Catalytic C-H Amination Mediated by Dipyrrin Cobalt Imidos

Article abstract of DOI:10.1021/jacs.9b01262

Reduction of (^ArL)Co^IIBr (^ArL = 5-mesityl-1,9-(2,4,6-Ph₃C₆H₂)dipyrrin) with potassium graphite afforded the novel Co^I synthon (^ArL)Co^I. Treatment of (^ArL)Co^I with a stoichiometric amount of various alkyl azides (N₃R) furnished three-coordinate Co^III alkyl imidos (^ArL)Co(NR), as confirmed by single-crystal X-ray diffraction (R: CMe₂Bu, CMe₂(CH₂)₂CHMe₂). The exclusive formation of four-coordinate cobalt tetrazido complexes (^ArL)Co(κ²-N₄R₂) was observed upon addition of excess azide, inhibiting any subsequent C-H amination. However, when a weak C-H bond is appended to the imido moiety, as in the case of (4-azido-4-methylpentyl)benzene, intramolecular C-H amination kinetically outcompetes formation of the corresponding tetrazene species to generate 2,2-dimethyl-5-phenylpyrrolidine in a catalytic fashion without requiring product sequestration. The imido (^ArL)Co(NAd) exists in equilibrium in the presence of pyridine with a four-coordinate cobalt imido (^ArL)Co(NAd)(py) (K_a = 8.04 M^-1), as determined by ¹H NMR titration experiments. Kinetic studies revealed that pyridine binding slows down the formation of the tetrazido complex by blocking azide coordination to the Co^III imido. Further, (^ArL)Co(NR)(py) displays enhanced C-H amination reactivity compared to that of the pyridine-free complex, enabling higher catalytic turnover numbers under milder conditions. The mechanism of C-H amination was probed via kinetic isotope effect experiments [k_H/k_D = 10.2(9)] and initial rate analysis with para-substituted azides, suggesting a two-step radical pathway. Lastly, the enhanced reactivity of (^ArL)Co(NR)(py) can be correlated to a higher spin-state population, resulting in a decreased crystal field due to a geometry change upon pyridine coordination.

Full text of DOI:10.1021/jacs.9b01262

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Article
Catalytic C–H Amination Mediated by Dipyrrin Cobalt Imidos
Yunjung Baek, and Theodore A. Betley
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01262 • Publication Date (Web): 23 Apr 2019
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Catalytic C–H Amination Mediated by Dipyrrin Cobalt Imidos
Yunjung Baek and Theodore A. Betley
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Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge MA 02138
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords,
provide significant keywords to aid the reader in literature retrieval.
ABSTRACT: Reduction of (ArL)CoIIBr (ArL = 5-mesityl-1,9-(2,4,6-Ph3C6H2)dipyrrin) with potassium graphite afforded the
novel CoI synthon (ArL)CoI. Treatment of (ArL)CoI with a stoichiometric amount of various alkyl azides (N3R) furnished
three-coordinate CoIII alkyl imidos (ArL)Co(NR) as confirmed by single crystal X-ray diffraction (R: CMe2Bu,
CMe2(CH2)2CHMe2). The exclusive formation of four-coordinate cobalt tetrazido complexes (ArL)Co(κ2-N4R2) was observed
upon addition of excess azide, inhibiting any subsequent C–H amination. However, when a weak C–H bond is appended to
the imido moiety, as in the case of (4-azido-4-methylpentyl)benzene, intramolecular C–H amination kinetically
outcompetes formation of the corresponding tetrazene species to generate 2,2-dimethyl-5-phenylpyrrolidine in a catalytic
fashion without requiring product sequestration. The imido (ArL)Co(NAd) exists in equilibrium in the presence of pyridine
1
with a four-coordinate, cobalt imido (ArL)Co(NAd)(py) (Ka = 8.04 M1) as determined by H NMR titration experiments.
Kinetic studies revealed that pyridine binding slows down the formation of the tetrazido complex by blocking azide
coordination to the CoIII imido. Further, (ArL)Co(NR’)(py) displays enhanced C−H amination reactivity compared to the
pyridine-free complex enabling higher catalytic turnover numbers under milder conditions. The mechanism of C–H
amination was probed via kinetic isotope effect (KIE) experiments [kH/kD = 10.2(9)] and initial rate analysis with para-
substituted azides suggesting a two-step radical pathway. Lastly, the enhanced reactivity of (ArL)Co(NR’)(py) can be
correlated to a higher spin state population, resulting in a decreased crystal field due to a geometry change upon pyridine
coordination.
1. INTRODUCTION
is still limited to ligand functionalization, precluding
productive C–N bond formation. For example, a CoIII imido
(TptBu,Me)CoIII(NAd) reported by Theopold displays
amination of one of the peripheral tert-butyl C–H bonds of
the tris(pyrazolyl)borate ligand.35 The amination reactivity
is ascribed to a thermally accessible triplet spin state which
serves to destabilize the Coimido bond, rendering it more
reactive. Recently, three-coordinate (IMes)CoIV(NDipp)2
Direct incorporation of a nitrene functionality into
unreactive C–H bonds is a challenging1-2 but appealing
transformation given the ubiquity of N-functionalities in
natural products,3 agrochemicals, and synthetic
precursors.4 Thus, as an alternative to the traditional
approach utilizing pre-activated substrates, transition
metal catalyzed C–H amination has received great
attention.5-9 More specifically, the synthesis of late, first-
row transition metal-bound nitrene complexes (e.g.,
imido, M(NR2);10-12 iminyl, M(2NR);13-22 nitrene adducts,
M(3NR)23-25) is of interest as such species have been invoked
as viable and cost-effective nitrene group transfer reagents.
and [(IMes)CoV(NDipp)2][BArF ] bis-imido complexes have
4
been reported from the Deng group.36 Interestingly, the
CoIV imido (S = ½) undergoes intramolecular C–H
activation of a benzylic CH bond from the IMes ligand
(with a subsequent CN forming step), whereas the
analogous CoV imido (S = 0) is relatively inert. A leading
feature of reactive cobalt imidos is their open-shell spin
ground state or thermally accessible low-lying excited
states that gives rise to radical character along the metal–
imido bond vector, to generate more reactive entities.
Towards this end, our group has recently demonstrated
intermolecular C–H amination mediated by a three-
coordinate dipyrrinato FeIII imido, ascribing its reactivity
to an atypical high-spin electronic configuration.26 Cobalt
imidos, specifically those featuring a covalently bound
NR2–fragment (i.e., CoIII(NR)), however, have been
relatively less explored in the field of C–H amination as the
majority of these species feature closed-shell electronic
Similarly, our group has reported the synthesis of three-
coordinate dipyrrinato CoIII imidos featuring open-shell
electronic configurations.37 Studies revealed that
(ArL)CoIII(NtBu)
(ArL
=
5-mesityl-1,9-(2,4,6-
configurations,
resulting
in
remarkably
stable
Ph3C6H2)dipyrrin) exhibits thermal population of spin
excited states (S = 0 → 2), while the mesityl analogue
compounds.27-34 Although a handful of cobalt imidos
display C–H activation or functionalization, such reactivity
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(ArL)CoIII(NMes) adopts an S = 1 electronic ground state.
Ph3C6H2 aryl groups. (Figure 1b).
(ArL)CoIII(NtBu) displays typical two-electron nitrene group
transfer reactivity with PMe2Ph to quantitatively generate
phosphinimide PhMe2P(NtBu); however, no C–H bond
activation was observed. In contrast, (ArL)CoIII(NMes)
readily undergoes intramolecular benzylic C–H activation
to afford a metallacycloindoline (ArL)Co(κ2-NHC6H2-2,4-
Me2-6-CH2). Although neither imido complex is
competent for intermolecular C–H activation, we
hypothesized that given their propensity to adopt open-
shell electronic configurations, such cobalt imidos might
manifest intramolecular C–H amination reactivity instead.
We have previously demonstrated the catalytic synthesis
of substituted N-heterocycles from linear alkyl azides via
intramolecular C–H amination mediated by dipyrrinato
FeIII iminyl intermediates.14, 38 Likewise, we envisioned that
a cobalt linear alkyl imido complex could generate the
substituted pyrrolidine product upon intramolecular C–H
amination. Thus, we sought to examine the following
questions: (1) can we synthesize dipyrrinato CoIII imido
complexes using linear alkyl azide substrates? (2) If
possible, are these imidos competent for intramolecular C–
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Scheme 1. Synthesis of 2
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2.2. Reactivity of (ArL)Co (2) with Alkyl Azides. With
the CoI starting material 2 in hand, we sought to explore its
reactivity with a variety of substituted linear alkyl azides.
We envisioned that treatment of 2 with a linear alkyl azide
would furnish the corresponding CoIII imido which could
subsequently generate the substituted pyrrolidine via
intramolecular C–H amination.
To test our hypothesis, we subjected a series of aliphatic
azides such as 1-azidopentane, 1-azido-4-methylpentane,
and (4-azidobutyl)benzene to a solution of 2 in benzene-
d6. In each instance, we observed immediate consumption
of the azides and formation of the corresponding linear
imine along with regeneration of 2 instead of our
anticipated cyclized products (Scheme 2). We postulated
that the imines are generated via a rapid αH atom
abstraction (αHAA) via a CoIII imido intermediate.39 To
avoid such undesired reactivity, α-gem-dimethyl
substituted alkyl azides were employed. As a result, slow
addition of one equivalent of 2-azido-2-methylhexane or 2-
azido-2,5-dimethylhexane to a solution of 2 cleanly
H
amination to afford substituted pyrrolidines?
Furthermore, (3) is the amination reaction catalytic? To
this end, we report herein the intramolecular catalytic C–
H amination mediated by dipyrrinato CoIII imidos to afford
N-heterocyclic products. In addition to the structural
evidence of a CoIII imido as the species responsible for the
desired reactivity, kinetic studies were conducted to
elaborate mechanistic details of the CoI/CoIII catalytic
cycle. Lastly, our findings on ligand-accelerated C–H
functionalization reactivity will be discussed.
2. RESULTS AND DISCUSSION
afforded
a
new paramagnetic species by 1H NMR
2.1. Synthesis of Cobalt Synthons. We have previously
reported the preparation of dipyrrinato CoII and CoI
complexes, (ArL)CoCl(py) and (ArL)Co(py), respectively,
which possess one equivalent of pyridine bound to the
metal center.37 In an attempt to synthesize a more
spectroscopy. Single crystals of these species suitable for X-
ray diffraction were obtained from a benzene/hexane
solution at –35 °C to confirm formation of the
corresponding CoIII imidos (3) and (4), respectively
(Scheme 2). The X-ray crystal structures of both 3 and 4
revealed a trigonal planar geometry around the cobalt
center, which is consistent with our previously reported Co
imido, (ArL)CoIII(NtBu) (Figures 1c, S-44).37 Complexes 3
and 4 display Co–Nimido distances (3, 1.616(3); 4, 1.634(5) Å)
and Co–Nimido–C angles (3, 177.5(3)°; 4, 178.5(5)) consistent
with metrics for (ArL)CoIII(NtBu) (Co–Nimido: 1.609(3) Å, Co–
Nimido–C angle: 178.8(1)°).
sterically-accessible cobalt synthon, we employed
a
metalation protocol used for our recently described
solvent-free dipyrrin Fe congener.26 As such, refluxing
(ArL)Li with anhydrous CoBr2 in toluene for 15 h produced
the three-coordinate CoII complex (ArL)CoIIBr (1) as
determined by X-ray crystallographic analysis of single
crystals grown from a saturated solution of 1 in a
hexane/benzene mixture (2:1) stored at 35 C (Figure 1a).
Chemical reduction of 1 with potassium graphite (KC8) in
a thawing benzene solution cleanly afforded the reduced
compound (ArL)CoI (2) (Scheme 1). Crystals suitable for X-
ray diffraction were grown from a 2:1 hexane/benzene
mixture at −35 °C and the solid state structure is shown in
Figure 1b.
Gratifyingly, heating each of the isolated imidos 3 and 4
to 100 °C in benzene-d6 furnished the cyclized products,
2,2,5-trimethylpyrrolidine
tetramethylpyrrolidine, in 13% and 9% yield, respectively,
as determined by 1H NMR. Although the yields are low, the
formation of N-heterocycles demonstrates the capability of
3 and 4 to perform intramolecular C–H amination.
Moreover, regeneration of 2 was observed by 1H NMR upon
consumption of the imidos which suggests the potential
viability of 2 as a catalyst.
and
2,2,5,5-
1
Interestingly, 2 exhibits identical H NMR chemical
shifts to those observed for the pyridine-bound CoI
analogue, (ArL)Co(py). However, the solid-state structure
of 2 is distinct from that of (ArL)Co(py),37 displaying an
intramolecular η6-arene interaction between the cobalt
and one of the ortho-phenyl substituents from the 2,4,6-
To test whether 2 can indeed serve as a catalyst, a 10
mol% benzene-d6 solution of 2 was exposed to 2-azido-2-
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methylhexane
or
2-azido-2,5-dimethylhexane.
species distinct from the corresponding imido complex
was
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Surprisingly, in each case, formation of new paramagnetic
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Figure 1. Solid-state structures for (a) (ArL)CoIIBr (1), (b) (ArL)CoI (2), (c) (ArL)Co(NR) (3), R = C(CH3)2(CH2)3CH3 and (d) (ArL)Co(κ2-N4R2)
(5), R = C(CH3)2(CH2)3CH3 at 100 K with the thermal ellipsoids set at the 50% probability level (hydrogen atoms and solvent molecules are
omitted for clarity; Co aquamarine, C gray, N blue). Selected bond lengths (Å) and angles () for (3): Co–N1, 1.931(3); Co–N2, 1.926(3); Co–
Nimido, 1.616(3); Co–Nimido–C, 177.5(3).
Scheme 2. Reactivity between 2 and various linear alkyl azides
observed via 1H NMR and no desired cyclized product was
detected. The same paramagnetic species can be
independently prepared either from reaction of 2 with two
equivalents of azide or from reaction of the isolated imido
with one additional equivalent of azide in benzene at room
temperature (Scheme 2). The X-ray crystal structures of
these species revealed the formation of four-coordinate
cobalt tetrazido complexes, (ArL)Co(κ2-N4R2) (R: CMe2Bu,
5; CMe2(CH2)2CHMe2, 6) (Figures 1d, S-47). Similar
reactivity was previously reported by our group utilizing
the same ligand platform with both iron26 and cobalt.37
Such four-coordinate tetrazido species are presumably
generated via a rapid trapping of a second equivalent of
azide by a three-coordinate imido.40-42 Unfortunately,
these cobalt tetrazido complexes are remarkably stable. No
decay to the corresponding imido or pyrrolidine was
observed upon heating 5 or 6 to 100 °C in benzene-d6.
Likewise, heating either tetrazido complex in the presence
of excess alkyl azides yields no reaction.
The foregoing results demonstrate that under catalytic
conditions, the in situ generated cobalt imido is rapidly
converted into catalytically inactive tetrazido species
before undergoing intramolecular C–H bond activation,
thus preventing potential catalytic turnover. Therefore, to
achieve the desired catalytic intramolecular C–H
amination, the C–H bond activation step must kinetically
outcompete formation of the tetrazido species. We
hypothesized that cleavage of relatively weak C–H bonds
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such as benzylic C–H bonds may lower the activation
energy barrier for C–H activation such that intramolecular
cyclization occurs faster than bimolecular tetrazido
formation.
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Scheme 3. Intramolecular C–H amination of benzylic C–H
7
bonds
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1
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Figure 2. (a) H NMR spectrum of 2 in benzene-d6 (b) H NMR
spectrum taken following addition of 10 equiv. of azide 7 in
benzene-d6. Paramagnetic chemical shifts corresponding to imido
8 are colored in blue. (c) 1H NMR spectrum taken after 1 h and the
chemical shifts corresponding to tetrazene (ArL)Co(κ2-N4R’2) are
colored in red. (d) Reaction completed.
2.3. Catalytic CH Amination. To test this hypothesis,
we studied the reactivity of
2
with (4-azido-4-
methylpentyl)benzene (7) where a potential benzylic C–H
amination could take place to generate 2,2-dimethyl-5-
phenylpyrrolidine (9) as a product (Scheme 3).
The reaction progression of azide 7 with 10 mol% of 2 in
1
benzene-d6 was monitored by H NMR spectroscopy at
temperatures ranging from 25 °C to 80 °C. A time
progression for the reaction performed at 50 °C highlights
the paramagnetically shifted resonances for 2 (Figure 2a);
the conversion of 2 to the corresponding imido (8) upon
addition of azide 7 (10 equiv.) initially (Figure 2b, Scheme
3) and after 1 h (Figure 2c); and the final spectrum for the
tetrazido complex (Figure 2d). As illustrated in Figure
2ad, consumption of 8 occurred via two different
pathways over time: (1) formation of catalytically inactive
tetrazido species and (2) generation of the desired product
9 along with regeneration of 2 which is rapidly re-oxidized
to 8 (Figure 2c), indicating that 8 is the catalytic resting
state. Once all imido 8 is converted to the tetrazido species,
there is no further consumption of azide 7 and the reaction
stops (Figure 2d).
As the reaction temperature increases, the yield of
pyrrolidine 9 increases as well, reaching a maximum of
78% at 80 °C. To better understand the amination
reaction’s temperature dependence, we surveyed the ratio
between unreacted azide 7 and pyrrolidine 9 as a function
of temperature by 1H NMR (Figure 3). At low temperature,
a considerable amount of unconsumed azide 7 is present
as C–H amination is slow. As a result, the imido
intermediate 8 is exposed to large concentrations of azide
7 leading to predominant formation of the corresponding
tetrazido complex. As the temperature increases, however,
the amination pathway becomes more favorable,
promoting faster consumption of 7, higher yields of 9, and
minimizing formation of the tetrazido complex.
Figure 3. Diamagnetic region in 1H NMR spectra of the reactions
conducted at various temperatures. The singlet at 3.3 ppm
corresponds to 1,3,5-trimethoxybenzene which was used as an
internal standard for integration.
2.4. Kinetic Analysis of Catalytic C–H Amination. To
establish a detailed mechanism for the catalytic amination
reaction, we performed various kinetic experiments. As
shown in Figure 2b, the oxidation of 2 with excess azide 7
quantitatively affords imido 8 instantaneously, allowing us
to estimate the concentration of 8 based on the initial
concentration of catalyst 2. Furthermore, the initial
concentration of 8 remains constant during early stages of
the catalytic reaction since the concentration of azide 7 is
high enough to re-oxidize 2 to 8 upon pyrrolidine f
ormation, enabling initial rate kinetic analysis under
pseudo steady-state conditions. Additionally, the initial
rate kinetic analysis was necessary to exclude rate
diminishing caused by
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Figure 4. (a) First order dependence on the concentration of 8 at 50 °C in C6D6. (b) Zeroth order dependence on the concentration of 7 at
50 °C in C6D6. (c) KIE study employing 7/7-d2 at 50 °C in benzene-d6.
Figure 5. (a) Solid-state structure of (ArL)Co(NAd) (10) at 100 K with the thermal ellipsoids set at the 50% probability level (hydrogen
atoms and solvent molecules are omitted for clarity; Co aquamarine, C gray, N blue). (b) Job plot of 10 and pyridine at 25 °C. In all cases,
[10] + [py] = 4.25 mM in benzene-d6. (c) 1H NMR titration curve of 10 at 25 °C in benzene-d6. Black dashed line represents a result of fitting
based on 1:1 binding isotherms.
Figure 6 (a) Solid-state structure of (ArL)Co(κ2-N4Ad2) (11) at 100 K with the thermal ellipsoids set at the 50% probability level (hydrogen
atoms and solvent molecules are omitted for clarity; Co aquamarine, C gray, N blue). (b) Observed rates of formation of 11 as a function
of [py-d5] at 25 °C. In all cases, [10] = 8.50 mM and [N3Ad] = 85.0 mM in benzene-d6. (c) Observed rates of formation of 9 as a function of
[py-d5] at 25 °C. In all cases, [2] = 4.25 mM and [7] = 85.0 mM in benzene-d6.
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slow formation of the catalytically inactive tetrazido obtained using 10 mol% of 2. The diminished yield is
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8
species. We first examined the reaction order of amination
with respect to 8 by varying the catalyst loading. The rates
were determined by measuring the concentration of
product 9 (< 10% yield) over time at 50 °C in benzene-d6 via
1H NMR spectroscopy. As shown in Figure 4a, a plot of the
concentration of the imido (i.e., [8]) versus rates of product
formation displays a linear correlation suggesting that C–
H amination is first order in imido 8.
consistent with our proposed mechanism that formation of
tetrazido complex is favored at relatively high
concentrations of azide. Thus, while catalysis should be
most effective under slow addition of the azide substrate
or dilute reaction conditions, reaction time and volumetric
throughput would therefore be limited, respectively. An
alternative strategy to suppress tetrazido formation is to
employ an ancillary ligand that would competitively bind
the imido intermediate, thereby retarding or eliminating
tetrazido formation.
9
A similar kinetic analysis was conducted holding the
catalyst concentration constant and varying azide
concentration ([7]) to reveal a zeroth order dependence in
azide 7 (Figure 4b), corroborating the unimolecular nature
of the amination reaction. Lastly, we performed a kinetic
isotope effect (KIE) experiment to investigate the rate-
determining step during catalysis. The KIE value was
evaluated by comparing the initial rates of 5 mol% of 2 with
7 and its bis-deuterated form at the benzylic site (4-azido-
4-methylpentyl-1,1-d2)benzene (7-d2). The observed ratio of
the rate constants (kH/kD) was determined to be 7.6(2),
which is in agreement with the C–H bond activation step
being rate-determining (Figure 4c).43 Similarly, the
intramolecular KIE value obtained by employing a
stoichiometric amount of mono-deuterated azide 7-d1
showed three times greater selectivity for the C–H over the
C–D bond (Figure S-10).
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To this end, pyridine was a suitable option given its
modular steric and electronic profile. To study the binding
dynamics between pyridine and a three-coordinate CoIII
imido without concern for subsequent H–atom
abstraction, an adamantyl substituted imido (10) was
prepared as a model complex. Stoichiometric reaction of 2
with 1-azidoadamantane (N3Ad) cleanly produced
(ArL)Co(NAd) 10 in 87% isolated yield. Akin to imidos 3 and
4, the solid-state structure of 10 displays a trigonal-planar
geometry with a Co–Nimido distance of 1.620(7) Å and a
nearly linear Co–Nimido–C angle of 171.4(6)° (Figure 5a).
Table 1. Effect of pyridine concentration on C–H amination
reactivityc
Entry
[py-d5]
(mM)
Rate
(mM/min)
Yield
(%)a
Given all the kinetic data, we propose the following
catalytic sequence: (1) fast oxidation of 2 by an alkyl azide
affords CoIII imido 8; (2) 8 undergoes intramolecular
Hatom abstraction to generate a transient CoII amide
(Int, Scheme 4); followed by (3) rapid radical
recombination to afford the cyclized product 9.
Alternatively, a direct C–H insertion pathway from the CoIII
imido cannot be fully excluded (Figure S-3).
1
0
N/Ab
< 10
21
2
3
4
5
6
7
8
4.3
8.5
26
0.52(3)
0.70(5)
0.813(5)
1.12(2)
1.45(4)
1.63(4)
1.77(3)
22
35
89
89
91
174
300
430
2.5. Mechanism-driven Improvement of Catalytic
Performance. To the best of our knowledge, this is the
first example of catalytic C–H amination mediated by a
spectroscopically observable CoIII imido, whose identity
can be inferred from the structurally characterized
analogues 3 and 4. Furthermore, it is noteworthy that the
catalytic C–H amination we describe herein displays a
distinct kinetic profile from the similar ring-closing
catalysis mediated by a CoIII iminyl radical intermediate (in
particular the system reported by Zhang, de Bruin, and co-
93
93
a1H NMR yields using 1,3,5-trimethoxybenzene as
internal standard. Initial rate is not available due to a
b
c
slower formation of 9 at 25 °C. Reactions were conducted
with pyridine-d5 to manipulate kinetic experiments with 1H
NMR spectroscopy. In all cases, [2] = 4.25 mM and [7] =
85.0 mM in benzene-d6 at 25 °C.
workers) as opposed to
a
CoIII imido species.44-46
Specifically, as suggested by the KIE experiments, we have
observed that the C–H activation step as opposed to
activation of the azide moiety is the rate-determining.
Additionally, in contrast to our previously reported Fe-
based catalysis which requires Boc-protection of the
pyrrolidine products to regenerate the active catalyst,14, 38
the CoI/CoIII catalytic cycle showcased herein is capable of
yielding free saturated cyclic amines without requiring
product sequestration to eliminate product inhibition.
Encouraged by these results, we attempted to further
optimize the reaction conditions. Lowering the catalyst
loading to 5 mol%, however, afforded 31% of pyrrolidine 9
at 80 °C, a significantly diminished yield compared to 78%
With 10 in hand, we examined the complexation ratio
between the three-coordinate imido and pyridine in
solution using a Job plot analysis.47 The maximum value in
the Job plot (Figure 5b) appeared at 0.5 mole fraction of 10
and pyridine suggesting a 1:1 binding stoichiometry to
afford (10-py) in solution. Furthermore, the binding
equilibrium constant of pyridine to 10 (Ka = 8.04 M-1) was
1
determined by tracking the changes in H NMR chemical
shifts of 10 as a function of pyridine concentration (Figure
5c).48
Although the binding affinity of pyridine is weak, the
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potential kinetic effect resulting from pyridine
coordination on the rate of formation of the tetrazido
Scheme 4
complex may still
1
2
3
4
5
6
7
8
9
10
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be significant. Thus, we measured the conversion rate of
isolated imido 10 to the corresponding tetrazido complex
(ArL)Co(κ2-N4Ad2) (11, Figure 6a) as a function of pyridine-
d5 concentration. The rate obtained in the absence of
pyridine was defined as 1 and the following relative rates
(krel) were determined at 50% formation of 11.
1). In contrast, an increased rate is noted at the same
temperature in the presence of 5 mol% of pyridine-d5
(Table 1, entry 2). Likewise, the resulting initial rate
increases as the concentration of pyridine-d5 increases,
displaying an overall saturation kinetic behavior in
pyridine-d5 (Figure 6c). Furthermore, pyridine-d5 can used
as a solvent to produce 92% of 9 with 1 mol% of catalyst 2
at 80 °C. To summarize, pyridine slows down the formation
of the undesired tetrazido complex and functions as a co-
catalyst, permitting higher catalytic turnover numbers
under milder reaction conditions.
Indeed, a slower formation of 11 was observed at higher
concentrations of pyridine-d5, indicating that, as more
pyridine-bound imido 10-py is present in solution,
formation of the tetrazido complex is diminished (Figure
6b). These results support our original hypothesis that
blocking the fourth coordination site of a three-coordinate
imido with an additional ligand offers steric protection
against tetrazido formation.
2.6. Mechanistic Study of C–H amination in the
Presence of Pyridine. Excited by the enhanced C–H
functionalization reactivity of 8-py, we investigated
whether the mechanism of C–H activation changes in the
presence of pyridine. A KIE value of 10.2(9), which is above
the classical limit was observed in the presence of 10
equivalents of pyridine-d5 with respect to 2 suggesting a
stepwise radical pathway for C–H amination (Figure S-9).49
To further support a radical pathway, initial rates of
amination were measured for a series of para-substituted
azides under the same conditions. As a result, both
electron-donating and electron-withdrawing substituted
azides displayed slightly increased rates compared to the
parent azide 7 (Table 2), suggesting stabilization of
benzylic carboradical intermediates (Int or Int-py) upon
H-atom abstraction. Plotting log kR versus σ+ parameters
(Figure S-12) results in a non-linear correlation between
reaction rate and electron-donating ability of the para-
substituent on 7-X. However, plotting log kR versus the
spin delocalization parameters (σmb, σjj) developed by
Jiang and coworkers50 yields a more linear relationship
(Figure 7). Multiple coefficient linear regression for the
dual-parameter equation log kR = ρmbσmb + ρjjσjj provided
ρmb = 0.25 and ρjj = 0.72. The positive value of ρjj indicates
that the para-substituent (X) delocalizes spin in the
transition state. Furthermore, the large |ρjj/ρmb| value of
2.9 indicates that the spin delocalization effect dominates
Given these findings, we anticipated that yields of 9 may
be improved in the presence of pyridine. Indeed, a 5 mol%
catalytic reaction with 7 in the presence of 10 equivalents
of pyridine-d5 with respect to 2 afforded 90% of 9 at 80 °C,
greatly exceeding the amount of pyrrolidine product
formed in the absence of pyridine. Furthermore, as the
formation of the corresponding tetrazido complex is
suppressed, regenerated CoI catalyst (ArL)Co(py) is
observed when the reaction is completed (Figure S-19).
More surprisingly, not only were improved yields of 9
observed, but increased rates of C–H amination were also
detected, implying enhanced amination reactivity of the
pyridine-bound imido (8-py) relative to the three-
coordinate imido 8. Similar to the kinetic experiments
described in Section 2.4, initial rates of the C–H amination
were measured at varying concentrations of pyridine-d5
under pseudo steady-state conditions as the oxidation of 2
by azide 7 remained instantaneous and quantitative with
pyridine-d5 in solution (Table 1).
As shown in Table 1, in the absence of pyridine, an
attempt to measure the initial rate of amination at 25 °C
was not successful since the conversion of imido 8 to 9 is
too slow to be measured at this temperature (Table 1, entry
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in the amination reaction, similar to the previously
(ArL)Co(py), or (ArL)Co(py)2, both of which are active
catalysts to readily furnish 8-py.
reported iron catalyzed amination reaction.39
1
2
2.7. Catalysis with Substituted Pyridines. Given the
utility of added pyridine to facilitate the intramolecular
amination catalysis, we sought to determine the impact of
changing the pyridine donor on catalysis. To this end, the
amination reaction was run with azide 7 using 1 mol% 2 in
the presence of 20 equivalents of dimethylaminopyridine
(4–Me2N)py) in benzene-d6. The reaction afforded 91% of
9 at 80 °C, similar to the yield obtained from the reaction
conducted in neat pyridine. Motivated by this result, we
sought to investigate the effect of the para-substituent on
pyridine on the reaction rates and yields of C–H amination.
Specifically, we attempted to establish differences in values
of k2 among a series of para-substituted pyridines, where k1
and k2 are the first order rate constants of C–H amination
mediated by 8 and 8-py’, respectively (eq 1).51 Assuming
that k1 is negligible at 25 °C based on our experimental
results (Table 1, entry 1), the rate law can be further
simplified (eq 2).
3
4
5
6
7
8
9
Table 2. Initial rates and final yields of 9 with para-substituted
azide substrates
10
11
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60
Entry
p-substituent (X)
Relative rate (kR/kH)
1
1.00
1.11
H
CH3
OCH3
CF3
2
3
4
1.39
1.41
d[9]
dt
(eq
(eq
[ ]
= k1 8 + k2[8 - py']
1)
d[9]
dt
≈ k2[8 - py'] at 25 °C
2)
As shown in Table 3, electron-rich pyridines such as
4tBu)py and (4Me2N)py exhibit faster conversions as
well as higher yields of 9 compared to pyridine. Both [8-
py’] and k2 of each of the para-substituted pyridines were
calculated based on the independently determined
equilibrium binding constants using imido 10 (Ka, Table 3).
As a result, the values of k2 for pyridine, 4tBu)py, and
4Me2N)py are similar suggesting that the improved rates
are mostly attributable to the higher concentration of the
corresponding pyridine-bound imido complex, not to k2.
Interestingly, we found that the electron-poor 4(F3C)py
displays a stronger binding affinity than the unsubstituted
pyridine, yet slows formation of 9, resulting in a
considerably smaller k2 relative to the electron-rich
pyridines (Table 3, entry 4). The diminished rate
employing 4(F3C)py suggests that electronic effects may
also influence the reactivity of the pyridine-bound imidos,
albeit additional studies are necessary to evaluate such
contributions.
Figure 7. Linear free energy correlation of log kR vs. (σmb, σjj) for
the amination reaction of p-substituted aryl azide substrates
listed in Table 2 where ρmb = .25, ρjj = 0.72.
Taking all mechanistic studies together, our proposed
catalytic cycle for the intramolecular C–H amination in the
presence of pyridine is illustrated in Scheme 4. Several
mechanistic features are of note: (1) both 8 and 8-py are
competent species for catalytic C–H amination to afford
substituted pyrrolidine 9 in a two-step radical-type
pathway; (2) 8-py displays drastically improved rate of
amination compared to 8 along with slower formation of
the catalytically inactive tetrazido complex; (3) 2 exhibits
an equilibrium with pyridine, existing as either
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
Figure 8. (a) Solution magnetic moments of mixture of (10) and (10-(4-Me2Npy)) as a function of [4-Me2Npy] at 25 °C in benzene-d6. (b)
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Frontier MO description of (ArL)Co(NR’). (c) Frontier MO description of (ArL)Co(NR’)(py).
(e.g., S = 1, 2), or pyridine coordination could make the spin
excited states thermally more accessible.
Table 3. Catalytic activity of 2 with para-substituted pyridines
The observed changes in solution magnetic moments of
10 as a function of 4(Me2N)py concentration can be
rationalized by considering the frontier molecular orbitals
(FMOs). We have previously proposed a qualitative FMO
Ka (M1)a
p-
kR/kH
NMR yield
(%)b
k2
(min1)
RC4H4N
description of
a
three-coordinate cobalt imido
1
2
3
4
H
tBu
8.04
12.9
41.8
12.5
1.00
1.7(4)
3.1(7)
36.4
89.4
90.8
20.4
1.25
1.42
1.24
0.31
(ArL)Co(NtBu) to describe its thermal behavior (Figure
8b).37 Those FMOs would be further perturbed upon
coordination of a fourth ligand, and thus give rise to a
different electronic configuration. Pyridine coordination
could result in either a trigonal monopyramidal geometry
if the pyridine simply associates axially, or the geometry
could undergo a tetrahedral distortion as has been
observed for pyridine coordination in Holland’s iron-imido
work.52-54 To this end, we have performed geometry
optimizations for 10-py considering an S = 0, 1, or 2 spin
NMe2
CF3
0.36(2)
aBinding constants at 25 °C in benzene-d6. b1H NMR yields using
1,3,5-trimethoxybenzene as internal standard.
2.8. Spin State Consideration of the Pyridine-bound
Imido. We sought to determine if the pyridine-bound
imido displays a different electronic structure as compared
to the three-coordinate, pyridine-free imido. Our attempts
to isolate 10-py were unsuccessful due to the weak binding
affinity of pyridine. Thus, we measured the solution
magnetic moment of 10 as a function of concentration of
4Me2N)py, assuming that the total magnetic moment
(µeff) is the summation of two individual components, μ’eff
and μ”eff arising from 10 and 10-(4-Me2Npy), respectively
(eq 3). The mole fraction (χ) of each species at a given
concentration of 4(Me2N)py was calculated based on the
Ka of 4(Me2N)py.
ground state, and the results suggest
a trigonal
monopyramidal geometry for all cases (Table S-10).
Moreover, at the optimized geometries of 10-py
corresponding to the S = 1 and 2 spin ground states were
found to be more stable than that for the S = 0 spin state
by 6.1 and 7.7 kcal/mol, respectively. As such, we will
present our FMO analysis using the S =2 spin ground state
as an example, although we cannot fully exclude of the
possibility for an S = 1 spin ground state given the subtle
energy difference between the S = 1 and 2 spin states.
A geometry change from trigonal planar to trigonal
monopyramidal upon pyridine coordination impacts both
the σ and π-bonding within the molecule. Assuming that
pyridine approaches along the y-axis, the imide fragment
falls below the xz plane (Figure 8c). Consequently, the
πoverlap between the Co and imido N (Co 3 dxz + N 2 px
μeff = μ'eff(χ10) + μ''eff(χ10 - dmap
)
(eq 3)
In the absence of 4-(Me2N)py, where μeff is the same as
μ’eff, 10 shows a μeff of 2.5 μB resulting from its S = 0 ground
state (by analogy to (ArL)Co(NtBu)) and population of
thermally accessible excited states (e.g., S = 2). As the
concentrations of 4Me2N)py increases, the total solution
magnetic moment of the mixture increases (Figure 8a)
resulting in a μ”eff of 4.0 μB. The μ”eff value suggests that the
pyridine-bound imido complex could change the spin
ground state from the singlet, three-coordinate imidos
*
Co 3 dyz + N 2 py) is diminished, lowering both dxz (σL +
2
πNx*) and dyz (πNy*) in energy. In contrast, 3 dz and 3 dx y
(πNy
2
2
)
are destabilized (σ*CoNpy), while dxy remains
*
nominally non-bonding. The net result of the geometric
configuration is to decrease the overall 3 d energy gap (i.e.,
Δ(3dxz – 3dxy) is diminished), leading to the higher spin
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state populations observed (Figure 8a). The qualitative intramolecular benzylic C–H bonds proximal to the imido
1
2
3
4
5
6
7
8
orbital interaction analysis agrees with the DFT results
(Figure S-55); however, further studies will be necessary to
quantitatively analyze the frontier molecular orbital
compositions given the extent of CoNimido πinteraction
varies as a function of the imido fragment deviation from
the xz plane.
moiety promoted C–H bond amination. Kinetic studies
support the viability of the structurally characterized
three-coordinate dipyrrinato CoIII imido as a competent
nitrene-group transfer species. Furthermore, the desired
C–H amination reactivity was improved in the presence of
pyridine. We found that pyridine plays critical roles during
the catalytic reaction: (1) pyridine coordination prevents
2.9. Origin of the Enhanced Reactivity of the
Pyridine-bound Imido. Many transition metal
complexes featuring metal-ligand multiple bonds display
enhanced group transfer reactivity upon coordination of
an exogenous ligand.55-58 For example, epoxidation of
olefins mediated by either a CrV-oxo59 or MnV-oxo60
complex proceeds more efficiently upon ligation of
pyridine N-oxide to these metal-oxo active species. This
effect has also been observed for Hatom abstraction
reactivity, however, the reported transition metal
complexes are not capable of productive group transfer.
The Goldberg group has demonstrated the enhanced
Hatom abstraction reactivity of a MnV-oxo corrolazine
complex in the presence of halide anions.61 Similarly, the
Holland group showcased that an iron imido complex
formation of
a catalytically-inactive, four-coordinate
cobalt tetrazido complex and, more importantly, (2) the
resulting pyridine-bound CoIII imido displays enhanced
rate of C–H amination. As a result, we were able to
accomplish greater catalytic performance under milder
conditions with pyridine as a co-catalyst. We rationalize
the improved nitrene group transfer reactivity of the
pyridine-bound imido might be resulting from
perturbations in its geometric and electronic structures
along with potential changes in reaction thermodynamics.
We believe this study demonstrates the importance of
understanding the salient features of such transition metal
ligand multiple bonds to better design new catalysts. Given
our findings, we are currently interested in further
tailoring our systems to expand the group transfer catalysis
protocol.
9
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(
MeL)Fe(NAd) undergoes Hatom transfer only upon
ligation of 4tBu)py.51
ASSOCIATED CONTENT
Given these precedents, we propose the following
potential explanation to understand how pyridine
influences the rate of C–H amination in this study. Based
on our FMO analysis and the theoretical studies conducted
on 10-py (Section 2.8), we propose that the pyridine-
bound, four-coordinate Co imido complex features an
attenuated CoN bond order by accessing higher spin
states as compared to the three-coordinate analogue.
Furthermore, as the DFT results suggest, the trigonal
monopyramidal geometry obtained upon pyridine ligation
may resemble the structure of the transition state for
Hatom abstraction more closely. As such, the H-atom
abstraction step should be more kinetically favored.
Supporting
Information.
General
experimental
considerations and procedures, multinuclear NMR data, solid
state molecular structures, crystallographic CIF files, and
crystallography data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Corresponding Author
* betley@chemistry.harvard.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
3. CONCLUSIONS
This work was supported by a grant from the NIH (GM-115815),
the Dreyfus Foundation (Teacher-Scholar Award to T.A.B.),
and Harvard University. Y.B. gratefully acknowledges a
Kwanjeong Graduate Student Fellowship.
The foregoing results demonstrate catalytic C–H
amination mediated by dipyrrin-supported, CoIII imidos to
afford substituted pyrrolidines from alkyl azides. Although
our previously reported cobalt-based alkyl imido
(ArL)Co(NtBu) does not display intermolecular C–H
activation reactivity, our strategy to introduce
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