C-H activation of phenyl imines and 2-phenylpyridines with [Cp *MCl2]2 (M) Ir, Rh): Regioselectivity, kinetics, and mechanism

Article abstract of DOI:10.1021/om9000742

Sodium acetate promoted C - H activation in a series of para-substituted phenyl imines has been examined using [Cp^*MCl₂] ₂ (M) Ir, Rh). The regioselectivity was investigated using a series of meta-substituted phenyl imines

Full text of DOI:10.1021/om9000742

3492
Organometallics 2009, 28, 3492–3500
C-H Activation of Phenyl Imines and 2-Phenylpyridines with
[Cp*MCl2]2 (M ) Ir, Rh): Regioselectivity, Kinetics, and
Mechanism
Ling Li, William W. Brennessel, and William D. Jones*
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
ReceiVed January 30, 2009
Sodium acetate promoted C-H activation in a series of para-substituted phenyl imines has been
examined using [Cp*MCl2]2 (M ) Ir, Rh). The regioselectivity was investigated using a series of meta-
substituted phenyl imines (-OMe, -CH3, -F, -COOMe, -CF3, and -CN) and 2-phenylpyridines
(-OMe, -CH3, and -CF3). It was found that substrates with electron-donating substituents react
significantly faster than substrates with electron-withdrawing substituents, which is consistent with an
electrophilic C-H activation mechanism. It was also found that the regioselectivity of the C-H activation
was extremely sensitive to steric effects, with a meta methyl group leading to only one regioisomer.
Solvent and temperature studies showed that the reaction rate can be increased both by increasing
temperature and by using polar solvents such as methanol. The regioselectivity was solvent dependent
for the reaction with [Cp*IrCl2]2 but independent of solvent for the reaction with [Cp*RhCl2]2. The
regioselectivity was temperature independent for both metals. With added acid, the aromatic C-H
activation was shown to be reversible. Kinetic studies were performed, leading to the conclusion that
[Cp*M(OAc)]+ is the key catalytic species responsible for the electrophilic C-H activation.
condensation reactions.22-26 Consequently, the successful prepa-
ration of cyclometalated complexes is a key step for the
Introduction
Cyclometalated complexes have been broadly investigated
since the 1960s.1 The rapid emergence of this advanced area
of organometallic chemistry became of such interest because
cyclometalated complexes are widely involved in many
carbon-carbon or carbon-heteroatom bond-forming reactions
under relatively mild reaction conditions, which oftentimes
would be hard to achieve by conventional organic methods. One
important class of metallacycles is palladacycles, which are
generally believed to be the catalysts or catalyst precursors in
a series of well-known reactions,2-7 such as Heck coupling,8-11
Suzuki coupling,12-16 Stille coupling,17-21 and aldol-type
development of synthetic applications. Generally, it is straight-
forward to synthesize palladacycles, especially for five-
membered metallacycles with nitrogen-containing ligands to
direct the intramolecular C-H activation in the presence of a
suitable base.27-29 However, high-yield processes that proceed
under mild conditions have been elusive with palladium.
Despite the success in pharmaceutical and biological synthetic
applications of palladium chemistry, other cyclometalated
complexes, including cobalt,30-32 nickel,33-36 ruthenium,37-42
(20) Nova, A.; Ujaque, G.; Maseras, F.; Liedos, A.; Espinet, P. J. Am.
Chem. Soc. 2006, 128, 14571.
(21) Ariafard, A.; Lin, Z.; Fairlamb, I. J. S. Organometallics 2006, 25,
5788.
* To whom correspondence should be addressed. E-mail: jones@
chem.rochester.edu.
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10.1021/om9000742 CCC: $40.75
2009 American Chemical Society
Publication on Web 05/04/2009

C-H ActiVation of Phenyl Imines and 2-Phenylpyridines
Organometallics, Vol. 28, No. 12, 2009 3493
and rhodium,43-45 have already shown promising synthetic
applications to produce functionalized hydrocarbons, in which
cyclometalated complexes were formed as intermediates during
the reactions or were employed as catalysts directly. It was
necessary to prepare these cyclometalated complexes separately
so that the catalytic reactivities and mechanisms could be fully
investigated. These cyclometalations typically require strong
base46 or acid,47 mercury reagents,48-51 silver tetrafluorobo-
rate,52 sodium tetraphenylborate,53 or potassium hexafluorophos-
phate46,54 to provide a driving force to activate the C-H bonds.
Recently, a new efficient sodium acetate promoted C-H
activation was developed by the Davies group using [Cp*MCl2]2
(M ) Rh, Ir).55-59 In the presence of sodium acetate acting as
both catalyst and base, the C-H bonds were cleaved for certain
substrates at room temperature and the expected cyclometalated
complexes were formed almost stoichiometrically. We have
recently employed this methodology to prepare metallacycles
formed with benzaldimines and their polycyclic derivatives that
can react sequentially with dimethyl acetylenedicarboxylate and
copper(II) chloride to produce isoquinoline salts in high yield.60
It is worth noting that facile C-H activation with [Cp*IrCl2]2
only works for limited substrates, such as amines, imines, and
oxazolines. [Cp*RhCl2]2 works with fewer substrates, and only
a limited number of amines and imines were employed in the
published examples. It was therefore deemed worthwhile to
investigate the reactivity and scope for a series of functionalized
substrates, so that this methodology could be extended to broader
applications. In this paper, we employ a series of para-substituted
phenyl imines to probe how electronic factors affect the C-H
activation. Furthermore, the regioselectivity for the C-H
Figure 1. Molecular structures and atom numbering schemes for
(a) 2a and (b) 2b with 50% displacement ellipsoids. H atoms are
omitted for clarity.
activation was also investigated using a series of meta-
substituted phenyl imines and 2-phenylpyridines. Control of
regioselectivity is one feature important to the modern phar-
maceutical industry to synthesize pure active pharmaceutical
ingredients. The studies described here demonstrate how ste-
reoelectronic effects influence the C-H activation step in
metallacycle formation. Kinetic studies were also performed to
reveal details of the mechanism of the activation.
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Pfeffer, M. Inorg. Chem. 2001, 40, 6529.
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Org. Chem. 2003, 68, 7538.
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3113.
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Results and Discussion
(43) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001,
123, 2685.
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Organomet. Chem. 2006, 691, 2221.
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J.; Li, J.-H.; Nelson, J. H. Organometallics 1993, 12, 4464.
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M. Organometallics 1995, 14, 4559.
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2002, 21, 5437.
Reactivity Investigation. By analogy to Davies’ work with
similar substrates,56-59 the reactivity of aromatic C-H bonds
was investigated in N-(4-methoxybenzylidene)aniline (a) and
N-(4-(trifluoromethyl)benzylidene)aniline (b) with [Cp*MCl2]2
(M ) Ir (1), Rh (1′)) under similar reaction conditions, as shown
in eq 1. It was observed that the reactions with [Cp*IrCl2]2 were
2-4× faster than the reactions with [Cp*RhCl2]2 with the same
substrate. For the case of 1 with b, the reaction was complete
overnight at room temperature, but for the reaction of 1′ with
b, less than 1% conversion was observed overnight in CH2Cl2
under the same conditions. It was also observed that the reactions
with an electron-donating substituent (p-OMe) are faster than
the reactions with an electron-withdrawing substituent (p-CF3),
which confirmed an electrophilic C-H activation mechanism.
Single-crystal X-ray structures of 2a, 2′a, 2b, and 2′b were
obtained, and the iridium examples are shown in Figure 1.
Selected bond lengths and angles are summarized in Table 1.
(54) Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R. J.
Organomet. Chem. 2002, 662, 43.
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W. Eur. J. Inorg. Chem. 1998, 485.
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S. T.; Russell, D. R. Dalton Trans. 2003, 4132.
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C.; Macgregor, S. A. Organometallics 2006, 25, 5976.
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Organomet. Chem. 2006, 691, 2221.
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Polleth, M. J. Am. Chem. Soc. 2006, 128, 4210.
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130, 12414.
From Table 1, the similar angles do not change much from
2a and 2′a to 2b and 2′b. However, the bond lengths M(1)-C(1)

3494 Organometallics, Vol. 28, No. 12, 2009
Li et al.
Table 1. Selected Bond Lengths (Å) and Bond Angles (deg) for 2a, 2′a, 2b, and 2′ba
2a
2′a
2b
2′b
M(1)-C(1)
M(1)-Cl(1)
M(1)-N(1)
N(1)-C(7)
C(6)-C(7)
C(6)-C(1)
2.0328(17)
2.4038(5)
2.0881(15)
1.304(2)
1.430(2)
1.422(2)
2.0233(14)
2.3943(4)
2.0889(13)
1.295(2)
1.435(2)
1.422(2)
2.025(2)
2.4015(6)
2.0869(19)
1.302(3)
1.438(3)
1.416(3)
2.014(2)
2.3936(6)
2.0917(2)
1.293(3)
1.446(3)
1.412(3)
C(1)-M(1)-N(1)
C(1)-M(1)-Cl(1)
N(1)-M(1)-Cl(1)
C(6)-C(1)-M(1)
C(1)-C(6)-C(7)
C(6)-C(7)-N(1)
C(7)-N(1)-M(1)
77.76(6)
84.99(5)
86.74(4)
115.37(12)
113.61(15)
116.61(15)
116.55(12)
78.45(6)
85.81(4)
89.22(3)
114.63(11)
114.11(13)
116.63(14)
116.05(11)
77.85(8)
85.42(6)
87.34(5)
115.62(16)
113.6(2)
116.3(2)
116.62(16)
78.64(8)
85.96(6)
89.77(5)
115.05(16)
113.93(19)
116.6(2)
115.66(15)
a M ) Ir for 2a and 2b; M ) Rh for 2′a and 2′b.
Figure 2. Molecular structures and atom numbering schemes for (a) 3c, (b) 2d, (c) 3e, (d) 2f, (e) 2g, and (f) 2h with 50% displacement
ellipsoids. H atoms are omitted for clarity.
of 2b and 2′b are noticeably shorter than those of 2a and 2′a,
respectively, and the bond lengths C(6)-C(7) of 2b and 2′b
are slightly longer than those of 2a and 2a′, respectively, both
of which favor electrophilic C-H activation as proposed by
the Davies group.59 Interestingly, the bond length Ir(1)-N(1)
is shorter from 2a to 2b, while the bond length Rh(1)-N(1) is
marginally lengthened from 2′a to 2′b.
favoring C-H activation ortho to a C-F bond.61-65 A series
of single-crystal X-ray structures were determined of these
metallacycles, with the selected iridium series shown in Figure
2. Selected bond lengths and angles for the X-ray structures
are summarized in Tables S1 and S2 (Supporting Information).
Note from the Tables S1 and S2, the bond lengths Ir(1)-N(1)
are shorter than Rh(1)-N(1) for 2f/2′f and 2g/2′g, as mentioned
before.
Regioselectivity Investigation. A series of meta-substituted
phenyl imines (-OMe (c), -CH3 (d), -F (e), -COOMe (f),
-CF3 (g), -CN (h)) were reacted with [Cp*MCl2]2 (M ) Ir
(1), Rh (1′)) under the same reaction conditions, as shown in
eq 2. The regioselectivity results to produce 2 or 3 are
summarized in Table 2. Once again, reactions with electron-
donating substitutions are faster than the reactions with electron-
withdrawing substitutions, which is attributed to an electrophilic
C-H activation mechanism. Importantly, it was found that the
regioselectivity was extremely sensitive to steric effects, giving
rise to a preference for isomers 2. For example, even with a
less bulky substituent such as a methyl group, only one
regioisomer was observed, offering opportunities for potential
synthetic applications. Also from Table 2 it can be seen that
for the m-fluoro substituent 3e and 3′e were the major regioi-
somers, which can be attributed to the known “ortho effect”
The regioselectivity was also investigated in the reactions of
a series of meta-substituted 2-phenylpyridines (-OMe (i), -CH3
(j), and -CF3 (k)) with [Cp*MCl2]2 (M ) Ir (1), Rh (1′)) under
(61) McDaniel, D. H.; Brown, H. C. J. Am. Chem. Soc. 1955, 77, 3756.
(62) Foster, H. J. Am. Chem. Soc. 1960, 82, 3780.

C-H ActiVation of Phenyl Imines and 2-Phenylpyridines
Organometallics, Vol. 28, No. 12, 2009 3495
Table 2. Regioselectivities in the Reactions of Phenyl
3-R-benzaldimines with [Cp*MCl2]2
when the solvent is more polar, while with rhodium the ratio
of the two regioisomers does not change at all with solvent.
Pure regioisomer 3c was isolated from the mixture of 2c and
3c by column chromatography. 3c was then subjected to the
reaction conditions, and it was found that 2c began to grow in
after adding 2 equiv of acetic acid. There was about 5%
conversion after standing overnight at room temperature in
MeOH, as shown in eq 5. This interconversion implies that the
aromatic C-H activation is reversible but that it is very slow
with a weak acid such as acetic acid. The half-life for the
conversion is about 2-3 days. When acetic acid was replaced
with the stronger trifluoroacetic acid, equilibrium was achieved
within 2 h at room temperature in MeOH (2c:3c ) 1.1:1).
Similar acid-promoted rearrangements of palladium metalla-
cycles have been observed previously.66
R
M ) Ir, 3:2
M ) Rh, 3′:2′
OMe (c)
Me (d)
F (e)
1:1.7
2d only
2.3:1
1:1.7
2′d only
8.5:1
COOMe (f)
CF3 (g)
CN (h)
2f only
2g only
1:1.3
2′f only
2′g only
1:1.3
Table 3. Regioselectivities in the Reactions of Meta-Substituted
2-Phenylpyridines with 1 and 1′
R
M ) Ir, 3:2
M ) Rh, 3′:2′
OMe (i)
Me (j)
CF3 (k)
1:1.1
2j only
1:6.4
1:2.5
1:50
1:8.4
the same reaction conditions, as shown in eq 3. The regiose-
lectivity results are summarized in Table 3. An electrophilic
mechanism was once again in agreement with the observation
that electron-withdrawing substituents inhibit these reactions.
It was also observed that, for the same substituent, the
regioselectivity for the reactions with 2-phenylpyridines is not
as good as with meta-substituted phenyl imines under similar
reaction conditions. This is probably because the pyridyl group
is slightly less bulky than the phenyl imines. A series of single-
crystal X-ray structures were determined, with the selected
iridium series shown in Figure 3. Selected bond lengths and
angles for the structures are summarized in Table S3 (Supporting
Information).
Reaction Differences between [Cp*IrCl2]2 and [Cp*RhCl2]2.
As mentioned above, the reactions with [Cp*IrCl2]2 are faster
than with [Cp*RhCl2]2 with the same substrate under identical
reaction conditions. When the substrate 2-benzylpyridine (n)
was reacted with [Cp*IrCl2]2, cyclometalation occurred after
standing overnight at room temperature in high yield (eq 6).
The X-ray structure of this rare six-membered cyclometalated
iridium complex is shown in Figure 4, and selected bond lengths
and bond angles are given in the Supporting Information. In
contrast, there is no C-H activation observed with [Cp*RhCl2]2,
even at elevated temperature. Not even nitrogen coordination
was observed, which is unexpected in light of the known ability
of weak donor ligands to cleave the dimer 1′.67 The increased
reactivity of iridium vs rhodium suggests that the former is more
electrophilic. Electrophilic alkane C-H activation has been
established with [Cp*Ir(PMe3)(CH3)(OTf)].68
The high regioselectivity attributable to steric effects men-
tioned above can be further substantiated by a reaction with a
substrate (m) in which competitive C-H activation occurs (eq
4). The structure for the major regioisomer can be established
by 1H NOE spectroscopy, which shows proximity of the MeO
group to only one aromatic hydrogen but proximity of the Me
to two aromatic hydrogens. Since the methyl group is more
bulky than the methoxy group, 2m and 2′m are the predominant
regioisomers.
Kinetic and Mechanism Investigation. As mentioned above,
the reaction with [Cp*IrCl2]2 is faster than the reaction with
[Cp*RhCl2]2 for a given substrate; also, the reactions with
substrates bearing electron-donating substituents are faster than
the reactions with substrates bearing electron-withdrawing
substituents. In order to obtain quantitative kinetic data, the
reactions of both 1 and 1′ with an equal number of equivalents
of para-substituted imines a (p-OCH3) and b (p-CF3) were
conducted under identical, stoichiometric reaction conditions,
and the reaction rates were measured by monitoring the
Solvent and Temperature Effects. Solvent and temperature
effects were investigated using substrate c. The results with the
ratios of two regioisomers are summarized in Table 4. The
reaction is faster when the temperature is increased, but the ratio
of the two regioisomers does not change. When methanol is
used as the solvent instead of dichloromethane or acetonitrile,
the reaction is faster than in dichloromethane. For example, in
MeOH the reaction of c with [Cp*IrCl2]2 was complete within
1 h, and the reaction with [Cp*RhCl2]2 was complete in ∼3 h,
With iridium, the ratio of the two regioisomers is closer to 1:1
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Organometallics 2006, 25, 4215.
(64) Selmeczy, A. D.; Jones, W. D.; Partridge, M. G.; Perutz, R. N.
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Oelckers, B.; Perutz, R. N. Chem. Commun. 2003, 490.
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(68) Arndtsen, B. A.; Bergman, R. G. Science 1995, 270, 1970.

3496 Organometallics, Vol. 28, No. 12, 2009
Li et al.
Figure 3. Molecular structures and atom numbering schemes for (a) 3i, (b) 2j, and (c) 2k with 50% displacement ellipsoids. H atoms are
omitted for clarity.
Table 4. Regioselectivity in the Reactions of 1 and 1′ with Imine c
as a Function of T and Solvent
solvent
T (°C)
M ) Ir, 3c:2c
M ) Rh, 3′c:2′c
CH2Cl2
CH3CN
MeOH
CH2Cl2
CH3CN
CH3CN
CH3CN
25
25
25
45
45
65
85
1:1.7
1:1.4
1:1.1
1:1.7
1:1.3
1:1.3
1:1.3
1:1.6
1:1.7
1:1.7
1:1.7
formation of metallacycles. The kinetics of the reaction were
investigated under the actual stoichiometric reaction conditions,
rather than with a pseudo-first-order excess of the imine, as high
imine concentrations change the rate-determining step of the
reaction (vide infra). The plots of concentration of imine reactant
vs time are shown in Figure S1a-d (Supporting Information).
The reaction order for each reaction was determined by plotting
ln([a]t/[a]0) or ln([b]t/[b]0) versus time for first-order simulation
and 1/[a]t - 1/[a]0 or 1/[b]t - 1/[b]0 versus time for second
order simulation, separately. The plots are shown in Figures 5
and 6, respectively.
The first-order plots in Figure 5 all show upward curvature
and poor linearity. The second-order plots in Figure 6, however,
show that the reactions match best with a second-order reaction,
with the exception of the reaction of 1′ with a, for which the
reaction order is between 1 and 2. Note that the observation of
linearity of these plots implies that dimers 1 and 1′ have been
converted to monomeric species under the reaction conditions
(vide infra). The second-order rate constants are summarized
in Table 5. It was found that, for a given substrate, the reaction
with [Cp*IrCl2]2 is a few times faster than the reaction with
[Cp*RhCl2]2, and the reactions with p-methoxyl substitutions
are over 10 times faster than the reactions with p-trifluoromethyl
substitutions.
Figure 5. First_order plot for each reaction: (a) 1 and a; (b) 1′ and
a; (c) 1 and b; (d) 1′ and b. The reaction conditions are as follows:
[1] ) [1′] ) 0.5 × 10-2 M, [a] ) [b] ) 1.0 × 10-2 M, [NaOAc]
) 3.0 × 10-2 M in 1 mL of CD3OD at room temperature.
In considering the mechanism of the aromatic C-H activa-
tion, the Davies group put forth both oxidative addition and
electrophilic substitution reaction pathways,56 and an acetate-
chelated intermediate was also proposed. However, no direct
experimental evidence was provided to delineate the mechanism
of activation. Furthermore, in the intermediates proposed it was
uncertain whether the intermediate was coordinated by acetate
or chloride. Subsequent DFT calculations were done by Davies
and Macgregor, indicating that [Cp*Ir(κ2-OAc)]+ was the
species reacting with dimethylbenzylamine in the electrophilic
C-H activation.59 Further experiments are needed to investigate
the mechanism of the reaction with imines and the role of
sodium acetate, especially considering the recent rapid progress
of acetate-assisted transition-metal synthesis of heterocycles.69-71
Since C-H activation is involved, the existence and magnitude
of a primary kinetic isotopic effect can provide a clue as to
how this bond is broken. The primary kinetic isotopic effect
was examined by reacting of a mixture of phenylimine-d0 and
Figure 4. Molecular structure and atom-numbering scheme for
2n with 50% displacement ellipsoids. H atoms are omitted for
clarity.
(69) Stuart, D. R.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
(70) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407.
(71) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362.

C-H ActiVation of Phenyl Imines and 2-Phenylpyridines
Organometallics, Vol. 28, No. 12, 2009 3497
Figure 7. Second-order plot for each reaction of Cp*Rh(OAc)Cl
with a. The reaction conditions are as follows: [Cp*Rh(OAc)Cl]
) [a] ) 1.0 × 10-2 M in 1 mL of CD3OD at room temperature.
Figure 6. Second-order plot for each reaction: (a) 1 and a; (b) 1′
and a; (c) 1 and b; (d) 1′ and b.
Figure 8. Plots for reactions of Cp*Rh(OAc)2 with a and b: (a)
first-order plot for Cp*Rh(OAc)2 with a; (b) second-order plot for
Cp*Rh(OAc)2 with b. The reaction conditions are as follows:
[Cp*Rh(OAc)2] ) [a] ) [b] ) 1.0 × 10-2 M in 1 mL of CD3OD
at room temperature.
Table 5. Reaction Rate Constants for Reactions of 1 and 1′ with a
and b
a
reactants
kobsd (L mol-1 h-1
)
1 and a
1′ and a
1 and b
1′ and b
505 (4)
∼345 (12)
39.4 (0.1)
9.20 (0.05)
acetate-coordinated metallacycle, which was confirmed by the
addition of sodium chloride to the solution to quickly form 2′a.
In the reaction of Cp*Rh(OAc)2 with a containing an excess of
NaOAc, it was observed that the reaction rate was strongly
retarded. These observations imply that loss of one acetate group
to form the reactive cationic species [Cp*Rh(OAc)]+ is the rate-
limiting step in this particular reaction. The reaction of
Cp*Rh(OAc)2 with b without additional sodium acetate, how-
ever, showed good second-order reaction kinetics (Figure 8b),
giving the acetate-coordinated metallacycle. The reaction is
faster than the reaction of 1′ with b but slower than the reaction
of Cp*Rh(OAc)2 with a.
In order to determine if the compounds Cp*Rh(OAc)2 and
Cp*Rh(OAc)Cl were actually formed under the reaction condi-
tions, the reaction of 1′ with 3 equiv of sodium acetate at the
same concentration as in the kinetic experiments was monitored
by NMR spectroscopy at room temperature. Within 5 min in
CD3OD both Cp*Rh(OAc)2 and Cp*Rh(OAc)Cl were observed,
as well as a small quantity of [Cp*RhCl2]2, as determined by
the observation of the distinct Cp* resonances for these
compounds (see the Supporting Information). This observation
further confirms that the monomeric mono- and bis-OAc
compounds are formed from [Cp*RhCl2]2 at the beginning of
the reaction and accounts for the observation that the use of a
1:1 ratio of metal to imine results in good agreement for a
second-order kinetic treatment. The ratio of these species
changed at different concentrations, which implies that all of
these rhodium species are in rapid equilibrium. Also, at least
80% of the metal is present as monomeric species so that the
metal concentration is approximately the same as the substrate
concentration.
a Errors given in parentheses are standard deviations.
partially deuterated phenylimine-d5 with 1 under similar reaction
conditions. A large primary isotopic effect of >5 was observed,
which is consistent with an electrophilic activation mechanism.72
Since computational studies show that the ligand κ2-OAc can
assist intramolecular C-H activation,59 the two κ2-OAc chelated
compounds Cp*Rh(OAc)2 and Cp*Rh(OAc)Cl were prepared
as reported in the literature,73 and the role of these two
compounds was examined. The reaction of [Cp*RhCl2]2 with
NaOAc was examined in methanol at several different concen-
trations. Monitoring by UV-vis showed immediate reaction to
give Cp*Rh(OAc)Cl, which formed when only a few equivalents
of NaOAc were added (∼1 mM). Formation of Cp*Rh(OAc)2
required higher concentrations of NaOAc (∼0.02 M). Details
are provided in the Supporting Information.
The reactions of Cp*Rh(OAc)Cl with an equal concentration
of substrate a or b without additional sodium acetate in CD3OD
at room temperature showed good second-order kinetics (Figure
7). The reaction rate was comparable with that of the reaction
of 1′ with a or b with 3 equiv of sodium acetate, which implies
that formation of Cp*Rh(OAc)Cl is very fast under these
conditions, as seen in the UV-vis studies. It is not unreasonable
that these species are solvated in methanol, as Cp*Rh(OAc)2 is
known to bind water.73
However, the reaction of Cp*Rh(OAc)2 with a without
additional sodium acetate showed a very fast reaction that
followed first-order kinetics (Figure 8a). The product is the
(72) Bullock, R. M. Isotope effects in reactions of transition metal
hydrides. Transition Met. Hydrides 1992, 263.
(73) Both Cp*Rh(O2CPh)2 and Cp*Rh(OAc)2(H2O) have been character-
ized by X-ray studies. See: Boyer, P. M.; Roy, C. P.; Bielski, J. M.; Merola,
J. S. Inorg. Chim. Acta 1996, 245, 7.
On the basis of the above kinetic studies, a simple mechanism
is proposed as shown in Scheme 1. All three compounds 1-3
are formed rapidly and are in equilibrium. Both 2 and 3 can
dissociate the coordinated chloride or acetate, respectively, to

3498 Organometallics, Vol. 28, No. 12, 2009
Li et al.
Scheme 1. Proposed Mechanism for Metallacycle Formation
Figure 9. Energy diagram for electrophilic C-H activation and
metallacycle formation. The red pathway denotes portions where
no chloride is bound, and the blue pathway denotes the portions
where chloride is bound. Legend: 1, [Cp*MCl2]2; 2, Cp*MCl(OAc);
3, M(OAc)2; 4, [Cp*M(OAc)]+; 5, Cp*M(OAc)(metallacycle); 6,
Cp*MCl(metallacycle). The barrier labeled ii represents the imine
coordination and rate-determining C-H activation step. For reaction
of 1′ and a, barriers i and ii are about the same.
imines and 2-phenylpyridines has been investigated. Electron-
donating functional groups favor C-H activation, while electron-
withdrawing functional groups inhibit C-H activation, which
is consistent with an electrophilic mechanism for C-H activa-
tion. The aromatic C-H activation is reversible with added acid.
The regioselectivity results show that the reaction is highly
sensitive to steric effects, which renders the cyclometalation
reactions more stereoselective. Kinetic studies revealed that the
cation [Cp*M(OAc)]+ is the species responsible for the elec-
trophilic activation of the aromatic C-H bond and that the
bound acetate participates in the cleavage. Furthermore, the
increased reactivity of iridium vs rhodium suggests that
the former is more electrophilic.
form the key intermediate cation 4. While the second-order
kinetics for the overall reaction only require that the imine must
be bound in or prior to the rate-determining step, the presence
of a large isotope effect indicates that C-H/C-D cleavage, not
imine binding, must be the rate-determining step. The acetate-
coordinated product 5 is formed, followed by rapid conversion
to the observed chloride product 6, since chloride coordinates
with the metal more tightly than an η1-acetate. For the case of
reaction of 1′ with a, the rate of the step of losing the chloride
from 2 to form the cation 4 (step i) is comparable with the
subsequent rate-limiting step (step ii), which makes the observed
reaction order appear between 1 and 2. A qualitative free energy
diagram consistent with the data is shown in Figure 9 for both
the chloro- and acetate-only ligated situations.
The transition state for the acetate-promoted C-H activation
via electrophilic substitution pathway from the intermediate
cation 4 to the acetate-coordinated product 5 is also shown in
Scheme 1. This proposed transformation is similar to that
calculated for acetate-promoted C-H activation of dimethyl-
benzylamine at [Cp*Ir(OAc)]+ and at Pd(OAc)2.59,74 Other
calculations of related acetate-promoted sp3 C-H activations
on palladium have also appeared.75,76 Of special note, early
mechanistic work by Ryabov and co-workers on the palladium
acetate cyclometalation of benzylamines proposed exactly such
a transition state for C-H activation.77
Experimental Section
General Information. RhCl3 · 3H2O and IrCl3 · 3H2O were
purchased from Pressure Chemical Co., and their dimers
[Cp*RhCl2]2 and [Cp*IrCl2]2 were prepared by literature methods.78
Dichloromethane, acetonitrile, and methanol were used without
drying. Reagents were purchased from the following suppliers:
p-anisaldehyde, m-anisaldehyde, m-tolualdehyde, 2-benzylpyridine,
N-bromosuccininimide (NBS), benzoyl peroxide, sodium ethoxide,
2-nitropropane, palladium acetate, and 10% palladium on activated
charcoal from Aldrich; m-fluorobenzaldehyde, p-(trifluoromethyl)-
benzaldehyde, 3-formylbenzonitrile, 3,5-dimethylanisole, pyridine
N-oxide, and 3-bromobenzotrifluoride from TCI America; m-
(trifluoromethyl)benzaldehyde, 3-bromoanisole, and ammonium
formate from Alfa Aesar; methyl 3-formylbenzoate from Acros
Organics; 3-bromotoluene from Eastman Chemicals; tri-tert-bu-
tylphosphonium tetrafluoroborate from Strem. N-(4-Methoxyben-
zylidene)aniline, N-(4-(trifluoromethyl)benzylidene)aniline, N-(3-
methoxybenzylidene)aniline, N-(3-methylbenzylidene)aniline, N-(3-
fluorobenzylidene)aniline, methyl 3-(phenylimino)methylbenzoate,
N-(3-(trifluoromethyl)benzylidene)aniline, 3-(phenylimino)methyl-
benzonitrile, and N-(3-methoxy-5-methylbenzylidene)aniline were
prepared by mixing aniline with the corresponding aldehydes in
methanol overnight at room temperature or at elevated temperatures.
2-(3-(Trifluoromethyl)phenyl)pyridine, 2-(3-methoxyphenyl)pyri-
dine, 2-(m-tolyl)pyridine, and 3-methoxy-5-methylbenzaldehyde
were prepared as described in the literature.79,80 All reactions
described below were carried out under nitrogen. However, once
Conclusions
In summary, the reactivity and regioselectivity of aromatic
C-H activation in a series of para- and meta-substituted phenyl
(74) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754.
(75) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 14570.
(76) Chaumontet, M.; Piccardi, R.; Audic, N.; Jitce, J.; Peglion, J.-L.;
Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157.
(77) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K. J. Chem.
Soc., Dalton Trans. 1985, 2629.
(78) Kang, J. W.; Moseley, K.; Maitlis, P. M. J. Am. Chem. Soc. 1969,
91, 5970.
(79) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020.

C-H ActiVation of Phenyl Imines and 2-Phenylpyridines
Organometallics, Vol. 28, No. 12, 2009 3499
the reactions were completed, further workups were done without
precaution, as the compounds are air-stable. All NMR spectra were
recorded on a Bruker AMX400, an AVANCE400, or AVANCE500
spectrometer in CDCl3 (δ 7.26). Elemental analyses were performed
by Columbia Analytical Services.
Ratios of products reported in the tables are taken from the
reaction mixtures before workup. Descriptions of representative
reactions for 2a, 2′a, 2b, 2′b, 2c/3c, and 2′c/3′c are given below.
Complete experimental details for the remaining metallacycles are
included in the Supporting Information.
Preparation of 2a. A mixture of [Cp*IrCl2]2 (50.0 mg, 0.063
mmol), NaOAc (30.0 mg, 0.39 mmol), N-(4-methoxybenzylidene)-
aniline (29.0 mg, 0.14 mmol), and p-anisaldehyde (trace) were
stirred at room temperature in 20 mL of dichloromethane for 5 h.
The mixture was filtered through Celite and evaporated to dryness.
The solid obtained was washed with hexane to remove excess
ligand. Cyclometalated compound 2a was isolated as a red-orange
solid (69.6 mg, 97%). Anal. Calcd for C24H27ClIrNO: C, 50.30, H,
4.75, N, 2.44. Found: C, 50.53, H, 4.94, N, 2.50. 1H NMR: δ 8.20
(s, 1H, HCdN), 7.56 (dd, 2H, J ) 8.1, 7.7 Hz), 7.55 (d, 1H, J )
8.5 Hz), 7.37 (m, 3H), 7.26 (dd, 1H, J ) 7.8, 6.9 Hz), 6.60 (dd,
1H, J ) 8.3, 2.4 Hz), 3.92 (s, 3H, OMe), 1.48 (s, 15H, C5Me5).
13C NMR: δ 173.91 (HCdN), 173.09 (Ir-C), 162.67, 152.04,
140.77, 131.27, 129.08 (2 C’s), 127.03, 122.80 (2 C’s), 119.56,
108.82, 89.17 (C5Me5), 55.25 (OMe), 8.91 (C5Me5).
1H, J ) 7.5 Hz), 1.43 (s, 15H, C5Me5). 13C NMR: δ 185.46 (d, J
) 135.7 Hz, Rh-C), 171.76 (HCdN), 150.88, 149.08, 132.79 (q,
J ) 14.6 Hz), 131.67 (q, J ) 123.1 Hz), 129.41 (2 C’s), 129.03,
127.99, 124.48 (q, J ) 1047.3 Hz, CF3), 122.18 (2 C’s), 119.93
(q, J ) 14.8 Hz), 96.88 (d, J ) 24.5 Hz, C5Me5), 9.08 (C5Me5).
Preparation of 2c and 3c. The reaction was carried out as for
2a, using [Cp*IrCl2]2 (50.0 mg, 0.063 mmol), NaOAc (30.0 mg,
0.39 mmol), N-(3-methoxybenzylidene)aniline (29.0 mg, 0.14
mmol), and m-anisaldehyde (trace) in 20 mL of CH2Cl2 at room
temperature overnight. Cyclometalated compounds 2c and 3c in a
ratio of 1.7:1 were isolated as a red solid (67.3 mg, 94%). Anal.
Calcd for C24H27ClIrNO: C, 50.30, H, 4.75, N, 2.44. Found: C,
49.87, H, 5.07, N, 2.44. The mixture was separated by column
1
chromatography using 0.8% MeOH in CH2Cl2. H NMR for the
major regioisomer 2c: δ 8.30 (s, 1H, HCdN), 7.71 (d, 1H, J ) 8.3
Hz), 7.57 (d, 2H, J ) 7.5 Hz), 7.40 (dd, 2H, J ) 8.0, 7.5 Hz), 7.29
(dd, 1H, J ) 7.5, 7.4 Hz), 7.16 (d, 1H, J ) 2.7 Hz), 6.92 (dd, 1H,
J ) 8.4, 2.7 Hz), 3.79 (s, 3H, OMe), 1.47 (s, 15H, C5Me5). 13C
NMR for 2c: δ 175.38 (HCdN), 160.88 (Ir-C), 155.85, 152.03,
147.26, 135.66, 129.17 (2 C’s), 127.47, 122.68 (2 C’s), 120.78,
1
113.57, 89.19 (C5Me5), 55.61 (OMe), 8.95 (C5Me5). H NMR for
the minor regioisomer 3c: δ 8.37 (s, 1H, HCdN), 7.59 (d, 2H, J )
7.4 Hz), 7.39 (dd, 2H, J ) 8.0, 7.5 Hz), 7.29 (d, 1H, J ) 7.9 Hz),
7.28 (dd, 1H, J ) 7.5, 7.4 Hz), 7.02 (dd, 1H, J ) 7.7, 7.6 Hz),
6.73 (d, 1H, J ) 7.9 Hz), 3.85 (s, 3H, OMe), 1.46 (s, 15H, C5Me5).
13C NMR for 3c: δ 176.22 (HCdN), 162.52 (Ir-C), 159.07, 152.08,
147.72, 129.16 (2 C’s), 127.32, 123.65, 123.05, 122.62 (2 C’s),
114.15, 89.70 (C5Me5), 56.20 (OMe), 9.07 (C5Me5).
Preparation of 2′a. The reaction was carried out as for 2a, using
[Cp*RhCl2]2 (50.0 mg, 0.081 mmol), NaOAc (40.0 mg, 0.49 mmol),
N-(4-methoxybenzylidene)aniline (34.9 mg, 0.17 mmol), and p-
anisaldehyde (trace) in 20 mL of CH2Cl2 at room temperature
overnight. The cyclometalated compound 2′a was isolated as an
orange solid (77.1 mg, 98%). Anal. Calcd for C24H27ClNORh: C,
Preparation of 2′c and 3′c. The reaction was carried out as for
2a, using [Cp*RhCl2]2 (50.0 mg, 0.081 mmol), NaOAc (40.0 mg,
0.49 mmol), N-(3-methoxybenzylidene)aniline (36.2 mg, 0.17
mmol), and m-anisaldehyde (trace) in 20 mL of CH3CN at 65 °C
for 6 h. Cyclometalated compounds 2′c and 3′c in a ratio of 1.7:1
were isolated as an orange solid (73.3 mg, 94%). Anal. Calcd for
C24H27ClNORh: C, 59.58, H, 5.62, N, 2.89. Found: C, 59.34, H,
1
59.58, H, 5.62, N, 2.89. Found: C, 60.01, H, 5.83, N, 2.81. H
NMR: δ 8.06 (d, 1H, J ) 3.8 Hz, HCdN), 7.60 (d, 2H, J ) 7.5
Hz), 7.48 (d, 1H, J ) 8.5 Hz), 7.39 (d, 1H, J ) 2.4 Hz), 7.38 (dd,
2H, J ) 8.1, 7.5 Hz), 7.27 (dd, 1H, J ) 7.4, 7.3 Hz), 6.59 (dd, 1H,
J ) 8.3, 2.4 Hz), 3.92 (s, 3H, OMe), 1.43 (s, 15H, C5Me5). 13C
NMR: δ 188.11 (d, J ) 132.2 Hz, Rh-C), 171.02 (HCdN), 161.37,
151.26, 139.82, 130.83, 129.15 (2 C’s), 126.96, 122.43 (2 C’s),
121.14, 109.34, 96.23 (d, J ) 24.6 Hz, C5Me5), 55.31 (OMe), 9.09
(C5Me5).
Preparation of 2b. The reaction was carried out as for 2a, using
[Cp*IrCl2]2 (50.0 mg, 0.063 mmol), NaOAc (30.0 mg, 0.39 mmol),
N-(4-(trifluoromethyl)benzylidene)aniline (31.5 mg, 0.13 mmol),
and p-(trifluoromethyl)benzaldehyde (trace) in 20 mL of CH2Cl2
at room temperature overnight. Cyclometalated compound 2b was
isolated as a red solid (75.3 mg, 98%). Anal. Calcd for
C24H24ClF3IrN: C, 47.17, H, 3.96, N, 2.29. Found: C, 46.67, H,
4.01, N, 2.23. 1H NMR: δ 8.40 (s, 1H, HCdN), 8.07 (s, 1H), 7.69
(d, 1H, J ) 7.9 Hz), 7.58 (d, 2H, J ) 7.8 Hz), 7.43 (dd, 2H, J )
8.0, 7.5 Hz), 7.33 (dd, 1H, J ) 7.4, 7.2 Hz), 7.25 (d, 1H, J ) 7.9
Hz), 1.48 (s, 15H, C5Me5). 13C NMR: δ 174.80 (HCdN), 170.36
(Ir-C), 151.69, 150.02, 132.63 (q, J ) 122.0 Hz), 131.55 (q, J )
14.9 Hz), 129.31 (2 C’s), 128.00 (2 C’s), 124.39 (q, J ) 1087.2
Hz, CF3), 122.54 (2 C’s), 119.11 (q, J ) 14.5 Hz), 89.98 (C5Me5),
8.89 (C5Me5).
1
5.72, N, 2.98. H NMR for the major regioisomer 2′c: δ 8.14 (d,
1H, J ) 3.8 Hz, HCdN), 7.72 (d, 1H, J ) 8.3 Hz), 7.62 (d, 2H,
J ) 8.2 Hz), 7.42 (dd, 2H, J ) 8.1, 7.4 Hz), 7.30 (dd, 1H, J ) 7.4,
7.3 Hz), 7.12 (d, 1H, J ) 2.8 Hz), 6.98 (dd, 1H, J ) 8.4, 2.9 Hz),
3.79 (s, 3H, OMe), 1.43 (s, 15H, C5Me5). 13C NMR for 2′c: δ 174.86
(d, J ) 133.5 Hz, Rh-C), 172.25 (HCdN), 156.37, 151.09, 145.96,
136.60, 129.17 (2 C’s), 127.35, 122.17 (2 C’s), 119.45, 113.87,
1
96.12 (d, J ) 24.8 Hz, C5Me5), 55.55 (OMe), 9.03 (C5Me5). H
NMR for the minor regioisomer 3′c: δ 8.20 (d, 1H, J ) 3.9 Hz,
HCdN), 7.66 (d, 2H, J ) 8.2 Hz), 7.41 (dd, 2H, J ) 8.0, 7.4 Hz),
7.30 (dd, 1H, J ) 7.4, 7.3 Hz), 7.23 (dd, 1H, J ) 7.6, 0.9 Hz),
7.06 (dd, 1H, J ) 7.8, 7.6 Hz), 6.81 (d, 1H, J ) 7.9 Hz), 3.88 (s,
3H, OMe), 1.42 (s, 15H, C5Me5). 13C NMR for 3′c: δ 173.04
(HCdN), 172.67 (d, J ) 140.4 Hz, Rh-C), 163.46, 151.31, 146.99,
129.20 (2 C’s), 127.30, 124.23, 123.06, 122.29 (2 C’s), 113.89,
96.70 (d, J ) 25.3 Hz, C5Me5), 56.18 (OMe), 9.12 (C5Me5).
Screening Other Nitrogen-Containing Substrates. Other sub-
strates have been tried with [Cp*MCl2]2 under similar reaction
conditions, such as N-((pyridin-2-yl)methylene)aniline, N-((pyridin-
4-yl)methylene)aniline, 2-(pyridin-2-yl)pyridine, 2-(pyridin-4-yl)py-
ridine, and bis(pyrazole)methane. It was found that only partial
C-H activation was observed, with mostly nitrogen coordination
instead. 8-Methylquinoline was also tried, and no C-H activation
of the methyl group was seen, which implies that this methodology
probably cannot be extended to alkyl C-H activation.
Preparation of 2′b. The reaction was carried out as for 2a, using
[Cp*RhCl2]2 (50.0 mg, 0.081 mmol), NaOAc (40.0 mg, 0.49 mmol),
N-(4-(trifluoromethyl)benzylidene)aniline (43.0 mg, 0.18 mmol),
and p-(trifluoromethyl)benzaldehyde (trace) in 20 mL of CH3CN
at 65 °C for 2 days. Cyclometalated compound 2′b was isolated as
a
yellow-orange solid (84.0 mg, 99%). Anal. Calcd for
C24H24ClF3NRh: C, 55.24, H, 4.64, N, 2.68. Found: C, 54.71, H,
4.77, N, 2.55. 1H NMR: δ 8.24 (d, 1H, J ) 3.8 Hz, HCdN), 8.09
(s, 1H), 7.64 (d, 2H, J ) 7.6 Hz), 7.61 (d, 1H, J ) 7.8 Hz), 7.45
(dd, 2H, J ) 8.0, 7.4 Hz), 7.35 (dd, 1H, J ) 7.6, 7.4 Hz), 7.31 (d,
Procedure for the KIE Experiment. To a solution of 1′ (37.2
mg, 0.06 mmol) and sodium acetate (29.6 mg, 0.36 mmol) in
methanol (20.0 mL) was added phenylimine-d0 (3.6 mg, 0.02 mmol)
and partially deuterated phenylimine-d5 (18.5 mg, 0.10 mmol). An
aliquot of this sample was taken every 1 h, and the ratio of the two
metallacycles was determined by measuring the integration of the
(80) Koyama, H.; Kamikawa, T. J. Chem. Soc. Perkin Trans. 1 1998,
2, 203.

3500 Organometallics, Vol. 28, No. 12, 2009
Li et al.
characteristic imine resonance for nondeuterated metallcycle and
the integration of the Cp* resonance for both metallacycles.
General Procedures for the Kinetics Experiments. In a
solution of 1 (3.9 mg, 0.005 mmol) or 1′ (3.1 mg, 0.005 mmol)
and sodium acetate (2.5 mg, 0.03 mmol) in CD3OD (1.0 mL) in a
J-Young tube at room temperature, substrate a (2.1 mg, 0.01 mmol)
or b (2.4 mg, 0.01 mmol) was added into the solution. The reaction
rate was measured by monitoring the disappearance of imine and
formation of metallacycles by monitoring each of their characteristic
Supporting Information Available: Text, tables, figures, and
CIF files giving complete experimental details for the preparation
of metallacycles 2d, 2′d, 2e/3e, 2′e/3′e, 2f, 2′f, 2g, 2′g, 2h/3h, 2′h/
3′h, 2i/3i, 2′i/3′i, 2j, 2′j/3′j, 2k/3k, 2′k/3′k, 2m/3m, 2′m/3′m, and
1
2n, H and 13C NMR spectra of cyclometalated products, NMR
spectra of [Cp*RhCl2]2, Cp*Rh(OAc)Cl, Cp*Rh(OAc)2, and a
mixture of [Cp*RhCl2]2 plus 3 equiv of NaOAc, a UV-vis study
of the reaction of [Cp*RhCl2]2 with NaOAc, tables of selected bond
lengths and angles and structural data for the complete iridium series
2a,b, 3c, 2d, 3e, 2f-h, 3i, and 2j,k,n and the complete rhodium
series 2′a,b, 3′c, 2′d-f, 2′g, 3′h,i, and 2′j,k, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org. The structures are also available in the Cam-
bridge Crystallographic Database as CCDC Nos. 702293-702315.
1
imine singlet/doublet resonances by H NMR spectroscopy. Data
are shown in the text for both first- and second-order analyses.
X-ray Crystal Structure Determinations. Data were collected
on a Bruker SMART APEX II CCD Platform diffractometer at
100.0(1) K. The data collection was carried out using Mo KR
radiation. The intensity data were corrected for absorption. The
structure was solved using SIR9781 and refined using SHELXL-
97.82 All non-hydrogen atoms were refined with anisotropic
displacement parameters. All hydrogen atoms were placed geo-
metrically and refined with relative isotropic displacement parameters.
OM9000742
(81) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. SIR97: A new program for solving and refining crystal structures; Istituto
di Cristallografia, CNR, Bari, Italy, 1999.
Acknowledgment. Financial support from the National
Science Foundation (No. CHE-0717040) is gratefully
acknowledged.
(82) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.