A diruthenium catalyst for selective, intramolecular allylic C-H amination: Reaction development and mechanistic insight gained through experiment and theory

Article abstract of DOI:10.1021/ja203576p

The mixed-valent paddlewheel complex tetrakis(2-oxypyridinato) diruthenium(II,III) chloride, [Ru₂(hp)₄Cl], catalyzes intramolecular allylic C-H amination with bis(homoallylic) sulfamate esters. These results stand in marked contrast to reactions performed with dirhodium catalysts, which favor aziridine products. The following discussion constitutes the first report of C-H amination using complexes such as [Ru ₂(hp)₄Cl] and related diruthenium adducts. Computational and experimental studies implicate a mechanism for [Ru₂(hp) ₄Cl]-promoted C-H amination involving hydrogen-atom abstraction/radical recombination and the intermediacy of a discrete, albeit short-lived, diradical species. The collective data offer a coherent model for understanding the preference of this catalyst to oxidize allylic (and benzylic) C-H bonds.

Full text of DOI:10.1021/ja203576p

ARTICLE
pubs.acs.org/JACS
A Diruthenium Catalyst for Selective, Intramolecular Allylic CꢀH
Amination: Reaction Development and Mechanistic Insight Gained
through Experiment and Theory
Mark Edwin Harvey,† Djamaladdin G. Musaev,*,‡ and J. Du Bois*,†
†Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
‡Emerson Center for Scientific Computation, Emory University, Atlanta, Georgia 30322-0001, United States
S Supporting Information
b
ABSTRACT: The mixed-valent paddlewheel complex tetrakis-
(2-oxypyridinato)diruthenium(II,III) chloride, [Ru2(hp)4Cl],
catalyzes intramolecular allylic CꢀH amination with bis-
(homoallylic) sulfamate esters. These results stand in marked
contrast to reactions performed with dirhodium catalysts, which
favor aziridine products. The following discussion constitutes
the first report of CꢀH amination using complexes such as
[Ru2(hp)4Cl] and related diruthenium adducts. Computational
and experimental studies implicate
a mechanism for
[Ru2(hp)4Cl]-promoted CꢀH amination involving hydrogen-atom abstraction/radical recombination and the intermediacy of a
discrete, albeit short-lived, diradical species. The collective data offer a coherent model for understanding the preference of this
catalyst to oxidize allylic (and benzylic) CꢀH bonds.
’ INTRODUCTION
complexes, including those derived from copper, manganese,
iron, cobalt, ruthenium, silver, and gold, can effect CꢀH
amination.4ꢀ11 None of these systems, however, appears to
match the universal performance of dirhodium tetracarboxylate
catalysts for both intra- and intermolecular CꢀH bond oxidation.
Studies in our lab to identify mononuclear metal complexes [e.g.,
Ru(II)ꢀarene adducts] that promote CꢀH amination have met
with minimal success. By contrast, Che and Blakey have
described in independent accounts the impressive perfor-
mance of porphyrin- and pybox-derived Ru(II) complexes,
respectively, for CꢀH amination reactions.9 These reports
have inspired our continued examination of ruthenium com-
plexes as N-atom-transfer catalysts.
Synthetic and spectroscopic studies of mixed-valent diruthe-
nium paddlewheels find extensive literature discourse.12 Despite
a rich history of investigation, these complexes have seldom
found use in catalytic reaction development (examples include
sulfide oxygenation and amine and alcohol oxidation).13 Ger-
mane to our interests, recent reports by Berry describe the
preparation and characterization of a unique diruthenium nitride
complex capable of stoichiometric aryl CꢀH amination of a
ligand residue.14 For our purposes, one evident advantage of
these mixed-valent ruthenium dimers for catalytic atom-transfer
processes is the high one-electron oxidation potentials for both
tetracarboxylate and tetraamidate complexes.15 Accordingly,
diruthenium catalysts derived from a number of bridging ligand
Diruthenium Catalysts. Tetra-bridged dirhodium(II) com-
plexes (e.g., [Rh2(OAc)4]) hold a certain distinction among metal
catalysts that mediate selective CꢀH and π-bond functionaliza-
tion. These systems appear to be uniquely suited for stabilizing
reactive carbene and nitrene intermediates and can bias the
formation of products in a controlled and highly predictive
manner. Substitution of the ligand architecture is possible with
a number of bridging ligand types, such as carboxylates, amidates,
and ortho-metalated arylphosphines. The majority of these
complexes effectively engage diazoalkane substrates to promote
CꢀC bond formation or olefin cyclopropanation; the ability to
choose among such disparate catalyst systems makes possible
reagent-level control of reaction selectivity.1 For dirhodium-
mediated CꢀH amination, the range of ligandꢀmetal architec-
tures that promote this transformation is decidedly smaller,
limited primarily to tetracarboxylate-based designs. The facility
with which the dirhodium core oxidizes under the conditions of
nitrenoid formation appears to be, at least in part, responsible
for the inability to conduct amination reactions with a more
diverse set of dirhodium catalysts. Such is the case with rhodium
tetraamidates (e.g., the caprolactamate adduct [Rh2(cap)4];
E1/2 = 11 mV vs SCE), which oxidize immediately in the presence
of iodine(III) reagents to catalytically inactive forms.2,3
For some time, we have sought new catalyst systems for CꢀH
amination that would provide greater flexibility in ligand design.
In principle, judicious modification of the ligand sphere could
enable reagent-controlled chemo- and/or stereoselective CꢀN
bond formation. In addition to rhodium, a variety of metal
Received: April 19, 2011
Published: October 07, 2011
r
2011 American Chemical Society
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Figure 1. Controlling product selectivity through catalyst design.
types should be stable against the oxidizing conditions of the
amination reaction.
The following report highlights the unique properties of
diruthenium complexes for CꢀH amination. One catalyst in
particular, tetrakis(2-oxypyridinato)diruthenium(II,III) chloride,
[Ru2(hp)4Cl], has proven markedly effective at favoring allylic
CꢀH amination over competing aziridination of unsaturated
sulfamate esters (Figure 1).16 The bias displayed by this
catalyst for allylic oxidation is distinguished from analogous
reactions with dirhodium systems and rationalized mechan-
istically through experimental and computational analysis, as
described below.
Chemoselective CꢀH Amination. Selective oxidation of
allylic CꢀH bonds in unsaturated substrates presents a con-
siderable challenge in methods development research. The de-
sign of palladium-based catalytic processes, which operate
through CꢀH activation and the intermediacy of π-allyl species,
offers an elegant solution to this problem, enabling access to both
allylic alcohol and amine derivatives.17 For reactions that proceed
via heteroatom-transfer mechanisms, oxidation of unsaturated
substrates typically results in mixtures of CꢀH- and π-bond-
functionalized products, generally favoring the latter. Notable
exceptions can be found for intramolecular reactions of sulfamate
esters with select dirhodium and mononuclear ruthenium
catalysts.9,18 In these cases, allylic amine derivatives are obtained
as the predominant products. A related example of intermole-
cular allylic amination in which the specific combination of
dirhodium catalyst and nitrogen source (sulfonimidamides)
appears to be critical for achieving selective CꢀH bond oxidation
has also been demonstrated.19
Figure 2. ORTEP diagram of [Ru2(esp)2SbF6] 2DMF; the SbF6ꢀcoun-
terion and H atoms are not pictured. RuꢀRu bond distance = 2.267 Å.
Single crystals were grown by vapor-phase diffusion of toluene into a
DMF solution.
3
the ligand-exchange process can be followed by mass spectro-
metry and is generally quantitative given the appropriate reaction
time. It is possible to exchange the axially bound chloride ligand
with a noncoordinating anion by treatment of the complex with a
silver salt.
The notable performance of [Rh2(esp)2] for catalytic CꢀH
amination reactions motivated our interest in preparing the
analogous diruthenium adduct. The dicarboxylic acid α,α,α0,
α0-tetramethyl-1,3-benzenedipropionic acid (H2esp), when heated
with [Ru2(OAc)4Cl] in C6H5Cl, affords [Ru2(esp)2Cl] as a clay-
red powder. Treatment of this material with AgSbF6 yields the
Cl-exchanged product (orange), which was crystallized by vapor-
phase diffusion of toluene into an N,N-dimethylformamide
(DMF) solution to give single crystals suitable for X-ray diffrac-
tion. The ORTEP diagram (C2/c space group) reflects a
molecular structure having C2h symmetry with a measured
RuꢀRu bond distance of 2.27 Å (Figure 2). Such a value is in
accordance with a formal RuꢀRu bond order of 2.5. By contrast,
the metalꢀmetal bond length in [Rh2(esp)2] is slightly longer
at 2.38 Å, consistent with a RhꢀRh single bond. Other metrical
parameters are largely conserved between the dirhodiumꢀ
and dirutheniumꢀesp complexes; for example, the metalꢀ
ligand RuꢀO distances (∼2.02 Å) are nominally shorter than
their rhodium counterparts (∼2.04 Å). In the structure of
To expand the scope of CꢀH amination technologies for fine-
chemicals synthesis, we desire catalysts that afford reagent
control over chemoselectivity. Our recent explorations involving
[Ru2(hp)4Cl] have shown the proclivity of this catalyst to furnish
products of selective allylic amination. This reactivity profile
appears to be general with a range of bis(homoallylic) sulfamate
esters.
[Ru2(esp)2SbF6] 2DMF, a DMF molecule is bound axially to
3
each ruthenium center.
Both the chloride and hexafluoroantimonate dirutheniumꢀesp
complexes are indefinitely stable in air under ambient conditions.
It should be noted that the structure of [Ru2(esp)2Cl] H2O has
3
been disclosed previously and that this complex has been shown
to catalyze sulfide oxygenation with t-BuOOH.13a
’ RESULTS AND DISCUSSION
To assess the performance of alternative, noncarboxylate-
derived diruthenium catalysts for CꢀH amination, we performed
metathesis reactions with [Ru2(OAc)4Cl] and both amide and
oxypyridine ligands. This report will focus principally on the
complex derived from 2-hydroxypyridine, given its unique re-
activity with unsaturated sulfamates. The synthesis of [Ru2(hp)4Cl]
proceeded in a manner analogous to that of [Ru2(esp)2Cl], and
the burgundy complex was isolated in 90% yield by filtration of
the reaction mixture. X-ray crystallographic analysis of a single
crystal of this product grown from DMF rendered the ORTEP
diagram shown in Figure 3. The pseudo-C4v symmetric hp
complex crystallizes in the C2/c space group with a measured
RuꢀRu bond length of 2.29 Å. The four 2-oxypyridinate groups
bind the diruthenium core in an all-polar arrangement (4,0
geometry) in which the four pyridine nitrogens coordinate the
same ruthenium center. The chloride ligand resides in a position
Preparation of Diruthenium Complexes. The preparation
of [Ru2(OAc)4Cl] was first described by Stephenson and
Wilkinson20 and proceeds by refluxing an acetic acid solution
containing RuCl3 xH2O, acetic anhydride, and LiCl. The reac-
3
tion can be followed by visual inspection, as a burgundy solid
slowly precipitates from the red-black solution. The acetate
complex provides a convenient starting material for accessing
all other analogous diruthenium adducts.
We have prepared a number of structurally disparate diruthe-
nium complexes by ligand metathesis with [Ru2(OAc)4Cl].
These reactions are performed in refluxing C6H5Cl, from which
the liberated acetic acid is distilled. Typically, the desired com-
plex is obtained as a brick-red solid that precipitates from the
C6H5Cl solution upon cooling. The paramagnetic nature of this
material renders characterization by NMR impractical; however,
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Table 1. Bis(homoallylic) Sulfamate Ester Cyclization Cata-
lyzed by Several Ruthenium and Rhodium Complexes
entrya
catalyst
I/Ab
1:3c
entry
catalyst
I/Ab
1
2
3
4
5
[Ru2(OAc)4Cl]
[Ru2(OAc)4SbF6] 1:3c
6
7
8
9
[Ru2(hp)4SbF6]
8:1
[Rh2(OAc)4]
2:1
1:2c
[Rh2(O2CCPh3)4] 1:5
Figure 3. ORTEP diagram of [Ru2(hp)4Cl] DMF. Ru1ꢀRu2 bond
[Ru2(esp)2Cl]
[Ru2(esp)2SbF6]
[Ru2(hp)4Cl]
3
distance = 2.295 Å.
1:5
[Rh2(esp)2]
1:1
3:1c
8:1 (68)d 10 [Rh2(hp)4]
a Reactions were performed at 40 ꢀC using 1.4 equiv of PhI(O2CtBu)2,
powdered 5 Å molecular sieves, and 2.5 mol % catalyst. b Product ratios
were estimated by integration of the 1H NMR spectrum of the
unpurified reaction mixture. c Less than 20% conversion to product.
d Isolated yield following chromatographic purification.
Figure 4. Intramolecular amination reactions on benzylic and tertiary
centers efficiently catalyzed by [Ru2(esp)2SbF6].
trans to the RuꢀRu bond on the more sterically hindered Ru2
center. A single DMF molecule, bound through oxygen, fills the
remaining coordination site of Ru1. The synthesis and crystal-
lographic characterization of a related oxypyridinate ruthenium
dimer has appeared previously.21
Catalytic CꢀH Amination Reactions. Initial attempts to
effect oxidation of 3-phenylpropyl sulfamate ester (1) using
[Ru2(OAc)4Cl] and PhI(OAc)2 provided exceptionally low
yields of heterocycle 2, a result ascribed to the markedly insoluble
nature of the ruthenium complex in all of the solvents tested. The
Figure 5. Oxidation of differentially substituted sulfamate esters cata-
lyzed by selected rhodium and ruthenium complexes.
molecular sieves in this reaction is presumably to scavenge
adventitious H2O.
ꢀ
corresponding SbF6 derivative fared only slightly better as a
catalyst for this reaction. By contrast, use of either esp complex
[Ru2(esp)2Cl] or [Ru2(esp)2SbF6] resulted in improved levels
of product conversion, the latter exhibiting clear superiority.
When used in combination with the more soluble oxidant
PhI(O2CtBu)2 and 5 Å molecular sieves, [Ru2(esp)2SbF6]
mediates efficient intramolecular amination of CꢀH bonds,
rivaling the established performance of its rhodium congener
(Figure 4). The oxidative cyclization of isoamyl sulfamate (3)
with only 0.15 mol % [Ru2(esp)2SbF6] is exemplary in this
regard.
Explorations into the reactivity and substrate scope of
[Ru2(esp)2SbF6] revealed that this and related diruthenium
adducts function optimally in refluxing CH2Cl2. The addition
of MgO, a useful additive for dirhodium-promoted CꢀH amina-
tion, is deleterious to the reaction with [Ru2(esp)2SbF6]. Other
soluble organic bases and salts such as Al2O3 are similarly
ineffectual. On the other hand, ground and activated 5 Å
molecular sieves significantly enhance the substrate conversion
(3 and 4 Å sieves give analogous results). Control experiments
indicated that small amounts of H2O, in addition to other polar,
coordinating solvents such as CH3OH, dioxane, DMF, and
isopropyl acetate, inhibit catalyst turnover. Thus, the role of
While diruthenium complexes derived from substituted car-
boxylate, amidate, and pyridinate groups all show some degree of
activity for the oxidation of trans-4-hexenyl sulfamate, only the
tetra-2-oxypyridinate ruthenium dimer [Ru2(hp)4Cl] rivals the
catalytic efficiency of [Ru2(esp)2SbF6] (Table 1). The hp system,
however, displays a greater bias toward allylic oxidation than any
other catalyst we have examined to date and gives the oxathia-
zinane heterocycle in 68% yield.22 Interestingly, the analogous
[Rh2(hp)4] complex demonstrates a similar predilection for
CꢀH amination over aziridination, although the general perfor-
mance of this catalyst is quite poor. The ineffectiveness of this
dirhodium complex at promoting amination is likely due to both
poor solubility and the facility by which it is oxidized under the
amination conditions.
A series of amination reactions using bifunctional substrates
enabled an assessment of chemoselectivity differences between
diruthenium and dirhodium catalysts. Reactions with the three
substrates shown in Figure 5 were performed with PhI(O2CtBu)2
and 5 Å molecular sieves; product conversions were quantitative
in all cases except when [Rh2(hp)4] was employed. While the
variations in the product profiles are admittedly small, the data
clearly reflect the preference of [Ru2(hp)4Cl] to oxidize allylic
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Table 2. Allylic Amine Formation Catalyzed by [Ru2(hp)4Cl]
Figure 6. Comparison of selected bond distances in [Ru2(hp)4Cl] from
computational and crystallographic data.
derivatives. The low product yield and poor chemoselectivity
afforded by 4-pentenyl sulfamate (entry 1) may reflect the
instability of an intermediate radical (see below). As noted
previously for the dirhodium-catalyzed process, electron-with-
drawing groups proximal to the desired site of oxidation tend to
decrease the overall reaction performance. Chiral substrates
afford oxathiazinane products with modest levels of diastereo-
control (12:1 and 2:1 dr for entries 6 and 7, respectively).23 The
preferred sense of induction in these reactions can be rationalized
through a putative chairlike transition structure.24
The evident bias of [Ru2(hp)4Cl] for allylic CꢀH bond
oxidation over the range of substrates depicted in Table 2
encouraged a deeper examination of the reaction mechanism,
the results of which are discussed below.
Mechanistic Analysis: Computational. General. There exist
two general and limiting mechanistic scenarios for CꢀH amina-
tion by a metalꢀnitrene complex. The first operates by way
of a closed-shell singlet nitrene, resulting in a concerted (likely
asynchronous) oxidative process. An alternative pathway pro-
ceeds through a stepwise mechanism involving initial H-atom
abstraction followed by diradical recombination. A substantial
body of experimental and computational evidence on dirhodium-
mediated CꢀH insertion implicates a concerted process.25 By
contrast, related mechanistic studies on monomeric ruthenium
amination catalysts (e.g., [Ru(TPP)CO]) support a stepwise
oxidative event.26 In an effort to understand the operative mechan-
ism for diruthenium-catalyzed amination, a comprehensive the-
oretical analysis of the reaction coordinate for both allylic
oxidation and π-bond aziridination was undertaken.
In the following section, relevant energies (298.15 K, 1 atm)
are tabulated as ΔH(ΔG)[ΔGs] for gas-phase enthalpy, gas-
phase Gibbs free energy, and solvated Gibbs free energy, the
last of which was estimated as ΔGs = ΔGsolv(PCM-calculated) +
[ΔE ꢀ ΔG]gas. Cartesian coordinates for all of the B3LYP/
LANL2DZ-optimized structures are presented in Table S2 in the
Supporting Information.27 High-spin states were calculated for
all reported structures; computed molecular orbitals were then
used to determine both open- and closed-shell low and inter-
mediate spin states.
Initial calculations were able to recapitulate to within close
approximation the crystallographic data obtained for [Ru2(hp)4Cl]
and indicated that the most stable isomer should maintain a (4,0)
ligand geometry with chloride bound to the more sterically
congested ruthenium center (Figure 6). The ground electronic
state of [Ru2(hp)4Cl] is a 4A state with three unpaired spins, in
agreement with magnetic susceptibility measurements on this
and analogous diruthenium complexes.12 The open-shell 2A state
is 8.4(8.7)[17.9] kcal/mol higher in energy. The spin-paired
“closed-shell” doublet (ÆS2æ = 0.76) is higher in energy by
13.1(13.9)[21.2] kcal/mol and was not further examined.
a All reactions were performed with 2.5 mol % [Ru2(hp)4Cl], 1.4 equiv
of PhI(O2CtBu)2, and powdered 5 Å molecular sieves in CH2Cl2 at
40 ꢀC. b Product ratios were estimated by integration of the 1H NMR
spectrum of the unpurified reaction mixture. c Product obtained as a 12:1
mixture of diastereomers; major product shown. d Product obtained as a
2:1 mixture of diastereomers; major product shown. e Product obtained
as a > 20:1 mixture of diastereomers.
and benzylic CꢀH bonds over both π bonds and tertiary
centers. Notably, in the two examples involving this catalyst
and an unsaturated sulfamate ester, the aziridine product was not
detected. These selectivity trends diverge unmistakably from
data recorded for [Rh2(esp)2] and other tetracarboxylate rho-
dium dimers. We believe that the identification of [Ru2(hp)4Cl]
represents an important breakthrough for CꢀH amination
technology, affording us the ability to influence reaction chemo-
selectivity in a single substrate with a simple choice of catalyst.
The utility of [Ru2(hp)4Cl] was explored against a collection
of structurally disparate substrates. The reaction afforded in all cases
the oxathiazinane heterocycle as the major (or exclusive) product
of oxidation (Table 2). The reactions were easily conducted
without the need for rigorously dried solvent or oxygen-free
conditions and reached completion in less than 24 h. The process
appears to be compatible with a number of common functional
groups and proceeds efficiently with di- and trisubstituted alkene
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Figure 7. Model reaction for evaluating the putative nitrenoid oxidant.
Mulliken spin-density analysis of [Ru2(hp)4Cl] in the
4A ground state indicated that 1.71 unpaired α-spins reside on
Ru1, whereas almost one full α-spin is localized on Ru2. The Cl
center and bridging N and O atoms of the oxypyridinate (hp)
ligands bear additional small amounts of unpaired α-spin. The
number of unpaired spins on Ru2 does not change in the 2A state,
while that on Ru1 is reduced from 1.71 to 0.40. In the 2A state,
both the N and O atoms of the hp ligands support small amounts
of unpaired β-spins. This spin distribution, along with the
calculated ÆS2æ value of 1.76, confirms the antiferromagnetically
coupled nature of the open-shell doublet of [Ru2(hp)4Cl]. Table
S1 in the Supporting Information (SI) summarizes these data.
Having validated the choice of basis set and functional, we
evaluated the structure of the putative [Ru2(hp)4Cl]ꢀnitrene
complex 6. A general scheme for performing this analysis
combines [Ru2(hp)4Cl] with neutral nitrene fragment 5
(Figure 7). Table S1 in the Supporting Information contains
calculated spin densities of relevant atoms for intermediates,
transition states, and products in both the quartet and open-shell
doublet states for the reaction between [Ru2(hp)4Cl] and trans-
4-hexenyloxysulfonylnitrene (5).
Figure 8. Calculated structures for the [Ru2(hp)4Cl]-catalyzed allylic
amination pathway: metal-bound nitrenoid 6, transition state TS1,
diradical intermediate 7, and metal-bound oxathiazinane adduct Ru2 O.
3
Numerical values represent selected bond lengths (in Å) for doublet
electronic states. Corresponding values for quartet electronic states are
in parentheses.
The ground electronic state of alkoxysulfonylnitrene 5 is a
triplet with two unpaired electrons occupying degenerate orbitals
on the N center. An open-shell singlet state for 5 (ÆS2æ = 1.01)
lies 11.5(12.4)[11.5] kcal/mol higher in energy. The closed-
shell singlet state of this free nitrene (ÆS2æ = 0.00) appears to be
18.6(19.9)[18.5] kcal/mol higher than the triplet state and was
not evaluated further.28
energetically similar, both were studied for all possible transition
states, intermediates, and products of the reaction (for both
CꢀH amination and olefin aziridination). The computed en-
ergies of these structures are reported relative to the correspond-
ing doublet and quartet states of 6, unless otherwise stated.
Allylic CꢀH Amination Pathway. Intramolecular allylic amine
formation from 6 occurs via insertion of a ruthenium-bound
nitrene into the allylic C3ꢀH bond. The transition state TS1
associated with this process (starting from the ground-state
doublet form of 6) is shown in Figure 8; the analogous quartet
TS is predicted to be only 1.8(1.1)[1.0] kcal/mol higher in
energy. The general pathway for this reaction starting from
Combining the 4A and 2A states of [Ru2(hp)4Cl] with triplet
and singlet forms of 5 generates Ruꢀnitrene complex 6 in three
possible electronic states: doublet, quartet, and sextet. Our
calculations suggest that 6 is a ground-state doublet with 0.82
unpaired α-spins located on Ru2 (Figure 8). The Ru1 and
sulfonyl nitrogen (N5) centers bear small contributions of 0.09
α-spin and 0.07 β-spin, respectively. This spin distribution is in
accord with a Ruꢀnitrene double bond in the doublet state of
complex 6. The quartet state of 6 resides 9.8(6.7)[5.4] kcal/mol
higher in energy than the doublet state; the calculated spin
densities (0.92, 0.96, and 0.64 α-spins in Ru1, Ru2, and N5,
respectively) indicate that Ru1ꢀN5 is a single bond in quartet 6.
The sextet state energy lies significantly above those calculated
nitrenoid intermediate 6 is given by 6 f TS1 f 7 f Ru2 O.
3
2
In the A TS, 0.68 unpaired α-spin is located on the distal Ru2
center, while other atoms bear insignificant spin densities (see
Table S1 in the Supporting Information). In the 4A TS, however,
the Ru1, Ru2, N5, C3, and C5 centers harbor significant α-spin
densities (0.97, 0.76, 0.48, 0.27, and 0.23, respectively). These
data intimate that the quartet state of TS1 may represent a
proton-coupled electron-transfer (PCET) process. Calculations
on the 2A state for TS1 suggest insignificant spin contributions at
both the C3 and C5 centers.
Calculated bond distances for both doublet and quartet TS1
show that the former reflects a more advanced TS by virtue of the
significant elongation of the H1ꢀC3 bond and closer proximity
of H1 to the electrophilic nitrene. Conversely, for the 4A state, the
allylic hydrogen remains more closely associated with C3. The
Ru1ꢀN5 bond in both depictions of TS1 more closely approx-
imates a single bond, and this change is matched with an
2
4
for the A and A states, so further discussion of this state has
been omitted.
The estimated Ru1ꢀN5 bond distances for the A and A
states of 6 are consistent with the predicted bond orders. The
short Ru1ꢀN5 distance of 1.789 Å in doublet 6 is characteristic of
doubly bonded RuꢀN. In the quartet form, the predicted
Ru1ꢀN5 distance of 1.904 Å more closely resembles a metalꢀ
nitrogen single bond. Association of the nitrene to Ru1 elongates
the Ru1ꢀRu2 distance from 2.327 to 2.559 and 2.508 Å for
doublet and quartet states of 6, respectively. The consequence of
this bond lengthening is a decrease in the bonding overlap
between the two ruthenium centers. Since the doublet and
quartet electronic states of the metalꢀnitrene complex are
2
4
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increased metalꢀmetal interaction and a contracted Ru1ꢀRu2
bond length. The barrier heights, calculated as the energy difference
between complex 6 and TS1, were found to be 14.8(16.7)[14.5]
kcal/mol for doublet TS1 and 6.8(11.2)[10.0] kcal/mol for quartet
TS1.
The identification of a discrete diradical intermediate 7
(Figure 8) on the reaction coordinate for CꢀH amination with
[Ru2(hp)4Cl] explains the penchant of this catalyst to effect
allylic oxidation. The diradical species follows TS1 as the result of
H1-atom transfer to the metal-bound nitrogen. The computed
electronic structure of 7 favors a ground-state quartet with three
unpaired α-spins located primarily on the Ru1, Ru2, C3, and C5
centers (see Table S1 in the SI). The doublet state of complex 7 is
higher in energy by 7.8(12.7)[4.8] kcal/mol, with the unpaired
spin distributed across the Ru1, Ru2, C3, and C5 centers. The
pathway to allylic amination thus begins with nitrenoid complex
6 in a doublet electronic ground state, proceeds through a
14.8(16.7)[14.5] kcal/mol energy barrier at the doublet state
TS1, and leads to diradical intermediate 7 as a lowest-energy
quartet. The doublet and quartet potential energy surfaces for the
sequence 6 f TS1 f 7 cross only after transition state TS1.
Intermediate 7 is a local minimum on the potential energy
surface (i.e., it has no imaginary frequencies) but is unstable
both kinetically and thermodynamically and converges readily to
Figure 9. Possible transition structures for the alkene aziridination
pathway. For clarity, only one of the four 2-oxypyridinate ligands in each
structure is shown.
the alkoxysulfonamide complex Ru2 O (see Figure 8).
3
All attempts to locate the TS associated with the conversion of
diradical 7 to the complexed product Ru2 O failed. Scanning the
3
potential energy surface of the reaction 7 f Ru2 O by fixing the
3
reaction coordinate and the N5ꢀC3 distance and then optimiz-
ing all other geometry parameters suggested a 0.5ꢀ0.8 kcal/mol
energy barrier for the radical rebound step. This small kinetic
barrier should require minimal structural reorganization for the
biradical intermediate to pass through the associated transition
state and on to Ru2 O.
3
As depicted in Figure 8, the alkoxysulfonamide product (i.e.,
oxathiazinane) remains loosely associated with the diruthenium
complex (as the adduct Ru2 O) following CꢀN bond forma-
3
tion. The geometrical parameters for the diruthenium core of
Figure 10. Computed structures of transition states TS2-C4 and TS2-
C5 and their corresponding diradical intermediates C4-I and C5-I
on the aziridination pathway. Numerical values represent bond lengths
(in Å) for doublet electronic states. Corresponding values for quartet
electronic states are in parentheses.
Ru2 O closely parallel those of the parent catalyst [Ru2(hp)4Cl];
3
both the free complex and the oxathiazinane adduct have a
quartet electronic ground state. Dissociation of the heterocycle
from Ru2 O is calculated to be exothermic by 2.1(13.7)[9.8]
3
kcal/mol.
In summary, the CꢀH insertion pathway beginning with doublet
nitrenoid complex 6proceedsthrougha 14.8(16.7)[14.5] kcal/mol
energy barrier at transition state TS1 (doublet), which leads
to the quartet state diradical intermediate 7. This process
can be described as a severe CꢀH bond polarization from
C3 to the coordinated nitrene N5 followed by homolytic
bond scission and diradical formation. In the subsequent
steps, radical recombination proceeds over an energy barrier
The calculations suggest the viability of either TS2-C4 or
TS2-C5 but not the cyclic transition structure TS2-concerted,
which represents a higher-energy pathway that converges to
either TS2-C4 or TS2-C5. Both TS2-C4 and TS2-C5 (Figure 10)
are real and possess a single imaginary frequency, and both
are ground-state doublets. The quartet transition states are
higher in energy by 2.0(0.8)[0.8] kcal/mol for TS2-C4 and
3.0(1.1)[1.1] kcal/mol for TS2-C5. Quasi-intrinsic reaction
coordinate (quasi-IRC) calculations confirmed that TS2-C4 and
TS2-C5 connectthe nitrenoid complex 6 with intermediates C4-I
and C5-I, respectively.
Close inspection of the calculated metrical parameters for
TS2-C4 reveals that along this pathway the Ru1ꢀN5 and C4ꢀC5
bond distances are elongated by 0.178 and ∼0.06 Å, respectively,
relative to those of the starting Ruꢀnitrene 6. C4 approaches
N5 at 2.065 Å (doublet) or 2.185 Å (quartet). Weakening of the
Ru1ꢀN5 bond in TS2-C4 increases the Ru1ꢀRu2 bond strength
and re-establishes its multibonding character. These structural
of <1 kcal/mol to form the product-bound complex Ru2 O.
3
The overall conversion of the trans-4-hexenyl sulfamate
nitrenoid to the oxathiazinane heterocycle via the sequence
6 f TS1 f 7 f Ru2 O is calculated to be exothermic by
3
55.7(55.5)[51.8] kcal/mol.
Aziridination Pathway. The mechanism for alkene aziridina-
tion by [Ru2(hp)4Cl] was evaluated computationally in a manner
analogous to that described for allylic oxidation. Three limiting
transition structures for this process, which differ as a function of
the angle of approach of the olefin moiety to the nitrene ligand,
are depicted in Figure 9.
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Figure 12. Partial cisꢀtrans isomerization of 10 consistent with a short-
lived radical intermediate.
complex Ru2 A with a very small energy barrier; a transition state
3
for this process could not be located. The aziridination process
6 f TS2-C5 f C5-I f Ru2 A occurs exothermically by
3
38.7(37.4)[37.0] kcal/mol and in fact represents the lowest-
energy operative mode for the aziridination process. Dissociation
Figure 11. Relevant energies along the reaction coordinate for both
allylic amine formation and aziridination (lowest-energy pathway via
intermediate C5-I) computed for both doublet and quartet states.
of the fused bicyclic heterocycle from complex Ru2 A is exo-
3
thermic by 5.6(16.8)[15.4] kcal/mol. The doublet and quartet
potential energy surfaces of this reaction cross after intermediate
C5-I en route to product.
Summary. As shown in Figure 11, the reaction coordinates
for complementary amination pathways begin at the same
doublet nitrenoid complex 6. The allylic pathway proceeds
through a 14.8(16.7)[14.5]kcal/mol energy barrier at the doub-
let transition state TS1, characterized as a PCET TS, that leads
through intermediate 7 to the heterocycle-bound complex
modifications occur concomitantly with a spin density redistri-
bution as the reaction progresses (see Table S1 in the Supporting
Information).
Lengthening of the C4ꢀC5 bond apportions 0.60 β-spin as a
doublet or 0.53 α-spin as a quartet to the C5 center. In the
doublet electronic state, the Ru1 and N5 centers acquire 0.94 α-
spin and 0.33 β-spin, respectively. The doublet electronic state of
TS2-C4 differs from the quartet state essentially by a spin flip at
the N5 and C5 centers. This finding is consistent with the small
calculated energy difference of 2.0(0.8) kcal/mol between these
two electronic states as well as the ÆS2æ value of 1.58 for the
doublet state. Surmounting the 19.1(21.4) kcal/mol energy
barrier at TS2-C4 leads to the generation of intermediate C4-I
with incipient N5ꢀC4 bond formation at 1.511(1.499) Å
(Figure 10), which weakens and stretches the Ru1ꢀN5 bond
by 0.086(0.088) Å.
Ru2 O. The overall allylic CꢀH amination reaction leading
3
to Ru2 O is exothermic by 55.7(55.5)[51.8] kcal/mol. Alter-
3
natively, aziridination occurs through the favored doublet transi-
tion state TS2-C5 over a 15.9(18.0)[20.6] kcal/mol energy
barrier and follows a pathway through intermediate C5-I that is
downhill by 38.7(37.4)[38.0] kcal/mol. Thus, the energetic cost
for CꢀH amination from nitrenoid 6 is 1.0(1.3)[6.1] kcal/mol
less than that of the aziridination pathway. This calculated value
is consistent with the 8:1 product selectivity noted in the reac-
tion of 4-hexenyl sulfamate (see Table 1). Additionally, there is a
clear thermodynamic preference (by 17.0(18.1)[14.8] kcal/mol)
for six-membered-ring oxathiazinane formation through allylic
CꢀH amination.
Formation of the N5ꢀC5 bond follows via radical coupling to
furnish the bicyclic aziridine, which remains loosely bound to the
parent complex as [Ru2(hp)4Cl] aziridine (Ru2 A). Scanning
3
3
Mechanistic Analysis: Experimental. Experimental investi-
gations were undertaken in an effort to substantiate the conclu-
sions drawn from our DFT analysis. In order to distinguish a
CꢀH abstraction/radical rebound mechanism, cyclopropane
clock substrate 8 was subjected to amination conditions using
2.5 mol % [Ru2(hp)4Cl] (Figure 12). The rate constant for ring
opening of a related cyclopropylcarbinyl radical has been esti-
the potential energy surface for the reaction pathway C4-I f
Ru2 A by fixing the reaction coordinate and the N5ꢀC5 distance
3
and then optimizing all other geometry parameters leads us to
posit a 0.3ꢀ0.5 kcal/mol energy barrier from C4-I to Ru2 A.
3
Minimal structural reorganization is thus needed for C4-I to
proceed to product; the relevant transition structure was not
determined.
mated at 2 ꢁ 1011
s
ꢀ1, which translates to a radical lifetime on
The alternative aziridination pathway, operating through in-
itial approach of C5 to the N5 center, commences with metal-
bound nitrene complex 6 and proceeds through transition state
TS2-C5 (Figure 10). The calculated activation energy for
aziridination of 6 via the lowest-energy doublet state of TS2-
C5 was found to be 15.9(18.0)[20.6] kcal/mol. Quasi-IRC
calculations confirmed that transition state TS2-C5 connects 6
with intermediate C5-I (Figure 10). Both the geometry and spin
properties of C5-I exhibit a high degree of similarity to those of
complex C4-I, except that spin density is transferred in this case
to C4 rather than C5, which is the site of nascent bond formation.
Intermediate C5-I converges to the metal-associated aziridine
the order of picoseconds.29 Somewhat surprisingly, no fragmen-
tation product was observed in the reaction of 8, and the six-
membered oxathiazinane was obtained in 67% isolated yield.
Because of the possible reversibility of cyclopropylcarbinyl
radical ring fragmentation in 8, oxidation of the isomeric cis-
cyclopropane substrate 10 was also conducted. In this case,
HPLC analysis revealed that a small percentage (2ꢀ3%) of the
trans-cyclopropane had indeed formed. This latter result is
consistent with the intermediacy of a short-lived radical species
that can reversibly fragment the adjacent ring before undergoing
fast recombination.
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Figure 14. Deuterium-labeled sulfamate ester for KIE analysis.
Figure 15. Comparison of reaction outcomes for Rh- and Ru-catalyzed
amination reactions. All of the reactions were performed with 2.5 mol %
catalyst and PhI(O2CtBu)2 in CH2Cl2. MgO and 5 Å molecular sieves
were used as additives for reactions with the Rh and Ru catalysts,
respectively (see the SI for details).
insertion process (rhodium) to one involving homolytic or
heterolytic CꢀH bond cleavage (ruthenium). Such a stepwise
process through a radical or cationic intermediate would account
for the larger influence of substituent groups on the relative rates
of CꢀH amination in the diruthenium-mediated reactions.
To probe further the mechanism of the diruthenium-catalyzed
process, we measured the influence of deuterium substitution on
the rate of CꢀH oxidation. A straightforward kinetic isotope
effect (KIE) determination could be made by employing mono-
deuterated starting material 12 (Figure 14). Under typical
amination conditions with 2.5 mol % [Ru2(hp)4Cl], the ratio
of oxathiazinane isotopomers was determined to be 4.9 ( 0.2
(based on quantitative 13C NMR analysis; see Supporting Infor-
mation for details). This experimental value is in remarkably
precise accord with the DFT-computed value of 4.9. By compar-
ison, the experimentally measured KIE for the [Rh2(OAc)4]-
catalyzed reaction with 12 was 2.6 ( 0.2.30 These data strongly
implicate a stepwise mechanism for CꢀH oxidation promoted
by diruthenium catalysts. Such a pathway would be expected to
favor nitrogen insertion into CꢀH bonds with lower homolytic
bond strengths (i.e., allylic and benzylic).
Additional evidence in support of a [Ru2(hp)4Cl]-mediated
radical abstraction/rebound amination pathway follows from
product analysis data. When subjected to the diruthenium-
catalyzed amination process, one substrate, cis-5-phenyl-4-pen-
tenyl sulfamate, yielded two isomeric products arising from
partial scrambling of the double-bond geometry (Figure 15).
The same reaction performed with [Rh2(esp)2] gave exclusively
the cis product. This observation offers compelling evidence for
the intermediacy of a short-lived radical species en route to the
product heterocycle.31 A similar set of experiments involving
intermolecular aziridination of cis-stilbene further serves to high-
light the stepwise nature of the diruthenium-catalyzed process.
Taken together, these data offer definitive support for the stepwise
mechanism for CꢀH and π-bond amination revealed by DFT.
Figure 13. Hammett analysis data for competitive intramolecular
benzylic insertion using rhodium and ruthenium catalysts.
Insight into the transition structure of the oxidation event was
obtained through Hammett analysis using a series of competitive
sulfamate cyclization reactions on substrates possessing two
electronically disparate benzylic centers (Figure 13). Values of
F for reactions promoted by different metal complexes were
determined by linear regression analysis of the logarithm of
product ratios plotted against σ+. Analogous experiments with
the dirhodium tetraoctanoate complex [Rh2(oct)4], which likely
operates through a concerted asynchronous reaction manifold,
furnished a value of F = ꢀ0.55.25a This small negative number
reflects the stabilizing influence of electron-donating substituents
and is consistent with a concerted transition state. By compar-
ison, the F values for the two ruthenium catalysts [Ru2(hp)4Cl]
and [Ru2(esp)2SbF6] were determined to be ꢀ0.90 and ꢀ1.49,
respectively. Excellent fits to the data were obtained in all three
cases, providing R2 values near unity.
In comparison with [Rh2(oct)4], the more negative F values
for the two diruthenium complexes are indicative of transition
structures in which CꢀH bond breakage is pronounced. In
particular, [Ru2(esp)2SbF6], with a recorded F value of ꢀ1.49,
shows remarkable discrimination for the oxidation of electro-
nically dissimilar CꢀH bonds (e.g., [Ru2(esp)2SbF6] furnishes a
20:1 ratio of insertion products favoring reaction at benzylic over
p-nitrobenzylic centers). If one assumes that all three catalysts
function through a concerted pathway, the evident differences in
the Hammett data for the dirhodium- and diruthenium-catalyzed
CꢀH aminations are not easily explained. The ostensibly most
electrophilic catalyst, [Ru2(esp)2SbF6], which by inference
should afford the most reactive nitrenoid, operates with the
highest degree of chemoselectivity. An alternative interpreta-
tion of the data posits a change in mechanism from a concerted
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’ CONCLUSIONS
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We have demonstrated for the first time the efficacy of
diruthenium complexes for catalytic oxidative amination of
CꢀH bonds. The catalyst [Ru2(hp)4Cl] displays a preference
for amination of allylic and benzylic centers, a characteristic that
distinguishes its selectivity profile from dirhodium tetracarbox-
ylate counterparts. Both computational and experimental data
have revealed a mechanism for diruthenium-mediated CꢀH
insertion that is stepwise in nature and progresses through the
intermediacy of a short-lived diradical species. These conclusions
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opens the door to a new class of catalyst structures that can
accommodate a wider range of ligand types than simple carbox-
ylates. The discoveries detailed in this report therefore constitute
an important step forward in the evolution of reagent-controlled
methods for selective CꢀH bond oxidation.
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’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proto-
b
cols; characterization data for new compounds; complete ref
27a; calculated spin densities (in e) of important atoms of
reactants, intermediates, transition states, and products of allylic
amination and aziridination by complex 6 (Table S1); Cartesian
coordinates (in Å) of all structures calculated at the B3LYP/
LANL2DZ level of theory (Table S2); and crystallographic data
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
dmusaev@emory.edu, jdubois@stanford.edu
’ ACKNOWLEDGMENT
Funding for this project was provided by the National Science
Foundation Center for Stereoselective CꢀH Functionalization
(CSCHF). D.G.M. acknowledges NSF Grant CHE-0553581 and
the Cherry Emerson Center for Scientific Computation. We
thank Dr. Allen Oliver at the University of Notre Dame for
crystallographic analysis. We thank a reviewer for suggesting the
experiment with cis-cyclopropane 10.
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(27) All calculations were performed using the Gaussian 09 quan-
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revision B.01; Gaussian, Inc.: Wallingford, CT, 2010]. The geometries of
all species under investigation were optimized without symmetry
constraints at the B3LYP level of theory [see:(b) Becke, A. D. Phys.
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“B3LYP/LANL2DZ”. Hessian matrices were calculated for all species
under investigation. All reported transition states were confirmed to
have a single imaginary frequency corresponding to the reaction
coordinate. Quasi-IRC calculations were utilized for further elucidation
of the nature these transition states. The solvent effects were estimated at
17216
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