09 (br. s., 3H), 7.33 (d, J = 7.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H),
7.58 (s, 1H), 7.59 (d, J = 7.4 Hz, 1H).
Run A
Run B
3
ppm
1
2
3
4
5
6
1
2
4
5
H-2 7.73 0.91 0.86 0.82 0.76 0.66 0.48 0.8 0.53 0.42 0.20 0.16
H-6 7.41 1.0 0.98 0.92 0.85 0.77 0.59 0.89 0.61 0.43 0.30 0.24
1-(3-Fluorophenyl)ethanone: A total of 0.954 mg (6.9 mmol) of
1-(3-fluorophenyl)ethanone in 0.6 mL of CD2Cl2 was treated as
described in method
A with four aliquots of 0.116 mg
Run A
2
Run B
(0.145 mmol) of Crabtree’s catalyst for run A and 1.13 mg
(8.2 mmol) of 1-(3-fluorophenyl)ethanone with two aliquots of
0.044 mg of Crabtree’s catalyst. 1H NMR (500 MHz, CD2Cl2) d ppm
2.49 (s, 3H), 7.20 (td, J = 8.4, 1.8 Hz, 1H), 7.39 (td, J = 8.0, 5.6 Hz,
1H), 7.54 (ddd, J = 9.5, 1.7, 2.3 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H).
ppm
1
3
1
2
3
4
H-2
H-6
7.58
7.35
0.60
0.78
0.24
0.38
0.20
0.29
0.35
0.57
0.19
0.37
0.10
0.30
0.11
0.28
(the peak at 6.77 from the phenol was used as an internal standard for
integration).
Run A
Run B
N, N-dimethyl 3, 4-dichlorobenzamide: A total of 1.985 mg
(9.1 mmol) of N, N-dimethyl 3, 4-dichlorobenzamide in 0.75 mL of
CD2Cl2 was treated as described in method B with 0.320, 0.573
and 0.797 mg of Crabtree’s catalyst for run A and 6.471 mg
(29.6 mmol) of N, N-dimethyl 3, 4-dichlorobenzamide with five
aliquots of 0.514 mg of Crabtree’s catalyst. 1H NMR (500 MHz,
CD2Cl2) d ppm 2.98 (br. s., 3H), 3.08 (br. s., 3H), 7.30 (dd, J = 8.2,
1.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H).
ppm
1
2
3
4
1
2
H-2
H-6
7.54
7.66
0.57
1.0
0.40
1.0
0.16
0.88
0.18
1.0
0.25
0.75
0.07
0.24
1-(3-Hydroxyphenyl)ethanone: A total of 1.51 mg (12.0 mmol) of
1-(3-hydroxyhenyl)ethanone in 0.6 mL of CD2Cl2 was treated as
described in method A with three aliquots of 0.014 mg
(0.017 mmol) of Crabtree’s catalyst for run A and 1.51 mg
(12.0 mmol) of 1-(3-hydroxyphenyl)ethanone with three aliquots
of 0.029 mg (0.036 mmol) of Crabtree’s catalyst. 1H NMR
(500 MHz, CD2Cl2) d ppm 2.47 (s, 3H), 6.97 (dd, J = 7.9, 1.8 Hz,
1H), 7.27 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 1.5 Hz, 1H), 7.43 (d,
J = 7.6 Hz, 1H).
Run A
2
Run B
ppm
1
3
1
2
3
4
5
6
H-2 7.55
H-6 7.30
0.85
0.99
0.46
0.76
0.05
0.30
0.69
0.76
0.48
0.58
0.27
0.44
0.24
0.38
0.12
0.28
0
0.13
(the peak at 6.77 from the phenol was used as an internal standard for
integration).
Run A
2
Run B
2
ppm
1
3
1
3
N, N-dimethyl 3-chlorobenzamide:
A total of 6.258 mg
H-2
H-6
7.32
7.43
0.89
1.0
0.82
1.0
0.67
0.96
0.79
1.0
0.72
1.0
0.15
0.47
(34.0 mmol) of N, N-dimethyl 3-chlorobenzamide in 5 mL of
CH2Cl2 was treated as described in method B with five aliquots
of 0.771 mg (0.96 mmol) of Crabtree’s catalyst in 120 mL of CH2Cl2
for run A and 6.258 mg (34.0 mmol) of N, N-dimethyl 3-
chlorobenzamide with five aliquots of 1.543 mg (1.9 mmol) of
Crabtree’s catalyst in 240 mL of CH2Cl2. H NMR (500 MHz, C6D6)
d ppm 2.14 (br. s., 3H), 2.67 (br. s., 3H), 6.72 (t, J = 7.8 Hz, 1H), 7.01
(d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H).
1-(3, 4-Dimethylphenyl)ethanone: A total of 12.27 mg (82.3 mmol)
of 1-(3, 4-dimethylphenyl)ethanone in 6 mL of CH2Cl2 was treated
as described in method B with 0.086, 0.173, 0.173, 0.173, 0.173
and 0.173 mg (2.1mmol) of Crabtree’s catalyst for run A and
11.41 mg (7.70 mmol) of 1-(3, 4-dimethylphenyl phenyl)ethanone
with 0.086, 0.173, 0.173, 0.173, 0.173 and 0.173 mg (2.1mmol ) of
Crabtree’s catalyst. 1H NMR (500MHz, DMSO-d6) d ppm 2.29
(s, 6H), 2.53 (s, 3H), 7.28 (d, J = 7.9 Hz, 1H), 7.68 (dd, J = 7.8, 1.7 Hz,
1H), 7.73 (s, 1H).
1
Run A
3
Run B
3
ppm
1
2
4
5
1
2
4
5
H-2 7.28 0.87 0.84 0.74 0.55 0.32 0.81 0.43 0.20 0.13 0.11
H-6 7.04 0.98 0.96 0.86 0.72 0.56 0.96 0.64 0.36 0.28 0.29
Run A
Run B
ppm
1
2
3
4
5
6
1
2
3
4
5
6
N, N-dimethyl 3-iodobenzamide:
A
total of 10.95 mg
H-2 7.73 0.97 0.98 0.94 0.89 0.81 0.66 0.98 0.92 0.94 0.87 0.71 0.39
H-6 7.68 0.94 0.90 0.7 0.55 0.39 0.25 0.89 0.80 0.68 0.57 0.29 0.08
(39.8 mmol) of N, N-dimethyl 3-iodobenzamide in 6 mL of CH2Cl2
was treated as described in method B with five aliquots of
0.433 mg (0.54 mmol) of Crabtree’s catalyst for run A and
10.95 mg (39.8 mmol) of N, N-dimethyl 3-iodomethylbenzamide
1-(3-Chlorophenyl)ethanone: A total of 10.8mg (69.9 mmol) of
with four aliquots of 0.862 mg of Crabtree’s catalyst. 1H NMR 1-(3-chlorophenyl)ethanone in 6 mL of CH2Cl2 was treated as
(500 MHz, DMSO-d6) d ppm 2.88 (br. s., 3H), 2.96 (br. s., 3H), 7.24 described in method B with six aliquots of 0.208 mg (0.25 mmol) of
(t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.80 (d, Crabtree’s catalyst for run A and 10.8mg (69.9 mmol) of 1-(3-
J = 7.9 Hz, 1H).
chlorophenyl)ethanone with five aliquots of 0.104 mg (0.13mmol)
J. Label Compd. Radiopharm 2009, 52 189–200
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

J. R. Heys and C. S. Elmore
of Crabtree’s catalyst. 1H NMR (500MHz, CDCl3) d ppm 2.59 (s, 3H), (0.13 mmol) of Crabtree’s catalyst for run A and 13.8 mg (67.6 mmol)
7.41 (t, J = 7.9 Hz, 1H), 7.53 (dd, J = 7.5, 1.7 Hz, 1H), 7.83 (d, of 1-(3-trifluromethoxyphenyl)ethanone with five aliquots of
J = 7.9 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H).
0.208 mg (0.26 mmol) of Crabtree’s catalyst. 1H NMR (500 MHz,
CDCl3) dppm 2.61 (s, 3H), 7.42 (dd, J= 8.2, 1.2 Hz, 1H), 7.51 (t,
J= 7.9 Hz, 1H), 7.80 (s, 1H), 7.88 (d, J=7.6Hz, 1H).
Run A
Run B
3
ppm
1
2
3
4
5
6
1
2
4
5
Run A
Run B
3
H-2 7.92 0.93 0.86 0.74 0.61 0.49 0.29 0.99 0.96 0.91 0.84 0.72
H-6 7.83 0.98 0.96 0.92 0.82 0.71 0.56 1.0 0.99 1.0 0.99 0.92
ppm
1
2
3
4
5
6
1
2
4
5
H-2 7.80 0.95 0.93 0.87 0.82 0.53 0.44 0.90 0.86 0.76 0.64 0.30
H-6 7.88 0.97 0.94 0.92 0.87 0.66 0.57 0.92 0.90 0.84 0.73 0.42
1-(3-Bromophenyl)ethanone: A total of 12.3 mg (61.8 mmol) of
1-(3-bromophenyl)ethanone in 6 mL of CH2Cl2 was treated as
described in method B with five aliquots of 0.102 mg (13 mmol)
of Crabtree’s catalyst for run A and 12.3 mg (61.8 mmol) of 1-(3-
bromophenyl)ethanone with five aliquots of 0.203 mg (25 mmol)
of Crabtree’s catalyst. H NMR (500 MHz, CDCl3) d ppm 2.59 (s,
3H), 7.35 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.87 (d,
J = 7.9 Hz, 1H), 8.08 (t, J = 1.7 Hz, 1H).
1-(3-Methoxyphenyl)ethanone: A total of 8.87 mg (59.0 mmol) of
1-(3-methoxyphenyl)ethanone in 6 mL of CH2Cl2 was treated as
described in method B with five aliquots of 0.102 mg (0.13 mmol)
of Crabtree’s catalyst for run A and 8.87 mg (59.0 mmol) of 1-(3-
methoxyphenyl)ethanone with five aliquots of 0.204 mg
(0.25 mmol) of Crabtree’s catalyst. 1H NMR (500 MHz, CDCl3)
d ppm 2.59 (s, 3H), 3.85 (s, 3H), 7.11 (dd, J = 8.2, 1.8 Hz, 1H), 7.36
(t, J = 8.0 Hz, 1H), 7.48 (m, 1H), 7.53 (d, J = 7.9 Hz, 1H).
1
Run A
3
Run B
3
ppm
1
2
4
5
1
2
4
5
Run A
3
Run B
3
H-2 8.08 0.93 0.90 0.84 0.76 0.56 0.85 0.79 0.70 0.58 0.45
H-6 7.87 0.97 0.9 0.76 0.97 1.0 0.86 0.75 0.62
ppm
1
2
4
5
1
2
4
5
1
1
H-2 7.48 0.95 0.93 0.78 0.64 0.42 0.83 0.74 0.64 0.50 0.36
H-6 7.53 0.98 0.94 0.87 0.76 0.65 0.91 0.85 0.77 0.63 0.51
1-(3-Iodophenyl)ethanone: A total of 15.5 mg (63.1 mmol) of 1-
(3-iodophenyl)ethanone in 6 mL of CH2Cl2 was treated as
described in method B with six aliquots of 0.207 mg (26 mmol)
of Crabtree’s catalyst for run A and 15.5 mg (63.1 mmol) of 1-(3-
iodophenyl)ethanone with six aliquots of 0.414 mg (0.51 mmol)
of Crabtree’s catalyst. H NMR (500 MHz, CDCl3) d ppm 2.58 (s,
3H), 7.21 (t, J = 7.8, 1.7 Hz, H), 7. 87(dt, J = 7.8, 1.7 Hz, 1H), 7.90 (dt,
J = 7.4, 1.7 Hz, 1H), 8.28 (t, J = 1.7 Hz, 1H).
[(cod)IrfP(C6D5)3g2]BF4 (3) was prepared according to the
procedure of Haines and Singleton.19 A suspension of 750 mg
(1.12 mmol) of [(cod)IrCl]2 in 32 mL of EtOH was stirred at rt and
1 g (3.61 mmol) of tri(phenyl-d5)phosphine was added. The
solids gradually went into solution. The reaction mixture was
stirred overnight. A yellow precipitate was removed by filtration.
A filtered solution of 766 mg (7.31 mmol) of ammonium
tetrafluoroborate in 40 mL of EtOH was added. The flask was
purged with N2 and then stored at ꢁ201C for 2 days. A red solid
was collected by filtration, which gave 428 mg (42%) after drying
overnight under high vacuum.
1
Run A
Run B
ppm
1
2
3
4
5
6
1
2
3
4
5
6
H-2 8.28 0.93 0.80 0.67 0.65 0.58 0.49 0.92 0.85 0.80 0.72 0.64 0.53
H-6 7.90 0.90 0.83 0.65 0.65 0.62 0.53 0.92 0.87 0.80 0.73 0.67 0.55
Reaction of [(cod)IrfP(C6D5)3g2]BF4 with (3-chlorophenyl)etha-
none: A solution of 5.8 mg (6.1 mmol) of 3 and 0.93 mg
(6.0 mmol) of (3-chlorophenyl)ethanone in 0.5 mL of D6-acetone
was prepared in an NMR tube. H2 was bubbled through the
solution for 1 min and the tube was then capped and parafilmed
1-(3-Trifluomethylphenyl)ethanone:
A
total of 8.89 mg
(47.2 mmol) of 1-(3-trifuoromethylphenyl)ethanone in 6 mL of
CH2Cl2 was treated as described in method B with five aliquots
of 0.327 mg (0.41 mmol) of Crabtree’s catalyst for run A and
8.89 mg (47.2 mmol) of 1-(3-trifluromethylphenyl)ethanone with
five aliquots of 0.656 mg (0.82 mmol) of Crabtree’s catalyst. 1H
NMR (500 MHz, CDCl3) d ppm 2.65 (s, 3H), 7.61 (t, J = 7.8 Hz, 1H),
7.82 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H).
1
1
and heated at 801C for 20 min and the H NMR was taken. H
NMR (500 MHz, D6-acetone) d ppm 7.55 (t, J = 7.8 Hz, 1H), 7.65 (d,
J = 7.0 Hz, 1H), 7.95 (m, 2H). The cap was then removed and the
tube attached to an N2 bubbler for 12 h. The 1H NMR was again
1
taken. H NMR (500 MHz, D6-acetone) d ppm 6.69 (d, J = 7.9 Hz,
0.44H), 6.85 (t, J = 7.3 Hz, 0.73H), 6.93 (d, J = 7.6 Hz, 0.65H), 7.09 (s,
0.32H), 7.16 (d, J = 8.5 Hz, 0.35H), 7.19 (d, J = 7.6 Hz, 0.64H), 7.36
(m, 0.81H), 7.55 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.69 (d,
J = 11.6 Hz, 0.30H), 7.95 (m, 1.3H). H2 was again bubbled through
the NMR tube and the tube capped and sealed with parafilm.
After 30 min the NMR was acquired again. 1H NMR (500, D6-
acetone) d ppm 7.52 (m, 0.6H), 7.55 (t, J = 7.8 Hz, 1H), 7.65 (d,
J = 7.9 Hz, 1H), 7.70 (d, J = 11.9 Hz, 0.3H), 7.95 (m, 1.6H)
Run A
3
Run B
ppm
1
2
4
5
1
2
3
4
5
H-2 8.21 0.99 1.0
H-6 8.14 0.96 0.94 0.87 0.75 0.65 0.97 0.95 0.94 0.90 0.85
0.99 1.0
1.0
0.99 1.0
1.0
1.0
0.99
Reaction of [(cod)IrfP(C6D5)3g2]BF4 with (3-trifluromethylphenyl)-
1-(3-Trifluomethoxyphenyl)ethanone: A total of 13.8 mg (67.6 mmol) ethanone: The reaction was run as described for the reaction
of 1-(3-trifluoromethoxyphenyl)ethanone in 6 mL of CH2Cl2 was of (3-chlorophenyl)ethanone with 3 using 8.23 mg (8.6 mmol) of
treated as described in method B with six aliquots of 0.104 mg 3 and 1.44 mg (7.7 mmol) of (3-trifluromethylphenyl)ethanone.
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 189–200

J. R. Heys and C. S. Elmore
1H NMR (500MHz, D6-acetone) d ppm 7.79 (t, J = 7.8 Hz, 1H), 7.97 pairs. The acceleration of C2 labeling by the more powerful
(d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H). 19F NMR substituents may be exploitable for regioselective labeling,
(471 MHz, acetone) d ppm 25.48 (s, 4.2F), 25.54 (s, 1F), 114.13 (s, especially if the progress of reactions is monitored (a
5.9F). After heating under N2: 1H NMR (500MHz, D6-acetone) noninvasive method for real-time monitoring of HDE reactions
d ppm 6.89 (d, J = 7.9 Hz, 1.8H), 7.32 (s, 1.8H), 7.39 (d, J = 7.6Hz, is available for certain substrates).20 No definite mechanistic
2.74H), 7.70 (d, J = 11.6 Hz, 0.3H), 7.79 (t, J = 7.6Hz, 1H), 7.96 (d, explanation is yet available to account for the positive influence
J = 7.9 Hz, 1H), 8.26 (s, 1H), 8.28 (s, 1H). After bubbling H2 through of some C3 substituents on the rate of C2 hydrogen isotope
1
the solution: H NMR (500 MHz, D6-acetone) d ppm 7.39 (br. s., exchange catalyzed by organoiridium complexes. Application of
0.5H), 7.56 (d, J = 12.3 Hz, 0.19H), 7.66 (t, J = 7.6Hz, 1H), 7.83 (d, isotope studies, such as those presented here, may be useful in
J = 7.6 Hz, 1H), 8.13 (br. s., 1H), 8.15 (d, J = 7.9 Hz, 1H). There was investigations into these mechanistic questions.
no change to the 19F NMRs of the later two samples.
Reaction of [(cod)IrfP(C6D5)3g2]BF4 with (3-fluorophenyl)etha-
none: The reaction was run as described for the reaction of (3-
chlorophenyl)ethanone with 3 using 11.4 mg (11.9 mmol) of 3
1
and 1.49 mg (10.8 mmol) of (3-fluorophenyl)ethanone. H NMR
References
(500 MHz, D6-acetone) d ppm 7.40 (td, J = 8.2, 2.3 Hz, 1H), 7.56
(m, 1H), 7.68 (dd, J = 9.8, 1.5 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H). 19F
NMR (471 MHz, acetone) d ppm 25.5 (s, 1.6F), 25.6 (s, 7.3F), 63.1
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[3] A. Y. L. Shu, J. R. Heys, J. Labelled Compd. Radiopharm. 1994, 34,
587–596.
[4] D. Hesk, P. R. Das, B. Evans, J. Labelled Compd. Radiopharm. 1995,
36, 497–502.
1
(s, 1.3F), 63.4 (s, 1F). After heating under N2: H NMR (500 MHz,
D6-acetone) d ppm 6.52 (t, J = 7.8 Hz, 1.24H), 6.58 (m, 0.17H), 6.84
(dt, J = 7.6, 4.9 Hz, 1.23H), 6.89 (m, 0.12H), 7.08 (d, J = 7.6 Hz,
1.28H), 7.15 (m, 0.14H), 7.23 (m, 0.07H), 7.40 (t, J = 8.4 Hz, 1H),
7.58 (m, 1H), 7.68 (d, J = 9.8 Hz, 0.66H), 7.84 (d, J = 7.6 Hz, 1H). 19
F
[5] See for an overview and references J. R. Heys, J. Labelled Compd.
Radiopharm. 2007, 50, 770–778.
NMR (471 MHz, acetone) d ppm 25.54, (s, 22.6F), 25.59 (s, 6.7F),
63.1 (s, 1.4F), 63.4 (s, 3.1F), 84.6 (s, 1F), 84.7 (br. s., 4.2F). After H2
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Isotopically Labelled Compounds 1994, Proceedings of the 5th
International Symposium, Strasbourg, France (Eds.: J. Allen,
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1
bubbling: H NMR (500 MHz, D6-acetone) d ppm 7.39 (m, 0.5H),
7.57 (d, J = 11.6 Hz, 0.2H), 7.66 (t, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz,
1H), 8.13 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H).
Reaction of [(cod)IrfP(C6D5)3g2]BF4 with (3-trifluromethoxyphe-
nyl)ethanone: The reaction was run as described for the reaction
of (3-chlorophenyl)ethanone with 3 using 6.37 mg (6.67 mmol)
of 3 and 1.32 mg (6.44 mmol) of (3-trifluromethoxyphenyl)etha-
none 1H NMR (500 MHz, D6-acetone) d ppm 7.59 (d, J = 7.3 Hz,
1H), 7.68 (t, J = 7.9 Hz, 1H), 7.86 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H). 19
F
NMR (471 MHz, acetone) d ppm 25.5 (s, 4F), 25.6 (s, 1F), 118.8 (s,
5F). After heating under N2: 1H NMR (500 MHz, D6-acetone)
d ppm 6.68 (d, 3.3H), 6.73 (d, J = 7.3 Hz, 2.6H), 6.95 (t, J = 7.8 Hz,
2.3H), 7.04 (s, 2.2H), 7.15 (d, J = 7.9 Hz, 1.7H), 7.26 (d, J = 8.5 Hz,
3.3H), 7.35 (t, J = 5.3 Hz, 2H), 7.38 (t, J = 5.3 Hz, 2H), 7.60 (s, 1.4H),
7.70 (m, 3.9H), 7.86 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H). 19F NMR
(471 MHz, acetone) d ppm 25.45 (s, 5.4F), 25.5 (s, 1.1F), 118.6
(s, 1.8F), 118.8 (s, 3.5F), 121.3 (s, 1F). After H2 bubbling: 1H
NMR (500 MHz, D6-acetone) d ppm 7.52 (t, J = 5.3 Hz, 1H), 7.59
(d, J = 7.9 Hz, 1H), 7.70 (m, 3.38H), 7.86 (s, 1H), 8.03 (d, J = 7.6 Hz,
1H). 19F NMR (471 MHz, acetone) d ppm 25.5 (s, 4F), 25.6 (s, 1F),
118.8 (s, 5F).
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Conclusions
Our studies show unambiguously the effects of a variety of
meta-substituents on the relative rates of deuterium exchange
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various meta-substituents produce similar effects, relative to one
H. Ushito, H. Nagasaki, M. Yuguchi, S. Yamashita, T. Yamazaki,
M. Tokuda, J. Org. Chem. 2006, 71, 5951–5958.
another, in all three substrate classes. Substituents lacking
electron lone pairs strongly retard C2 labeling relative to that at
C6, probably through steric blockade. In contrast, all substitu-
ents possessing electron lone pairs are associated either with
faster C2 labeling or C2/C6 labeling rate ratios less unfavorable
than those associated with substituents lacking electron lone
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J. Label Compd. Radiopharm 2009, 52 189–200
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

J. R. Heys and C. S. Elmore
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www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 189–200