Comparative investigations of cp*-based group 9 metal-catalyzed direct C-H amination of benzamides

Article abstract of DOI:10.1021/om5005868

Key mechanistic features of the [Cp*MCl₂]₂ (M = Ir, Rh, Co; all are in group 9) catalyzed C-H amination of benzamides with organic azides were investigated with a strong emphasis on the metal effects on the reaction mechanism, reveal

Full text of DOI:10.1021/om5005868

Article
pubs.acs.org/Organometallics
Comparative Investigations of Cp*-Based Group 9 Metal-Catalyzed
Direct C−H Amination of Benzamides
Travis M. Figg,†,⊥ Sehoon Park,‡,§,⊥ Juhyeon Park,§,‡ Sukbok Chang,*,‡,§ and Djamaladdin G. Musaev*,†
†Cherry L. Emerson Center for Scientific Computation, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Republic of Korea
§Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 305-701, Republic of Korea
S
* Supporting Information
ABSTRACT: Key mechanistic features of the [Cp*MCl2]2
(M = Ir, Rh, Co; all are in group 9) catalyzed C−H amination
of benzamides with organic azides were investigated with a
strong emphasis on the metal effects on the reaction mechanism,
revealing that the Rh- and Ir-catalyzed reactions follow a
similar reaction profile, albeit with different individual kinetic
and thermodynamic parameters. The observation that the Ir-
based system was much superior in terms of the rates and
efficiency in comparison to Rh was attributed to the intrinsically
strong relativistic effects in iridium. While a cobalt system [Cp*CoIII] showed little catalytic activity for most azides examined,
plausible [(BA)(Cp*)CoNR]+ intermediates of these reactions were characterized as a “Co(III)-nitrenoid radical” species with a
weak (“one electron−two center type”) Co−NPh bond. Its Rh and Ir analogues are characterized as diamagnetic metal
nitrenoids with a strong MNR double bond. The provided experimental and computational investigations indicate that the
rate-limiting step of the reaction resides in the final stage (protodemetalation) that takes place via a concerted metalation−
deprotonation (CMD) mechanism. While experimental measurements of thermodynamic parameters were in good agreement
with DFT calculations, theoretical predictions on the electronic nature of key intermediates and energy barriers were successfully
used to rationalize the experimentally observed reactivity pattern.
also developed the Cp*-based Rh(III)11a−f and Ir(III)11g−j
catalysts for the direct C−H amination of arenes, alkenes, and
alkanes using various organic azides as the nitrogen source
INTRODUCTION
■
Less oxophilicity and rich functional-group compatibility of
late-transition-metal complexes, relative to those of early
transition metals, enable their employment as catalysts to
(Scheme 1).
install numerous polar functional groups into desired substrate
matrices in organic molecules.1 These properties of late-
transition-metal catalysts offer an efficient synthetic tool for
accessing diverse heteroatom containing compounds. Among
the numerous notable transformations, C−N bond formation is
one of the best examples,2 because this reaction serves as a
versatile and efficient synthetic strategy that provides access to
key building blocks widely utilized in medicinal, materials, and
synthetic organic chemitsry.3 To date, the Cu-4 and Pd-
catalyzed5 cross-coupling of aryl halides with amines via the
assistance of external ligands has been proven to be one of the
most practical methods for the synthesis of various aryl amines.
However, this procedure generates stoichiometric amounts of
chemical wastes such as base salts.
Scheme 1. Direct C−H Amination of Chelating-Group-
Containing Arenes with Organic Azides
Although previously we have investigated mechanistic aspects
of the Rh(III)- and Ir(III)-catalyzed direct C−H amina-
tion,11f,g,i a parallel comparison of mechanistic details between
metal complexes has not been carried out, either experimentally
or computationally. Furthermore, we envisioned the extension
of the Rh and Ir systems to their cobalt analogues in group 9 of
the periodic table. Gratifyingly, the availability (or synthetically
easy accessibility) of the metal complexes [Cp*MCl2]2 (M = Ir,
Rh, Co) offers an ideal situation to perform a comparative
A more atom-economical alternative to the aforementioned
cross-coupling reaction is the direct amination of C−H bonds
by amines or their precursors. This reaction allows the
formation of aniline products without requiring prefunctional-
ized aryl halides as starting materials. Due to such distinguished
advantages of the direct C−H amination approach, a range of
metal-mediated procedures, including Fe,6 Ru,7 Rh,8 Pd,9 and
Cu catalysis,10 have been developed. Recently, our group has
Received: June 2, 2014
Published: July 30, 2014
© 2014 American Chemical Society
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study in the direct C−H amination of arenes using organic
azides. Since metals of the same group have different
physicochemical properties (such as ionization potentials,
electronegativity, electron affinity, and electronic configura-
tions), it is highly rewarding to investigate factors controlling
their catalytic activities. To solve these problems, the use of
comprehensive and integrated experimental and theoretical
approaches would be essential. Herein we report findings from
our joint experimental and computational studies of the
mechanisms and controlling factors of the Co-, Rh-, and Ir-
catalyzed C−H amination of arenes with azides (Scheme 2).
azides possessing electron-withdrawing substituents to ensure
reasonable product yields. Since the relative catalytic perform-
ance was weighted and discussed on the basis of product yields
1
determined by H NMR analysis of crude reaction mixture,
each reaction was conducted twice, and an average value is
presented in this study for the sake of accuracy. Trace amounts
of amines (RNH2) were often observed in the course of
amination, which were derived from the employed azides
(RN3).
It was revealed that the reaction yield is keenly dependent on
the combination of metals and azides employed. While an Ir
catalyst system smoothly performed amination of 1a to give
93% yield at 65 °C when tosyl azide (2a) was employed (entry
2), the amidation efficiency was much lower for an Rh catalyst
under otherwise identical conditions (entry 1). However, the
reactivity trend became completely opposite when benzyl azide
(2b) was used: while the Rh system afforded a modest product
yield at 110 °C (entry 3), the outcome was much inferior for
the Ir catalyst (entry 4). Similar to the case for tosyl azide, the
amination with an aryl azide (2c) was observed to be more
effective for the Ir catalyst than for the Rh catalyst at 65 °C
(entries 5 and 6). Interestingly, the reactivity difference
between these two catalytic systems was dramatic when acyl
azide (2d) was employed as a reactant: whereas no desired
product was observed with the Rh system (entry 7), an amido
product was obtained quantitatively by the Ir catalysis within
1.5 h at room temperature (entry 8). Unlike the Rh and Ir
catalyst systems, the [CoCp*Cl2]2 complex was not effective, in
general, for these amination reactions. In fact, we observed only
small amounts of amination products of benzamide when
benzyl azide (2b) was employed (entry 10), while amination
with tosyl, aryl, or acyl azide (entries 9, 11, and 12) were almost
negligible.
Scheme 2. Cp*-Based Group 9 Metal Catalysts for the Direct
C−H Amination of Benzamides with Azides
RESULTS AND DISCUSSION
■
C−H Amination of Benzamides with Various Organic
Azides. We initially carried out amination reactions of N-tert-
butylbenzamide (1a, BA-H) with four different types of organic
azides using Cp*MIII complexes (M = Co, Rh, Ir) as catalysts
(Table 1). On the basis of our previous optimized conditions,11
[Cp*MCl2]2 was used as a precatalyst in the presence of
AgSbF6 (4 equiv relative to the dimeric metal species) in
1,1,2,2-tetrachloroethane at room temperature. Knowing the
reactivity pattern of the Rh-11b,c and Ir-catalyzed11h C−H
amination of benzamides, we decided to use aryl and benzyl
We were highly intrigued by these contrasting reaction
behaviors upon the altered combination of metal catalyst and
azides, prompting us to launch comparative theoretical studies
to elucidate key mechanistic details. We envisioned that it
would be highly instructive and rewarding to compare
mechanistic details of the [Cp*MIII]-catalyzed direct C−H
amination, wherein the catalysts bear the same family of
transition metals (i.e., group 9 metals) with an identical ligand
system.
a
Table 1. Amination Reaction with Several Sets of Reagents
Computational Methods. The presented calculations
were carried out using the Gaussian 09 suite of programs.12
The geometries of all reported reactants, intermediates,
transition states, and products were optimized without
symmetry constraint at the M06 level of density functional
theory (DFT)13 in conjunction with the Lanl2dz basis set and
corresponding Hay−Wadt effective core potential (ECP) for all
transition metals (M = Co, Rh, Ir) and Sb.14 Standard 6-
31G(d,p) basis sets were used for all remaining atoms (below
we call this approach M06/{Lanl2dz+[6-31G(d,p)]} or M06/
BS1). In these calculations, the Cp* ligand, used in the
experiments, was modeled by Cp.15 A comparison of the
calculated parameters for the reaction of [(BA)(Cp)Rh]+ and
[(BA)(Cp*)Rh]+ with Ph-N3 shows that the Cp*-to-Cp
substitution only slightly changes the calculated energies and
important geometries of the reactants, intermediates, transition
states, and products and does not affect the final conclusions
(see below and also the Supporting Information). NBO analysis
was performed on each stationary point. The orbital
occupations, natural charges, and M−N orbitals were computed
b
entry
azide
M
temp (°C)
product
yield (%)
1
2a
2a
2b
2b
2c
2c
2d
2d
2a
2b
2c
2d
Rh
Ir
65
65
3a
3a
3b
3b
3c
3c
3d
3d
3a
3b
3c
3d
5
2
93
c
3
Rh
Ir
110
110
65
54
c
4
7
5
Rh
Ir
8
47
<1
95
<1
6
65
7
Rh
Ir
23
8
23
9
Co
Co
Co
Co
65
c
10
11
12
110
65
10
<1
<1
23
a
Conditions: 1a (0.25 mmol), 2 (0.35 mmol), [Cp*MCl2]2 (0.01
mmol), and AgSbF6 (0.04 mmol) in 1,1,2,2-tetrachloroethane-d2 (0.5
b
mL). Average yield of two runs determined by 1H NMR of the crude
c
reaction mixture using 1,4-dioxane as the internal standard. For 24 h.
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by NBO program as implemented in the current version of
Gaussian 09.
conditions, which may complicate the discussion of reactivity
patterns.11k Below, at first, we discuss in detail the mechanistic
aspects of the reaction [CpRhIII](SbF6)2 + Ar-N3 followed by
metal effects on the catalytic activity by establishing and
comparing energetics of the same reaction under [CpCoIII]-
(SbF6)2 and [CpIrIII](SbF6)2 catalyst systems.
The nature of each stationary point was characterized by the
presence of 0 or 1 imaginary frequency for minima and
transition states, respectively. Energetics were calculated under
standard conditions (1 atm and 298.15 K) and are reported as
relative free energies and enthalpies in kcal/mol with the
notation of ΔG (ΔH). Solvent effects were accounted for by
the PCM formalism16 in 1,2-dichloroethane (1,2-DCE, ε =
10.4), although the experiments were carried out in 1,1,2,2-
tetrachloroethane (1,1,2,2-TCE, ε = 8.4) as a solvent due to the
inappropriately lower boiling point of 1,2-dichloroethane. The
calculated parameters and geometries of key intermediates and
transition states in the course of DFT studies barely changed
upon substitution of 1,2-DCE with 1,1,2,2-TCE. Cartesian
coordinates for all reported structures are given in the
Supporting Information.
Key Mechanistic Features of the [CpRhIII](SbF6)2-
Catalyzed Amination of N-tert-Butylbenzamide. Forma-
tion of catalytically active species, [(BA)(Cp)Rh](SbF6), from
CpRhIII(SbF6)2 and N-tert-butylbenzamide (BA-H, 1a) was
calculated to be exergonic by 4.7 kcal/mol, where “BA” refers to
an ortho-deprotonated benzamide moiety bound to the metal
center (step 1). In general, this reaction may proceed via either
(a) deprotonation of 1a by SbF6− and subsequent coordination
of the deprotonated arene (BA−) to Rh through the oxygen
atom of its carbonyl group or (b) benzamide (1a) coordination
to Rh through a carbonyl oxygen atom and then deprotonation
at the ortho position of the arene. The amination reaction of 1a
with 2a under standard conditions using [Cp*MCl2]2 (M = Rh,
Ir) and AgNTf 2 (instead of AgSbF6) as a catalyst gave 10% and
96% yields of product 3a, respectively. These are very close to
the yields in entries 1 and 2 of Table 1. It implies that the ortho
On the basis of our previous report,11f a proposed catalytic
cycle would comprise four key steps: (i) the formation of
catalytically active species from the corresponding neutral
dimeric precursors, (ii) azide coordination and subsequent N2
dissociation leading to the formation of a metal−nitrenoid
intermediate, (iii) intramolecular insertion of the nitrenoid
moiety into a metallacyclic metal−Caryl bond, and finally (iv)
protodemetalation giving rise to the formation of an aminated
product (Figure 1).
−
deprotonation by a counteranion (i.e., SbF6− or NTf2 ) is not a
rate-determining step but a facile process.11f−h Therefore, we
do not report details of structures involved in this step (step 1)
of the amination reaction.
Our extensive computations have shown that the presence of
−
the counteranion SbF6 displays negligible effects on the
calculated parameters in the reaction [(BA)CpRhIII](SbF6) +
Ph-N3 (see the Supporting Information). Therefore, for
simplicity, through the paper we assume that the cationic
metal complex [(BA)(Cp)M]+ (1_M, where M = Co, Rh, Ir)
would be a catalytically active species.
Step 2: [(BA)(Cp)Rh]+ + Ph-N3 → [(BA)(Cp)RhNPh]+ +
N2. The calculated reactants, intermediates, and transition
states involved in the formation of the Rh−nitrenoid
intermediate 2_Rh_Ph (i.e., step 2), with their characteristic
geometrical parameters, are presented in Figure 2. As expected,
the initial step of this reaction is coordination of PhN3 to
[(BA)(Cp)Rh]+ (1_Rh) leading to the formation of the adduct
1_Rh_Ph (where “Ph” stands for the R group of azides R-N3)
with a bond distance of 2.24 Å between the Rh center and
N3Ph (not shown in Figure 2). This process is endergonic by
4.1 kcal/mol. From the resultant adduct the reaction proceeds
via N2 dissociation and Rh−nitrenoid bond formation (see
Figure 3), which occurs with an energy barrier of 30.9 kcal/mol
(in comparison to the separate reactants: 1_Rh + Ph-N3) at the
transition state TS1_Rh_Ph and is exergonic by 11.9 kcal/mol.
The exergonicity of this step (step 2) can be attributed to the
generation of the N2 molecule (the calculated ΔG value of the
reaction Ph-N3 → PhN (3A) + N2 is −7.8 kcal/mol)
accompanied by the formation of a RhNPh bond. NBO
analysis of the resultant 2_Rh_Ph complex reveals the existence
of a well-established double bond between the Rh center and
NPh fragment: a σ bond formed by electron donation from the
nitrogen atom to the Rh center and a π bond generated by
back-donation from the occupied dπ orbital of the Rh center to
the π* orbital of the NPh fragment (Figure 4). Close
examination of the structures 1_Rh_Ph and 2_Rh_Ph provides
additional support for this conclusion: the calculated Rh−N
bond length (1.91 Å) in 2_Rh_Ph is significantly shorter than
that in 1_Rh_Ph (2.24 Å). In the latter, the Rh−N interaction
Figure 1. Proposed catalytic cycle of the amination of N-tert-
butylbenzamide with azides, where M = Co, Rh, Ir and Z = Ts (2a),
Me, Ph, (m-CF3)2C6H3 (2c), (p-NO2)C6H4 (2e).
In this article, we describe factors affecting the energetics and
geometries of the proposed intermediates, transition states, and
products of steps 2−4 postulated in Figure 1 in the amination
reaction with aryl azides using group 9 metal catalysts Cp*MIII,
where M = Co, Rh, Ir. In a similar manner, we have also
performed computational studies on the analogous reaction
with alkyl and tosyl azides to understand the azide effects on the
reactivity. For the sake of clarity, we present these data in the
Supporting Information. However, we excluded acyl azides as
the nitrogen source in our computational study because it
readily undergoes Curtius rearrangement under certain reaction
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Figure 2. Optimized structures and geometries of 1_M, TS1_M_Ph,
and 2_M_Ph involved in the Ph-N3 coordination to [(BA)(Cp)M]+,
N2 dissociation, and M−nitrenoid formation (i.e., step 2). Values given
in the first line are for the singlet/triplet states of M = Co, and those
given in the second and third lines are for M = Rh, Ir, respectively.
Bond lengths are given in Å.
Figure 4. Visualization of the bonding (left) and antibonding (right)
counterparts of the σ donation and π back-donation orbitals of the
MNPh bond in the intermediate 2_M_Ph.
is weak and has no covalent character (see the Supporting
Information for details).
Thus, the presented computational analysis shows that step
2, [(BA)(Cp)Rh]+ + Ph-N3 → [(BA)(Cp)RhNPh]+ + N2,
involves a soft oxidation of the rhodium center from Rh(III) to
Rh(V). In the resultant intermediate 2_Rh_Ph, the formed
RhNPh has a double-bond character with donation (σ bond)
and back-donation (π* bond) components. Furthermore, upon
Figure 3. Calculated potential energy surface for the direct oxidative C−H amination of N-tert-butylbenzamide with the [(BA)(Cp)MIII]+ catalyst,
1_M, where M = Rh, Ir, utilizing aryl azide as the nitrogen source. Energetics are compared to those of complex 1_M + PhN3 and given as ΔG (ΔH)
in kcal/mol.
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the formation of 2_Rh_Ph, slight reorganization of electron
density between (BA)Rh and NPh fragments occurs, mostly via
a π channel: the calculated natural charges are +0.22 and −0.34
(in 1_Rh_Ph) and +0.24 and +0.01 (in 2_Rh_Ph) for Rh and
C (arene of BA), and −0.11 (in 1_Rh_Ph) and −0.26 (in
2_Rh_Ph) for the N center. The calculated Rh−N Wiberg
bond order is 1.0.
respectively. Since the azide coordination is more demanding
energetically by 8.4 kcal/mol than the benzamide coordination,
below we discuss in detail only the process initiated by the
benzamide coordination. The calculated key reactants,
intermediates, and transition states involved in this step of
the reaction are presented in Figure 6 with their characteristic
geometrical parameters.
Step 3: Nitrenoid C−Rh Insertion of [(BA)(Cp)Rh
NPh]+ Leading to C−N Bond Formation. As expected, the
Rh−nitrenoid intermediate 2_Rh_Ph is thermodynamically
fragile and, thus, would easily undergo a nitrenoid insertion
process. In fact, computations show that the nitrenoid insertion
into a Rh−Caryl bond to form an Rh(III) amido complex
(3_Rh_Ph, Figure 5) is exergonic by 41.1 kcal/mol and
Figure 6. Optimized structures of the transition state TS3_M_Ph and
product 5_M_Ph involved in the coordination of a second N-tert-
butylbenzamide to the intermediate 3_M_Ph. Values given in the first
line are for the singlet/triplet states of M = Co, and those given in the
second and third lines are for M = Rh, Ir, respectively. Bond lengths
are given in Å.
Figure 5. Optimized structures of the transition state TS2_M_Ph and
intermediate 3_M_Ph involved in the nitrenoid insertion. Values given
in the first line are for the singlet/triplet states of M = Co, and those
given in the second and third lines are for M = Rh, Ir, respectively.
Bond lengths are given in Å.
Coordination of a second benzamide (BA-H) leads to the
formation of the adduct 4_Rh_Ph (not shown in Figure 6),
where BA-H only weakly interacts with the Rh center via its
oxygen atom. This weak interaction initiates a concerted
metalation−deprotonation (CMD) process that involves
hydrogen transfer from an arene of the second benzamide
molecule to the amido nitrogen of the metallacycle 3_M_Ph.
Overall, step 4 is endergonic by 2.3 kcal/mol, calculated relative
to the intermediate 3_Rh_Ph and N-tert-butylbenzamide (BA-
H), and requires a 40.6 kcal/mol energy barrier at the CMD
transition state TS3_Rh_Ph (Figures 3 and 6). Comparison of
this energy barrier with 30.9 and 7.5 kcal/mol, reported for step
2 (at TS1_Rh_Ph) and step 3 (at TS2_Rh_Ph), respectively,
indicates that the C−H bond cleavage via CMD (at
TS3_Rh_Ph) mechanism is the rate-determining step in the
entire [(BA)(Cp)Rh]+-catalyzed C−H amination of N-tert-
butylbenzamide with phenyl azide. Alternatively, step 4 may
proceed via a stepwise pathway involving (i) the deprotonation
of the second benzamide (BA-H) by a counteranion, and (ii)
the protonation of the N1 center in amido complex 3_Rh_Ph
by other proton sources from the reaction medium (including
previously formed HSbF6). However, as shown for step 1, the
counteranionic effect on the reactivity has not been observed,
and we may exclude the possibility of the stepwise pathway as
an alternative. This conclusion is also supported by computa-
tional findings, which show a negligible impact on the presence
of counteranion SbF6− and on the calculated parameters of the
reaction [(BA)CpRhIII](SbF6) + Ph-N3 (see the Supporting
Information).
proceeds with a small energy barrier of 7.5 kcal/mol (calculated
relative to the prereaction complex 2_Rh_Ph) at the transition
state TS2_Rh_Ph.
An inspection of the geometries of 2_Rh_Ph, TS2_Rh_Ph,
and 3_Rh_Ph (Figures 2 and 5) shows an increase in the Rh−
N bond length from 1.91 Å (in 2_Rh_Ph) to 1.96 Å (in
TS2_Rh_Ph) and then to 2.09 Å (in 3_Rh_Ph). This is in line
with the loss of the Rh−N double-bond character and, as a
result, alteration of the N hybridization from sp2 to sp3.
Additionally, for the transition state TS2_Rh_Ph, NBO analysis
shows a loss of the Rh−N π bond and an increase of metal
character in the Rh−N σ bond. Thus, the kinetic and
thermodynamic feasibility of the nitrene insertion into the
Rh−arene bond (2_Rh_Ph → 3_Rh_Ph) is a consequence of
reduction of the Rh(V)−nitrene intermediate to the Rh(III)−
amido complex. Notably, protonation of the nitrene ligand in
2_Rh_Ph and subsequent amido insertion into the Rh−Caryl
bond, which is a process accompanied by no net change in the
+3 oxidation state of a rhodium metal center, was found to be
endergonic by ca. 34 kcal/mol, thus excluding the possibility of
this Rh(III) → Rh(III) transformation. In the resultant
intermediate 3_Rh_Ph, the Wiberg bond order of the Rh−
N1 bond was calculated to be 0.55, which is consistent with a
long Rh−N1 bond distance. Furthermore, in 3_Rh_Ph, the N1
center becomes more electron rich (compared to 2_Rh_Ph)
with a −0.49e natural charge.
As displayed in Figure 6, an inspection of geometries of
structures involved in step 4 reveals a direct hydrogen transfer
with little to no interaction with Rh, as the Rh−H distances
were calculated to be 2.49, 2.00, and 2.65 Å for complexes
4_Rh_Ph, TS3_Rh_Ph, and 5_Rh_Ph, respectively. It is noted
that the Cp-to-Cp* substitution only slightly affects the
calculated energetics of this process. Indeed, it does not change
the N2-extrusion barrier (step 2; the calculated barriers are 30.9
Step 4: Protodemetalation with Product Release.
From the intermediate 3_Rh_Ph, the final protodemetalation
process in a catalytic cycle may proceed via the coordination of
either a second N-tert-butylbenzamide substrate or a second
azide reactant to the Rh center. Extensive calculations show
that both cases are endergonic, by 14.5 and 22.9 kcal/mol,
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and 30.6 kcal/mol for L= Cp, Cp*, respectively), it reduces the
nitrenoid insertion barrier (step 3) from 7.5 to 5.6 kcal/mol,
and the barrier in the rate-determining C−H activation step
(step 4) is only slightly reduced from 40.6 to 38.8 kcal/mol
(see also the Supporting Information). Thus, modeling of the
Cp* ligand, used in experiments, by the Cp ligand does not
affect our major conclusions and can be safely used for other
reactions presented in this paper.
azide 2c. This computational finding is also in good agreement
with our experimental data presented in Table 1, showing only
slight changes in yields (see entries 1 and 5) upon changing the
substrate from 2a to 2c.
Metal Effects: [Cp*IrIII](SbF6)2 Catalyst. In experiments
(Table 1 and eqs 1 and 2),11 a dramatic difference in reaction
One should emphasize that a change in the electronic nature
of the azide fragment could have significant effects on the
calculated energetics of the [(BA)(Cp)Rh]+-catalyzed C−H
amination of N-tert-butylbenzamide (BA-H, 1a). For example,
calculations show that substitution of m-H’s by CF3 group(s)
(Ph-N3 → 2c) reduces both the N2-extrusion (from 30.9 to
23.7 kcal/mol) and CMD (from 40.6 to 35.4 kcal/mol)
barriers. Incorporation of a NO2 group at the para position
(Ph-N3 → 2e) also reduces both the N2-extrusion (from 30.9 to
27.0 kcal/mol) and the CMD (from 40.6 to 33.3 kcal/mol)
barriers. The calculated trend, N3-Ph (40.6 kcal/mol) > N3-
C6H3(m-CF3)2 (35.4 kcal/mol) > N3-C6H4(p-NO2) (33.3 kcal/
mol), in the rate-determining CMD barrier is closely correlated
with the electron-rich nature of the N1-center in 3_Rh_R:
calculated natural charges on N1 of 3_Rh_R are N3-Ph
(−0.49e) < N3-C6H3(m-CF3)2 (−0.52e) < N3-C6H4(p-NO2)
(−0.53e).
efficiency in terms of product yields was observed between the
[Cp*MIII](SbF6)2-catalyzed amination. In fact, the iridium
catalyst [Cp*IrIII](SbF6)2 displayed faster reaction rates as well
as higher product yields than the corresponding rhodium
catalyst for the reaction of N-tert-butylbenzamide with most
azides examined. One exception was the case of benzyl azide,
which reacts more efficiently under the [Cp*RhIII](SbF6)2
catalyst.
In order to elucidate key factors contributing to this dramatic
difference in catalytic reactivity, we performed computational
studies of an amination reaction with [Cp*IrIII](SbF6)2 catalyst.
We anticipated that a comparison of this result with that of the
corresponding [Cp*RhIII](SbF6)2 system, as discussed above, is
going to be instrumental in understanding the observed notable
dependence of amination activity on the metal center. Relative
energies of reactants, intermediates, transition states, and
products calculated for the [(BA)(Cp)Ir]+ (1_Ir)-catalyzed
amination of N-tert-butylbenzamide with phenyl azide (Ph-N3)
are given in Figures 2−6. As indicated in Figure 3, the step 2
process to form a nitrenoid species, [(BA)(Cp)Ir]+ + Ph-N3 →
[(BA)(Cp)IrNPh]+ + N2, proceeds with a 29.5 kcal/mol
energy barrier at the N2-extrusion transition state TS1_Ir_Ph
and is 18.9 kcal/mol exergonic. Comparison of these values for
M = Ir with the 30.9 kcal/mol barrier and 11.9 kcal/mol
exergonicity calculated for M = Rh suggests that the “Rh to Ir
replacement” makes the reaction thermodynamically more
favorable by 7.0 kcal/mol. This preferential exergonicity in the
Ir system over the Rh system is the consequence of the most
prominent characteristic feature of the electronic structure of Ir:
namely, the existence of strong (in comparison with Rh)
relativistic effects in Ir.17 In general, the relativistic contraction of
the 6s orbital in Ir results in greater involvement of its p and d
atomic orbitals in the metal−ligand bonding, which is
manifested in a stronger Ir−ligand bond (in comparison to
the Rh−ligand bond).17e Furthermore, the existence of strong
relativistic effects in Ir makes its +5 oxidation state more accessible
for the formation of the nitrenoid species [(BA)(Cp)Ir
NPh]+ (2_Ir_Ph).
Thus, the computational data presented above show that the
amination of N-tert-butylbenzamide with aryl azides catalyzed
by CpRhIII(SbF6)2 is an energy-demanding process and cannot
take place under ambient conditions. This computational
conclusion is consistent with the experimental data presented in
Table 2. As seen in this table, the amination of 1a (BA-H) or its
a
Table 2. Rh-Catalyzed Amination Reaction with Aryl Azide
b
entry
benzamide
temp (°C)
time (h)
product
yield (%)
1
2
3
4
5
1a
1b
1a
1b
1b
23
23
85
85
85
24
24
1.5
1.5
24
3e
3f
3e
3f
3f
<1
<1
33
54
68
a
Conditions: 0.25 mmol of 1, 0.35 mmol of 2e, 0.01 mmol of
[Cp*RhCl2]2, and 0.04 mmol of AgSbF6 in 0.5 mL of 1,1,2,2-TCE-d2.
b
1
Average yield of two runs determined by H NMR analysis of crude
reaction mixture using 1,4-dioxane as the internal standard.
derivative (1b) bearing a fluoro group at the para position
requires a relatively higher temperature (85 °C), giving rise to
the corresponding products 3e,f in 33% and 54% yields,
respectively (Table 2, entries 3 and 4). Furthermore, the yield
of 3f was increased to 68% with prolonged reaction time (entry
5). Computations also reveal insignificant change in the N2-
extrusion and CMD activation barriers in the arene C−H bond
activation with the use of tosyl azide 2a instead of aryl azide 2c.
For tosyl azide 2a, barriers of these two steps were calculated to
be 35.3 and 35.2 kcal/mol, respectively, which are comparable
with the rate-determining barrier of 35.4 kcal/mol for the aryl
Thus, the relativistic effects in Ir are instrumental in forming
a stronger IrNPh bond in comparison to RhNPh. Indeed,
as seen in Figure 4, in both components of the MNPh bond,
i.e. σ-donation and back-donation from nitrenoid to M and
from M to nitrenoid, respectively, the weights (percentage) of
accepting orbitals (in the case of donation, it is an spd hybrid
orbital of M, and in case of back-donation, it is a π* orbital of
the NPh moiety) are larger for M = Ir than for M = Rh. In
other words, one can see more efficient electron transfer (and,
accordingly, stronger orbital overlap) in both donation and
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back-donation components for the IrNPh bond in
comparison to RhNPh. Furthermore, this feature of the
MNPh bond is more pronounced in π bonding rather than σ
bonding (Figure 4). This difference in the nature of IrNPh
and RhNPh bonds is well reflected in the computed M−NPh
bond lengths (1.87 Å for Ir and 1.91 Å for Rh; see Figure 2)
and Wiberg bond orders (BO = 1.3 for Ir and 1.0 for Rh). As a
result, in 2_Ir_Ph, the N1 center is more electron rich with
−0.32e natural charge than in 2_Rh_Ph (with −0.26e natural
charge). Thus, the existence of large relativistic effects in Ir,
manifested in the generation of a stronger IrNPh bond and facile
accessibility of the Ir(V) oxidation state, is postulated to be a major
reason for greater (than for Rh) exothermicity of the nitrenoid
formation reaction: [(BA)(Cp)Ir]+ + Ph-N3 → [(BA)(Cp)Ir
NPh]+ + N2.
closely correlates with the electron-rich nature of the N1 center
of metal nitrenoid intermediates.
In order to validate the activation parameters obtained from
the computation, mechanistic experiments were conducted (eqs
3 and 4). For the purpose of the kinetic study, several attempts
Similar to the case of [(BA)(Cp)Rh]+, step 3 involves a
nitrenoid insertion into the Ir−Caryl bond in 2_Ir_Ph to afford
the Ir(III) amido complex (3_Ir_Ph). As expected, this process
is exergonic by 23.5 kcal/mol with an energy barrier of 7.1 kcal/
mol (calculated relative to the prereaction complex 2_Ir_Ph) at
the transition state TS2_Ir_Ph. Thus, the formation of
3_Ir_Ph is 17.6 kcal/mol less exergonic in comparison to the
formation of 3_Rh_Ph. NBO analysis shows that the N1 center
is more electron-rich in 3_Ir_Ph than that in 3_Rh_Ph: the
calculated NBO charges of N1 are −0.54e and −0.49e,
respectively. Higher electron density in the N1 center of
3_Ir_Ph makes the CMD step kinetically less demanding and
thermodynamically more favorable for [(BA)(Cp)Ir]+ than
[(BA)(Cp)Rh]+. Indeed, as seen in Figure 3, a CMD
transformation that transfers a hydrogen atom from the second
BA-H substrate to the inserted amido nitrogen to form the
intermediate 5_Ir_Ph is 7.6 kcal/mol exergonic relative to
3_Ir_Ph. For M = Rh, this process is 2.3 kcal/mol endergonic.
Furthermore, the CMD pathway occurs with a barrier of 33.9
kcal/mol at the transition state TS3_Ir_Ph, which is 6.6 kcal/
mol smaller than that for the [(BA)(Cp)Rh]+ catalyst.
On the basis of the above discussions, it becomes obvious
that strong relativistic effects in Ir significantly affect steps 2−4.
Namely, they increase electron density of the N1 center, reduce
the rate-determining CMD barrier, and make the product
formation (step 4) more exothermic. In other words, the
existence of relativistic effects in Ir enables the [(BA)(Cp)Ir]+
system to be more efficient than [(BA)(Cp)Rh]+ for this
amination reaction. This theoretical consideration is in
excellent agreement with our experimental observations
(Table 1). Computational data provide a clear explanation of
the observed difference in reactivity of [(BA)(Cp)Ir]+ and
[(BA)(Cp)Rh]+ catalysts.
to isolate or generate in situ 1_M through a stoichiometric
reaction of 1a, [Cp*MCl2]2 (M = Rh, Ir), and AgSbF6 even in
the presence of various bases have been preliminarily carried
out, but all were unsuccessful (<10% NMR yield of 1_M).
Since an initially designed reaction with (m-CF3)2C6H3-N3 (2c)
was observed to be quite slow at room temperature, tosyl azide
(2a) was employed as the nitrogen source instead of 2c for this
study. Conversion of BA-H (1a) to the corresponding product
1
(3a) was monitored by H NMR analysis. Excess 2a (10 equiv
relative to 1a) led the reaction to rigorously follow pseudo-first-
order kinetics with kobs = 0.00598 min−1 at 25 °C for the
formation of the aminated product 3a. The KIE measurement
based on the comparison of the initial rates between 1a and 1a-
d5 revealed a notable kinetic isotopic effect of 4.82 at 25 °C,
suggesting that the C−H bond cleavage is likely a turnover-
limiting step (eq 3). An Eyring plot of the rate constants
obtained at a series of temperatures (25−40 °C) provided the
activation parameters for this catalytic system: ΔH⧧ = 20.3
kcal/mol and ΔS⧧ = 1.5 cal/(mol K) (eq 4). Significantly, the
measured ΔH⧧ is in good agreement with that (ΔH⧧ = 17.9
kcal/mol) obtained from the DFT calculations (see the
Supporting Information for details on the activation parameters
determined by DFT calculations in the (Cp)Ir-catalyzed
amination of 1a with 2a).
Metal Effects: [Cp*CoIII](SbF6)2 Catalyst. Encouraged by
the excellent agreement between the experimental and
computational results for M = Rh, Ir systems discussed
above, we turned our attention to explore the feasibility of
[CpCoIII](SbF6)2 to be a greener and cheaper alternative of the
[CpRhIII](SbF6)2 and [CpIrIII](SbF6)2 catalysts. The use of 3d
metals in catalytic reactions is of great interest due to their
natural abundance, low cost, and potentially unique catalytic
activity in comparison to their 4d and 5d counterparts. The fact
that Ir, Rh, and Co are all in group 9 in the periodic table
provides us an ideal situation to compare the catalytic behaviors
of the corresponding complexes [Cp*MIIICl2]2 bearing identical
ligand systems working on the same amination reactions.
Since Co(III) complexes may have a high-spin ground
electronic state,18 we initially attempted to explore both singlet
and triplet electronic states of each stationary point of the
reaction steps 2−4 mediated by [(BA)CpCoIII]+. The
calculated relative energies of the reactants, intermediates,
transition states, and products in the amination of N-tert-
butylbenzamide (1a) with Ph-N3 by [(BA)CpCoIII]+ (1_Co)
catalyst are given in Figures 2, 5, and 6 (full geometries of all
calculated structures are given in the Supporting Information).
Similar to the case of [(BA)(Cp)Rh]+, a change in electronic
nature of aryl azides significantly affects the calculated
properties of the reaction. Upon the variation of aryl azides
from Ph-N3 to (m-CF3)2C6H3-N3 (2c) or (p-NO2)C6H4-N3
(2e), the calculated energy barriers are reduced in both N2-
extrusion and rate-determining CMD steps. In fact, the
activation barriers of the nitrenoid formation with the
concomitant release of N2 are ΔG (ΔH) = 29.5 (14.6) kcal/
mol (for N3-Ph), 23.9 (8.4) kcal/mol (for 2e), and 20.1 (6.1)
kcal/mol (for 2c). Likewise, the energy barriers in the CMD
step are ΔG (ΔH) = 33.9 (18.4) kcal/mol (for N3−Ph), 33.1
(16.6) kcal/mol (for 2e), and 29.5 (13.9) kcal/mol (for 2c).
However, they only slightly affect the exergonicity of steps 2−4.
The change in the rate-determining CMD barriers, once again,
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The ground electronic state of [(BA)(Cp)CoIII]+ was found to
be the triplet state with almost two (exactly 1.81) unpaired
electrons located in the Co center. Its closed-shell singlet state
was calculated to be 6.5 kcal/mol higher in energy.
40.6 kcal/mol for the Rh system and 33.9 kcal/mol for the Ir
system. Furthermore, the formation of the final product
5_Co_Ph (step 4) is highly endergonic by 12.1 kcal/mol in
comparison to both Rh and Ir catalyst systems, where step 4 is
endergonic by 2.3 kcal/mol for M = Rh but 7.6 kcal/mol
exergonic for M = Ir. Thus, the large CMD barrier and
endergonicity of the present reaction, 3_M_Ph + BAH →
5_M_Ph, eventually render the CMD step kinetically and
thermodynamically inaccessible in the [(BA)(Cp)CoIII]+
catalyst system. This conclusion is in good agreement with
our experimental observation given in Table 1.
Reaction of [(BA)CpCoIII]+ (1_Co) and phenyl azide (N3-
Ph) proceeds with a free energy barrier of 31.7 kcal/mol at the
singlet transition state TS1_Co_Ph, leading to the formation of
a triplet 2_Co_Ph complex. This intermediate lies 14.5 kcal/
mol lower in energy than the reactants (triplet 1_Co + Ph-N3).
See the Supporting Information for a more detailed potential
energy profile of this reaction.
A close examination of electronic structures of the triplet
intermediate 2_Co_Ph reveals that unpaired electrons are
mostly (ca. 1.34e) located on the N1 center of the CoNPh
bond, whereas the cobalt center bears only a 0.27e unpaired
electron. Therefore, this species can be characterized as a
“Co(III)−nitrenoid radical” species. Similar types of “nitrene
radical species” were previously reported as key intermediates
in olefin aziridination19 and allylic C−H amination.20 In
addition, the same electronic features as for the present
Co−NPh species (2_Co_Ph) were observed by Zhang and co-
workers in (Porphyrin)CoIII-NC(O)(OMe), where the “ni-
trenoid ligand” was described as a nitrogen-centered radical
species {RN•}− (as a “nitrene radical anion ligand”).21 In fact,
NBO analysis shows a weak bonding (with only 0.3 Wiberg
bond order) between the Co and NPh in our case, which could
be characterized as a weak bond of a “one-electron−two-center
type” between the “high-spin” Co(III) center and “nitrene
radical anion ligand”, suggesting that 2_Co_Ph is a highly
unfavorable species.
Thus, the 2_Co_Ph intermediate with a “Co(III)−nitrenoid
radical” character and weak one-electron−two-center type Co−
NPh bond is very different from the nitrenoids 2_Rh_Ph and
2_Ir_Ph characterized as diamagnetic species with double-
bond character between the metal(V) center and the NPh
fragment. Such a strong radical character of 2_Co_Ph can also
lead to different reactivity: for example, either a radical addition
reaction with a π nucleophile as a coupling partner or a
transformation to a highly favorable 3_Co_Ph intermediate.
On the basis of the reported energy barriers for the radical
addition reaction of the analogue of 2_Co_Ph,19b,c,e−i,20a,b,21e−i
we assume that a radical coupling reaction may require an
energy barrier larger than 4.4 kcal/mol (at the transition state
TS2_Co_Ph), which is needed for the 2_Co_Ph → 3_Co_Ph
transformation. In fact, this conversion was found to be highly
exergonic (47.5 kcal/mol) relative to the Rh (40.1 kcal/mol)
and Ir (23.5 kcal/mol) systems. Thus, the formation of a triplet
3_Co_Ph intermediate requires a lower barrier and is more
exergonic than its Rh and Ir counterparts. Therefore, a
subsequent radical addition reaction of the Co−nitrenoid
intermediate 2_Co_Ph is unlikely.
CONCLUSIONS
■
Here, we reported integrated experimental and theoretical
studies on the key mechanistic features of the
[Cp*MIII(SbF6)2]-catalyzed (where M = Co, Rh, Ir) direct
C−H amination of N-tert-butylbenzamide with organic azides.
Special emphases were made on the metal and azide effects on
the reactivity pattern and energy parameters.
(1) It was shown that this catalytic reaction is a multistep
process that includes four key steps: (i) the formation of the
catalytically active species [(BA)Cp*MIII]+ (step 1), (ii) azide
coordination and N2 extrusion to form a key nitrenoid species
(step 2), (iii) insertion of the formed nitrenoid moiety into the
metallacyclic metal−aryl bond (step 3), and (iv) protodeme-
talation of an inserted amido metallacycle via a concerted
metalation−deprotonation (CMD) mechanism to provide a
product with the regeneration of a catalytically active species
(step 4).
(2) Step 2, i.e. [(BA)(Cp)M]+ + R-N3 → [(BA)(Cp)M
NR]+ + N2, was found to be exergonic and to proceed with a
significant energy barrier. Its exothermicity decreases in the
order M = Ir > Co > Rh, while the N2-extrusion barrier heights
are almost the same for all three metals. The existence of strong
relativistic effects in Ir, manifested in the formation of a stronger
IrNR nitrenoid bond and accessibility of the +5 oxidation
state, is predicted to be a major reason for greater exothermicity
and slightly lower N2 extrusion barrier for M = Ir in comparison
to its Rh analogue.
(3) The product of step 2, i.e. the intermediate [(BA)(Cp)-
MNR]+, was reported to be a M(V)−nitrenoid species with a
closed-shell singlet electronic state and MNR double bond,
for M = Rh, Ir. However, for M = Co, it was characterized as a
“Co(III)−nitrenoid radical” with a weak single Co−N bond.
(4) Nitrenoid intermediates [(BA)(Cp)MNR]+ rapidly
undergo an amido insertion process to afford a [(Cp)MN(R)-
(BA)]+ intermediate with an energy barrier of a few kilocalories
per mole regardless of the nature of the metal center. This
process was calculated to be highly exergonic.
(5) The rate-determining step of the overall
[Cp*MIII(SbF6)2]-catalyzed C−H amination of N-tert-butyl-
benzamides with organic azides was found to be proto-
demetalation of the amido intermediate that occurs via a
concerted metalation−deprotonation (CMD) mechanism. It is
predicted that the electron-rich nature of the N1 center of the
amido-inserted metallacyclic intermediates 3_M_R renders the
rate-determining CMD step kinetically less demanding and
thermodynamically more favorable for the M = Ir system than
the corresponding Rh catalysis.
The findings presented above prove the comparative
experimental and computational study to be highly effective
in the rationalization of the observed periodic pattern of
reactivity and for a better understanding of the origin of metal
In the resultant intermediate 3_Co_Ph, the Co center, once
again, bears more unpaired electrons (1.22e) than the entire
HNPh(BA) fragment, which holds almost 0.68e unpaired spin
with 0.44e on the N center. This species can be characterized as
a Co(III)-[N(H)Ph(BA)] complex with a Co−N two-
electron−two-center single-bond character (the calculated
bond distance is 1.93 Å) and with electron density polarized
toward the N center. Again, this species could be involved
either in the radical coupling process or in a reaction with
another BA-H molecule via the CMD mechanism (step 4). The
calculated CMD barrier at the transition state TS3_Co_Ph is
51.9 kcal/mol, which is much larger than the energy barriers
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effects in the [Cp*MIII(SbF6)2]-catalyzed (where M = Co, Rh,
Ir) direct C−H amination of N-tert-butylbenzamide with
organic azides. This work is expected ultimately to be an
important basis for designing the next catalytic systems with
better kinetic and thermodynamic properties, especially by
scrutinizing the role of central metals in the same group in the
periodic table.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, tables, and xyz files giving detailed experimental
procedures and characterization data for new compounds,
Cartesian coordinates of computed structures, energetics of the
[(BA)(Cp)Rh]+ and [(BA)(Cp)Ir]+-catalyzed direct C−H
amination of N-tert-butylbenzamide with alkyl and tosyl azides,
and potential energy surfaces of the [(BA)(Cp)Co]+-catalyzed
direct C−H amination of N-tert-butylbenzamide with aryl
azides. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail for S.C.: sbchang@kaist.ac.kr.
*E-mail for D.G.M.: dmusaev@emory.edu.
Author Contributions
⊥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(NSF) under the Center for Chemical Innovation in Stereo-
selective C−H Functionalization (CHE-1205646), under NSF-
MRI-R2 grant (CHE-0958205), and the use of the resources of
the Cherry L. Emerson Center for computations. Financial
support was provided also from the Institute for Basic Science
(IBS) in Korea.
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