Catalytic C-N Bond-Forming Reactions Enabled by Proton-Coupled Electron Transfer Activation of Amide N-H Bonds

Article abstract of DOI:10.1021/acscatal.6b00486

Over the past three years, our group has become interested in the ability of proton-coupled electron transfer (PCET) to facilitate direct homolytic bond activations of common organic functional groups that are challenging substrates for conventional hydro

Full text of DOI:10.1021/acscatal.6b00486

Subscriber access provided by UNIVERSITY OF SASKATCHEWAN LIBRARY
Perspective
Catalytic C-N Bond Forming Reactions Enabled by Proton-
Coupled Electron Transfer Activation of Amide N-H Bonds
Lucas Q. Nguyen, and Robert R Knowles
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00486 • Publication Date (Web): 30 Mar 2016
Downloaded from http://pubs.acs.org on March 31, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street
N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 12
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
Lucas Q. Nguyen and Robert R. Knowles*
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Chemistry, Princeton University, Princeton, NJ 08544
Keywords: Proton-coupled electron transfer, hydrogen atom transfer, amidyl radicals, bond weakening, C-N bond for-
mation
ABSTRACT: Over the past three years, our group has become interested in the ability of proton-coupled electron transfer
(PCET) to facilitate direct homolytic bond activations of common organic functional groups that are challenging sub-
strates for conventional hydrogen atom transfer catalysts. This perspective details our efforts to develop oxidative PCET
platforms for activating the strong N-H bonds of amides, providing catalytic access to synthetically useful amidyl radicals.
We successfully identified compatible combinations of one-electron oxidants and Brønsted bases that, while unable to
activate the amide substrates independently, act concomitantly with the requisite energetics to selectively homolyze the
N-H bond via concerted PCET. The resulting amidyls were utilized in the development of new catalytic protocols for al-
kene carboamination and hydroamidation. We also highlight our efforts to develop a PCET-based bond-weakening pro-
tocol for the catalytic conjugate aminations using amide substrates. In this work, coordination to a Ti(III) catalyst signifi-
cantly decreases the strength of a ligated amide N-H bond, enabling a facile PCET event to occur with the weak H-atom
acceptor TEMPO. While this discussion focuses on amide activation, we anticipate that the design parameters presented
here are general and should provide a framework for the development of PCET catalyst systems for other challenging ho-
molytic bond activations as well.
I. Introduction
light several recent results relating to the development of
oxidative PCET reactions of N-aryl amide substrates and
applications of the resulting intermediates in catalytic C-
N bond forming reactions.
Hydrogen atom transfer (HAT) reactions play a central
role in organic free radical chemistry, enabling the direct
generation of open-shell intermediates from unfunction-
alized starting materials. While significant advances in
HAT catalysis have been made in recent years,1 there are
currently no general catalytic methods for H-atom ab-
straction from many of the most common organic func-
tional groups, such as the O-H bonds of aliphatic alcohols
or the N-H bonds of amides.2 This deficit is due in part to
the fact that these polar E-H bonds are exceptionally
strong, with bond dissociation free energies (BDFEs) of-
ten well in excess of 100 kcal/mol (Scheme 1).3 As such,
even the most powerful known molecular H-atom accep-
tor catalysts are not sufficiently reactive to effect efficient
H-atom abstractions from these donor bonds, nor to se-
lectively activate them in the presence of much weaker
aliphatic C-H bonds that are often present in the same
substrates.
II. Background
Amidyls are electrophilic, nitrogen-centered radicals
that are key intermediates in a wide range of classical rad-
ical reactions, including olefin additions and remote C-H
functionalization via directed H-atom abstraction.4 Con-
ventional methods for amidyl generation require either
stoichiometric prefunctionalization of the amide to its
corresponding N-halo-, N-nitroso-, or N-phenylthioamide
derivative, or the use of strong stoichiometric oxidants
(Scheme 2).5 While powerful, these methods have re-
quirements that may limit their applications in more
complex contexts, where selective N-functionalization
can be difficult to achieve. Moreover, as the activating
group is often incorporated into the product, these ap-
proaches restrict the scope of possible transformations
that can be accommodated. Accordingly, catalytic meth-
ods that enable the direct generation of amidyls from un-
functionalized amide N-H bonds are highly desirable.6
Our group has recently become interested in the ability
of concerted proton-coupled electron transfer (PCET)
reactions to address these limitations and expand the
scope of substrates amenable to homolytic bond activa-
tion in a catalytic manifold. In this perspective, we high-
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Established methods of amidyl generation and pro-
posed oxidative PCET methods
including the N-H bonds of amides, that are not tradi-
tionally substrates for classical H-atom transfer activa-
tion. These efforts evolved out of prior work from our
group on the reductive PCET activation of ketones to cat-
alytically furnish neutral ketyl radicals that can partici-
pate in a variety of catalytic and enantioselective C-C
bond forming reactions.10 In the following section, we
highlight several recent contributions from our lab to-
ward the design and implementation of oxidative PCET-
based mechanisms for amide N-H bond activation and
the use of the resulting nitrogen-centered radical inter-
mediates in the development of new catalytic C-N bond
forming reactions.
Scheme 1. BDFE values of common organic functional groups
and examples of hydrogen atom abstractors
In considering these issues, we became aware of recent
advances in the understanding and applications of pro-
ton-coupled electron transfer.7 PCET reactions are un-
conventional redox processes that couple proton motion
with an electron exchange event. PCET can occur in a
stepwise manner, or in a concerted fashion wherein both
particles are exchanged through a single transition state.
In this framework, classical HAT reactions can be consid-
ered as a subset of concerted PCET reactivity in which the
proton and electron travel jointly from a single bond in
the donor to a single bond in the acceptor. Multisite con-
certed PCET reactions are also common, where the elec
trons and protons travel to or from independent molecu-
lar acceptors and donors. While this type of concerted
PCET activation has rarely been invoked in synthetic ap-
plications, it is now recognized to be an important mech-
anism for charge transfer in biological redox catalysis,
playing a key role in photosynthetic water oxidation, oxy-
gen reduction, ribonucleotide reduction, and DNA re-
pair.8 Similarly, PCET has been incorporated as a design
feature in numerous synthetic inorganic catalysts for
small molecule activations relevant to renewable energy
concerns.9
III. Advantages of oxidative PCET activation
The goals above are predicated on several distinct fea-
tures of multisite PCET mechanisms that are particularly
well suited for strong bond activation. The first is that the
thermochemistry of multisite PCET is highly modular
and, in principle, covers a much broader range of energies
than is possible with conventional H-atom acceptor tech-
nologies. To illustrate this point, it is useful to draw an
analogy between the energetics of multisite PCET reac-
tions and the conventions used to define the strengths of
normal covalent bonds to hydrogen. Typically, BDFEs are
evaluated using a thermodynamic cycle comprised of two
readily accessible experimental parameters: pKas and re-
dox potentials. In this scheme, the BDFE is defined as the
energy required to heterolytically break the bond (repre-
sented as a pKa value) summed together with the energies
required to oxidize the resulting anion to a neutral radical
and reduce the remaining proton to H• (Figure 1).11 In
principle, this formalism provides actionable design pa-
rameters for engineering more reactive molecular HAT
catalysts. For example, to create a more reactive molecu-
lar H-atom acceptor, one must make the abstracting spe-
cies either a stronger one-electron oxidant, the resulting
reduced state a stronger Brønsted base, or some combina-
tion thereof. Unfortunately, within a single molecule
Based on these precedents, we questioned whether oxi-
dative PCET might serve as a viable mechanism for homo-
lytic activation in organic synthesis as well. In particular,
we hoped that several distinct mechanistic features of
multisite PCET might enable the development of new
catalytic methods for the selective homolysis of strong 
bonds found in many common organic functional groups,
ACS Paragon Plus Environment

Page 3 of 12
ACS Catalysis
tron transfer step.14 Since most polar N-H and O-H bonds
1
2
3
are excellent H-bond donors, we expected that it would
be possible to homolyze them selectively.
Lastly, the rates of multisite PCET mechanisms can be
significantly faster than the competing sequential transfer
pathways.15 As in electron transfer, PCET kinetics are
functions, in part, of the net driving force for the transfer
events. The concerted pathways lead directly to low ener-
gy products and avoid the higher energy intermediates
formed along the stepwise reaction coordinates. When
both stepwise intermediates are significantly high in en-
ergy relative to the reactants, the concerted pathways will
often dominate, providing a mechanism for cooperative
substrate activation by the oxidant-base pair under condi-
tions where neither partner is competent to engage the
substrate alone.16 Taken altogether, these advantages pro-
vided the foundation for our initial studies on amide acti-
vation via PCET.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
IV. Carboamination
Our initial synthetic efforts focused on developing a
new suite of catalytic olefin aminofunctionalization pro-
tocols. To begin, we focused on developing a novel cata-
lytic method for olefin carboamination.17 We envisioned a
catalytic cycle wherein a Brønsted base first engages with
a secondary anilide substrate via a hydrogen-bonded
complex to facilitate the PCET process with the excited
state of a visible light photoredox18 catalyst (Scheme 3).
The newly formed amidyl radical would then cyclize onto
a pendant alkene to form a C-N bond and an adjacent
carbon-centered radical. The nascent carbon-centered
radical would then undergo addition to an acrylate accep-
tor to form a new C-C bond and an -carbonyl radical.
Figure 1. Thermodynamic cycle for the determination of formal
BDFE values.
these two physical properties are inversely correlated and
interdependent.12 The energetic benefits of making an
acceptor more oxidizing will be largely compensated for
by a concomitant loss in basicity. Analogous difficulties
arise in the design of new reductive HAT reagents, where
in any increase in the acidity of an H-atom donor will be
compensated in part by a correlated decrease in the re-
ducing power of the conjugate base. These phenomena
complicate the rational design of more powerful H-atom
donors and acceptors through the variation of Brønsted
acidity and redox potentials alone.
PCET provides a means for overcoming this intrinsic
compensation problem. As described by Mayer and
coworkers, the thermochemistry of multisite PCET reac-
tions involving independent Brønsted bases and single
electron oxidants can be described using an analogous
thermochemical cycle (Figure 1) to the one described
above, wherein the free energy on the diagonal is likened
to an ‘effective’ bond strength.13 This ‘BDFE’ value repre-
sents a quantitative measure of the strength of a bond
that a given oxidant/base pair can break in a thermoneu-
tral reaction. However, unlike the HAT process, the pro-
tons and electrons in a multisite PCET are site-decoupled
and can be varied independently. As such, the effective
BDFE can be tuned over an arbitrarily wide range of ener-
gies, including combinations that are thermodynamically
competent to oxidize very strong  bonds.
Scheme 3. Proposed catalytic cycle for PCET-based amidyl
carboaminations
In addition to meeting the thermodynamic require-
ments for the homolysis of strong bonds, multisite PCET
also provides a mechanism for their selective activation in
the presence of much weaker aliphatic C-H bonds. Unlike
classical HAT reactivity where the weakest bonds in a
substrate are abstracted most rapidly, multisite PCET
requires a pre-equilibrium hydrogen bond between the
proton acceptor and the breaking bond prior to the elec-
Subsequently, reduction of this electrophilic radical to an
enolate by the reduced-state photocatalyst and favorable
proton transfer from the conjugate acid would furnish the
closed shell neutral product and regenerate the base and
photoredox catalysts to complete the catalytic cycle.
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 12
1
Table 1. Optimization of olefin carboamination
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To assist in the identification of effective base/oxidant
combinations competent to homolyze the anilide N-H
bond (BDE ~ 100 kcal/mol), we made use of Mayer’s effec
tive bond-strength formalism.12 Combinatorial evaluation
of five Ir(III) photocatalysts and four Brønsted bases with
effective BDFEs ranging from 80 kcal/mol to 110 kcal/mol
resulted in product formation only in the cases where the
effective BDFE is sufficiently close to or above the
strength of the N-H BDFE of the anilide (Table 1). Re-
markably, all of the iridium catalysts and all of Brønsted
the bases were found to successful in at least one combi-
nation, even when their respective pKas or redox poten-
tials fall short of those required to act directly on the am-
ide substrate. As in our early work with PCET of ketones,
these results suggest that simple thermodynamic consid-
erations can serve as a meaningful indicator of the feasi-
bility of multisite activation with a given catalyst pair.10
Scheme 4. Substrate scope for olefin carboamination
tion, this system is capable of accommodating a wide va-
riety of olefinic partners, including hindered trisubstitut-
ed and tetrasubstituted alkenes that are often challenging
substrates for metal-mediated carboamination protocols
involving migratory insertion into a M-N bond.19 In addi-
tion, more structurally complex systems can also be ac-
commodated, generating spirocyclic and fused bicyclic
systems, often with high diastereoselectivity. With regard
to the N-arylamine component, we found that electron-
rich, electron deficient, and heteroarene substrates were
all well-accommodated. Of particular note, the potential
for direct one-electron oxidation of the electron deficient
para-CN carbamates is ~600 mV more positive that that
of the Ir(III) excited state (*E1/2 = +1.0 V vs Fc/Fc+ in
MeCN),20 highlighting the ability of coupled proton ex-
change to enable electron transfer reactions that are oth-
erwise prohibitively endergonic.
From these results, we next explored the scope of the
carboamination
process
using
the
optimal
Ir(dF(CF3)ppy)2(bpy)PF6 / dibutyl phosphate catalyst pair
with irradiation from blue light-emitting diodes (LEDs)
(Scheme 4). These conditions enabled high yielding car-
boaminations of a variety of amide substrates, as well as
structurally related N-aryl carbamates and ureas. In addi-
ACS Paragon Plus Environment

Page 5 of 12
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5 Proposed catalytic cycle for PCET-based amidyl
hydroamidation
However, the stepwise pathway was ruled out on thermo-
dynamic grounds. Specifically, the large pKa difference
(pKa ~ 20) between the substrate and base suggests that
the N-H deprotonation would not be kinetically competi-
tive with luminescent decay of the Ir(III) excited state ( =
2.3 s).22 Taken together, these data are consistent with a
concerted PCET mechanism of amidyl formation being
operative in this carboamination protocol.
V. Hydroamidation
We sought to further extend the utility of this PCET-
based platform for amidyl generation by developing a new
catalytic method to an olefin hydroamidation.23 As in the
carboamination reaction, the proposed catalytic cycle for
such a process begins with the same excited state Ir(III)
photocatalyst and dialkyl phosphate base jointly activat-
Figure 2. (A) Ir luminescence quenching (red dot) solution with
constant N-phenylacetamide and varying concentrations of phos-
phate base (black square) solution with no N-phenylacetamide and
varying concentrations of phosphate base. (B) Ir luminescence
quenching (blue triangle) solution with constant phosphate base
and varying concentrations of N-phenylacetamide (red dot) solu-
tion with constant phosphate base and varying concentrations of
deuterated N-phenylacetamide (black square) solution with no
phosphate base and varying concentrations of N-phenylacetamide.
Table 2. Optimization of olefin hydroamidation
Kinetic and spectroscopic results were found to be con-
sistent with a concerted PCET mechanism for amidyl
formation. Luminescence quenching experiments demon-
strated that simple N-phenyl acetamide (E1/2 = 1.2 V vs
Fc/Fc+) does not measurably quench the excited state of
the iridium photocatalyst, while the phosphate base alone
is a weak quencher (kSV = 41 M-1). However, solutions con-
taining both amide and phosphate lead to highly efficient
quenching (kSV = 731 M-1) (Figure 2a). Further experiments
demonstrated that excited state quenching exhibited a
first-order kinetic dependence on the concentration of
each component. Lastly, independent reactions of the N-
H and N-D isotopologues of the amide substrate led to an
isotope effect of 1.15, consistent with the notion that the
labeled bond plays a specific role in the excited state
quenching event (Figure 2b).21 Both concerted PCET and
stepwise, rate-limiting deprotonation of the N-phenyl
acetamide by the phosphate base followed by oxidation of
the anilide anion are consistent with these observations.
ing an anilide N-H bond to generate the corresponding
amidyl radical (Scheme 5). This species would then un-
dergo addition to a pendant olefin to form a new hetero-
cycle and an exocyclic alkyl radical. Unlike in the carbo-
amination protocol, direct reduction of this radical to its
corresponding anion via electron transfer with iridium(II)
state of the catalyst is prohibitively endergonic. Instead,
we reasoned that inclusion of an appropriate H-atom do-
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 12
amounts of unproductive substrate consumption in the
1
absence of an added H-atom donor (Table 2, Entry 1).
Further study suggests that following amidyl cyclization,
the resulting carbon centered radical can abstract an H-
atom from the weak, allylic C-H bonds present in the
starting material. Consistent with this hypothesis, when
these allylic C-H bonds were replaced with methyl
groups, no product was observed (Table 2, Entry 2). Eval-
uation of a wide range of common H-atom donors, such
as phenols, arylamines, diphenyl acetonitriles, and tri-
phenyl silanes did not result in any meaningful enhance-
ment over the background reaction (Table 2, Entries 3-7).
However, simple thiophenol H• donors proved highly
effective, with inclusion of as little as 10 mol% of thiophe-
nol providing the desired hydroamidation product in 95%
yield (Table 2, Entry 8). Initially, this result was surprising
in the fact that aryl thiols are known substrates for multi-
site PCET activation and the S-H bond strength in thio-
phenol (BDFE ~ 79 kcal/mol) being more than 20
kcal/mol weaker than that of the amide substrate’s N-H
bond (BDFE ~99 kcal/mol).24
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To study the selectivity for N-H versus S-H bond activa-
Figure 3. (A) Ir luminescence quenching (red dot) solution with
constant phosphate base and varying concentrations of acetanilide
(black square) solution with no phosphate base and varying con-
centrations of acetanilide. (B) Ir luminescence quenching (red dot)
solution with constant phosphate base, constant thiophenol, and
varying concentrations of acetanilide (black square) solution with
constant phosphate base, constant acetanilide, and varying con-
centrations of thiophenol.
nor would reduce the carbon centered radical in a more
favorable process, forming the desired hydroamidation
product. Next, the oxidized form of the hydrogen-atom
donor would accept an electron from the reduced form of
the photocatalyst to form the corresponding anion. In
turn, the anion would be protonated by the phosphoric
acid produced during the PCET step to regenerate the
active forms of all three catalytic components.
Scheme 6. Substrate scope of olefin hydroamidation
Within this scheme, we were initially concerned about
the feasibility of effectively homolyzing a strong amide N-
H bond in the presence of a conventional H-atom donor.
Many HAT catalysts are known substrates for multisite
PCET, while others might be expected to reduce the
amidyl intermediate directly at the expense of productive
C-N formation. Wary of these concerns, our initial trials
demonstrated that upon irradiation of our model amide
with blue LEDs in the presence of both phosphate base
and iridium photocatalyst, the reaction mixture generated
small amounts of the desired lactam together with equal
tion, a series of competitive luminescence quenching ex-
periments were designed. As expected, neither the acet-
anilide nor the thiophenol alone were able to quench the
excited state of the Ir photocatalyst (Figure 3a). However,
solutions containing either the amide or thiol together
with
a phosphate base resulted in concentration-
dependent luminescence quenching consistent with
PCET activation (acetanilide ksv = 2860 M-1 and thiophe-
nol ksv = 470 M-1). However, in solutions containing vary-
ing concentrations of amide together with fixed concen-
ACS Paragon Plus Environment

Page 7 of 12
ACS Catalysis
tration of thiol and phosphate, luminescence quenching
retained a first-order kinetic dependence on the amide
1
2
concentration, albeit with slightly reduced efficiency (ksv
= 1250 M-1). However, analogous experiments employing
varying concentrations of thiol and fixed concentrations
of amide and phosphate exhibited no additional quench-
ing above background (Figure 3b). These results provide
strong support for amide activation via PCET as a kinet-
ically dominant pathway for radical generation from the
Ir(III) excited state. The origin for this selectivity likely
resides within the differential hydrogen bond donor abili-
ties between the amide and thiol moieties, a prerequisite
for multisite PCET activation. Density functional calcula-
tions (ωB97XD 6-31G++(2d,2p)CPCM=CH2Cl2) indicate
that formation of the amide-phosphate H-bond complex
is more favorable than the corresponding thiophenol-
phosphate H-bond complex by more than 5 kcal/mol,
translating to a significantly higher concentration of the
redox active amide-phosphate complex in solution.25
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Examples of homolytic bond weakening of ligands
in redox active transition metals
new covalent M-L bond. When favorable, these changes
can provide the driving force necessary to enable the ho-
molysis of normally strong bonds with comparatively
weak H-atom acceptors. Often, the degree of destabiliza-
tion can be dramatic (Scheme 7);27 however, this general
observation has not been systematically exploited in the
development of new catalytic methods. In fact, the stoi-
chiometric studies of Wood, Renaud, and Barrero on
bond weakening in water-complexed alkyl boranes are
among the only established synthetic examples.28 We be-
lieved that these mechanisms might serve as the basis for
a series of novel ‘soft’ hydrogen atom transfer reactions,
wherein normally strong bonds in a metal-coordinated
substrate could be formally abstracted using weak H-
atom acceptors to form reactive organometallic interme-
diates that can be further utilized in subsequent bond
forming processes.
With respect to scope, we found that this catalytic hy-
droamidation process accommodates extensive modifica-
tions to the substrate backbone, olefin, and N-aryl substi-
tution (Scheme 6). Hydroamidations of carbamates 18,
ureas 19, and thiocarbamates 20 proceeded efficiently
along with amide substrates under standard conditions.
With respect to the olefin component, a wide variety of
di-, tri-, and tetrasubstituted olefins with differing substi-
tution patterns were all efficiently hydroamidated. In ad-
dition, electron-deficient, electron-rich, and heteroaryl
amides substrates could also be accommodated. Lastly,
even more complex natural product-derived substrates
could be readily amidated in good yields, suggesting that
this catalytic protocol may find use in the synthesis of
more challenging targets as well.
The success of both our olefin carboamination and hy-
droamidation demonstrates that concerted multisite
PCET can be effectively employed to both activate strong
amide N-H bonds and utilize the resulting amidyl radical
in efficient bond forming reactions. The homolytic activa-
tion of strong N-H bonds can be achieved with a combi-
nation of an oxidant and base that provides the necessary
‘effective’ bond strength. Moreover, we show that that the
selectivity for the PCET event is governed in part by hy-
drogen bonding properties of the donor, enabling con-
trathermodynamic oxidations in the presence of much
weaker C-H and S-H bonds.
Scheme 8. Cuerva’s calculated BDE values for the O-H bond
in water B3LYP/6-31G(d)
VI. Bond Weakening
In line with the discussion above, we sought to develop
catalytic C-N bonding forming reactions based on the
‘soft homolysis’ of amide N-H bonds.29 In seeking catalyst
platforms to examine for this chemistry, we elected to use
TEMPO as the PCET oxidant given its ease of use and the
strongly negative potentials required for its one-electron
reduction. With respect to metal complexes, we were
drawn to reports from Cuerva and coworkers demonstrat-
ing that the O-H bonds in water are weakened by nearly
60 kcal/mol when complexed to Cp2Ti(III)Cl (Scheme
8).30 We questioned whether the N-H bonds in amide
While the studies above outlined our efforts to directly
homolyze amide N-H bonds using multisite PCET, we
have also explored an alternative method based on com-
plexation-induced bond weakening. The ability of redox-
active metals to homolytically weaken the bonds in coor-
dinated ligands has been documented for a wide range of
different metals and ligand-types.26 Mechanistically, these
processes function by kinetically coupling H-atom ab-
straction from a datively coordinated ligand to a one-
electron oxidation of the metal center and formation of a
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 12
compounds could be similarly weakened upon complexa- ing titanium enolate to form the desired product and ef-
1
2
3
4
5
6
7
8
tion, potentially enabling PCET activation by TEMPO
radical in solution. Such a process would then generate a
metallated aza-enolate nucleophile under completely
neutral conditions in the absence of an identifiable
Brønsted base. These intermediates could in turn serve as
nucleophiles in subsequent C-N bond forming reactions.
fects an electron transfer to generate Ti(III), thereby re-
generating the catalysts.
We evaluated the validity of this scheme by screening a
variety of differentially hindered titanocene catalysts in
conjunction with TEMPO in the conjugate amination of
N-aryl carbamate 32 (Table 3). Accordingly, Cp2Ti(III)Cl
Table 3. Optimization of conjugate amination enabled by
bond-weakening
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 9. Complexation induced HAT with TEMPO via
PCET
However, in considering this system, we were also cog-
nizant of the work of Waymouth demonstrating that
TEMPO reversibly forms a covalent adduct with an unu-
sually weak Ti(IV)-O bond in its reactions with Cp2TiCl.31
We reasoned that this undesired reactivity might be
avoided in the more sterically encumbered titanocene
complexes, which would be too bulky to bind TEMPO as
was not an effective catalyst, likely due to strong and un-
productive complexation to TEMPO. However, the more
reducing and hindered Cp*2Ti(III)Cl and Cp(Cp*)Ti(III)Cl
variants were highly effective, generating quantitative
yields of product 33 in 1 h at room temperature (Table 3,
Entries 3-4). Other nitroxyl radicals, such as AZADO,
could be also be used without diminishing yields (Table 3,
Entry 5).
Our optimal conditions for the Ti(III)-catalyzed conju-
gate amination of carbamate 32 gives the cyclized oxazol-
Scheme 10. Proposed catalytic cycle for bond-weakening in-
duced conjugate amination
a ligand, but would still enable substrate binding and co-
operative bond activation in combination with the nitrox-
yl oxidant (Scheme 9). In effect, such a process would
constitute a single-electron analogue to the popular ‘frus-
trated’ Lewis pair catalyst systems, wherein the reactive
catalyst components are sterically prevented from binding
strongly to each other but are competent to jointly acti-
vate a ligated substrate.
Scheme 11. Substrate scope for bond-weakening enabled con-
jugate amination
idinone product 33 in 94% yield (Scheme 11). The system
is also amenable to substitution with other atoms, provid-
ing access to N-phenyl pyrrolidone, thiazolidinone, and
imidazolidinones in good yields. One important note is
the accommodation of a base-sensitive fluorenylmethyl
ester (Fmoc) substrate 40 that successfully cyclized with-
out a detectable loss of the protecting group. Notably,
these conditions were not effective in cyclizing N-alkyl
amides, suggesting that Cp*2Ti(III)Cl does not weaken the
We chose to test the feasibility of these ideas in the
context of developing a new catalytic conjugate amination
reaction. We proposed a catalytic cycle where an amide
substrate first complexes with a titanocene(III) catalyst
(Scheme 10). Next, TEMPO abstracts H• from the weak N-
H bond of this complex via PCET. This step generates
TEMPO-H and a closed-shell Ti(IV) aza-enolate interme-
diate that subsequently undergoes C-N bond formation
with a pendant acrylate. TEMPO-H protonates the result-
ACS Paragon Plus Environment

Page 9 of 12
ACS Catalysis
The lack of appreciable binding was further corroborat-
1
ed by EPR experiments (Figure 4). Specifically, favorable
complexation of Ti(III) with TEMPO would result in a
closed-shell Ti(IV) species that would be EPR silent.31
However, spectra of solutions containing a 1:1 mixture of
Cp*2Ti(III)Cl and TEMPO exhibited signals identical to
those of each component alone, suggesting that the free
form of each catalyst is present in solution. Addition of
carbamate to a solution of both catalysts also resulted in
no observable EPR spectra changes, which suggests a sol-
vent-bound resting state for the titanocene catalyst. Last-
ly, the rate of the catalytic reaction was found to exhibit
first order kinetic dependence on the concentrations of
the carbamate substrate, Cp*2Ti(III)Cl, and TEMPO. Ad-
ditionally, a significant primary kinetic isotope effect of
7±1 was observed for the independent reactions of the
substrate N-H and N-D isotopologues. Taken together,
these results are consistent with a soft homolysis mecha-
nism whereby Cp*2Ti(III)Cl weakens an N-H bond fol-
lowed by a rate-limiting abstraction by TEMPO.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Scheme 12. Bond-weakening DFT calculations (UB3LYP 6-
31G(d) CPCM(MeCN))
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-H bonds of those substrates (~110 kcal/mol) sufficiently
for a favorable HAT with TEMPO.
VII. Conclusions
Preliminary mechanistic studies and calculations are
consistent with our proposed ‘soft homolysis’ mechanism
of substrate activation. We first quantified the ability of
Cp*2Ti(III)Cl to weaken the anilide N-H bonds. The coor-
dination of the Ti complex with N-phenyl propionamide
In this perspective, we have outlined the design and de-
velopment of two mechanistically distinct catalytic plat-
forms for the homolytic activation of strong N-H bonds
using PCET. In the first approach, we relied on the ability
of multsite PCET to decouple the electron and proton
transfer sites to overcome the thermodynamic challenges
typically associated with strong E-H bond activation, ena-
bling the catalytic generation of amidyl radicals via ra-
tionally selected oxidant-base pairs. We demonstrated
that the resulting amidyl radicals could be utilized in
novel and efficient catalytic protocols for olefin carbo-
aminations and hydroamidation. In addition, we devel-
oped an orthogonal PCET-based protocol for amide acti-
vation based on complexation-induced bond weakening.
We illustrated the use of bond weakening as the mecha-
nism of substrate activation in a catalytic conjugate ami-
nation process, whereby coordination to a simple Ti(III)
catalyst decreases the bond strength of an amide N-H
bond by more than 33 kcal/mol for facile HAT with
TEMPO. Synthetically these processes enable the genera-
tion of metallated organometallic species under com-
pletely neutral conditions. Although this perspective only
describes work relating to the activation of N-aryl amides,
these PCET-based protocols are potentially amenable to
the activation of many other common functional groups,
as well, including the much stronger N-H bonds found in
N-alkyl amides and the O-H bonds in alcohols. Efforts
toward these goals are currently underway in our labora-
tory and will be reported in due course.
Figure 4. EPR spectra and simulations demonstrating compatibil-
ity of Cp*2TiCl and TEMPO in MeCN solution.
decreased the N-H bond strength from 99 to 66 kcal/mol,
a weakening effect of 33 kcal/mol (Scheme 12). The desta-
bilization effect is even greater in the N-H bonds of car-
bamate substrates, characterized by a 39 kcal/mol weak-
ening. These BDFE values enable abstraction from the N-
H bond to TEMPO to be energetically feasible (O-H BDFE
TEMPO-H = 68 kcal/mol). Further DFT calculations indi-
cated that Ti-O bond between Cp*2Ti(III)Cl and TEMPO
is extraordinarily weak, with a BDFE of only ~2 kcal/mol,
some 23 kcal/mol less favorable than the Ti-O bond in the
less hindered Cp2Ti(III)Cl–TEMPO complexes reported by
Waymouth.31,32
* rknowles@princeton.edu
ACS Paragon Plus Environment

ACS Catalysis
Page 10 of 12
Am. Chem. Soc. 2004, 126, 5763-5775. (e) Migliore, A.; Polizzi, N.
The manuscript was written jointly by both authors.
1
2
3
4
5
6
7
8
F.; Therien, M. J.; Beratan, D. N. Chem. Rev. 2014, 114, 3381-3465.
(f) Smith, K. W.; Stroupe, M. E. Biochemistry 2012, 51, 9857-9868.
(g) Kennis, J. T. M.; Mathes, T. Interface Focus 2013, 3, 20130005.
(h) Reece, S. Y.; Hodgkiss, J. M.; Stubbe, J.; Nocera, D. G. Philos.
Trans. R. Soc., B 2006, 361, 1351-1364. (i) Barry, B. A. J. Photo-
chem. Photobiol. B 2011, 104, 60-71. (j) Lehnert, N.; Solomon, E. I.
J. Biol. Inorg. Chem. 2003, 8, 294-305. (k) Neidig, M. L.; Weck-
sler, A. T.; Schenk, G.; Holman, T. R.; Solomon, E. I. J. Am. Chem.
Soc. 2007, 129, 7531-7537. (l) Moiseyev, N.; Rucker, J.; Glickman,
M. K. J. Am. Chem. Soc. 1997, 119, 3853-3860. (m) Derat, E.; Shaik,
S. J. Am. Chem. Soc. 2006, 128, 13940-13949. (n) Wang, Y.; Chen,
H.; Makino, M.; Shiro, Y.; Nagano, S.; Asamizu, S.; Onaka, H.;
Shaik, S. J. Am. Chem. Soc. 2009, 131, 6748-6762. (o) Wang, H.;
Hirao, H.; Chen, H.; Onaka, H.; Nagano, S.; Shaik, S. J. Am.
Chem. Soc. 2008, 130, 7170-7171.
(9) (a) Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Murphy, C.
F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.; McCafferty,
D. G.; Meyer, T. J. Chem. Rev. 2012, 112, 4016-4093. (b) Costentin,
C. Chem. Rev. 2008, 108, 2145-2179. (c) Hammes-Schiffer, S.; Stu-
chebrukhov, A. A. Chem. Rev. 2010, 110, 6939-6960. (d) Dempsey,
J. L.; Winkler, J. R.; Gray, H. B. Chem. Rev. 2010, 110, 7024-7039.
(e) Hammes- Schiffer, S.; Hatcher, E.; Ishikita, H.; Skone, J. H.;
Soudackov, A. V. Coord. Chem. Rev. 2008, 252, 384-394. (f)
Costentin, C. Chem. Rev. 2008, 108, 2145-2179. (g) Gagliardi, C. J.;
Westlake, B. C.; Kent, C. A.; Paul, J. J.; Papanikolas, J. M.; Meyer,
T. J. Coord. Chem. Rev. 2010, 254, 2459-2471. (h) Hammarstrom,
L.; Styring, S. Philos. Trans. R. Soc., B 2008, 363, 1283-1291.
(10) (a) Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem.
Soc. 2013, 135, 10022-10025. (b) Rono, L. J.; Yayla, H. G.; Wang, D.
Y.; Armstrong, M. F.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135,
17735-17738. (c) Yayla, H. G.; Knowles, R. R. Synlett 2014, 20,
2819-2826.
Financial support for this work was provided by the NIH (R01
GM113105). R.R.K. is a fellow of the Alfred P. Sloan Founda-
tion.
(1) (a) Smith, D. M.; Pulling, M. E.; Norton, J. R. J. Am. Chem.
Soc. 2007, 129, 770-771. (b) Li, G.; Han, A.; Pulling, M. E.; Estes,
D. P.; Norton, J. R. J Am Chem Soc, 2012, 134, 14662-14665. (c)
King, S. M.; Ma, X.; Herzon, S. B. J. Am. Chem. Soc. 2014, 136,
6884-6887. (d) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc.
2014, 136, 1304-1307. (e) Iwasaki, K.; Wan, K. K.; Oppedisano, A.
Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136,
1300-1303. (f) Liu, W.; Huang, X.; Cheng, M. J.; Nielsen, R. J.;
Goddard, W. A.; Groves, J. T. Science 2012, 337, 1322-1325. (g)
Chen, M. S.; White, M. C. Science 2010, 327, 566-571.
(2) For a recent stoichiometric advance, see: (a) Wang, D.;
Farquhar, E. R.; Stubna, A.; Münck, E.; Que, L. Nat. Chem. 2009,
1, 145-150. (b) Wang, D.; Que, L. Chem. Comm. 2013, 49, 10682-
10684.
(3) (a) Luo, Y. R. Handbook of Bond Dissociation Energies in
Organic Compounds; CRC Press: Boca Raton, FL, 2003. (b) Mo-
yer, B. A.; Meyer, T. J. J. Am. Chem. Soc. 1978, 100, 3601-3603. (c)
Bryant, J. R.; Mayer, J. M. J. Am. Chem. Soc. 2003, 125, 10351-10361.
(d) Borovik, A. S. Chem. Soc. Rev. 2011, 40, 1870-1874. (e) Parsell,
T. H.; Yang, M.-Y.; Borovik, A. S. J. Am. Chem. Soc. 2009, 131,
2762-2763. (f) Green, M. T.; Dawson, J.H.; Gray, H. B. Science
2004, 304, 1653-1656.
(4) (a) Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M.
J. Am. Chem. Soc. 1998, 120, 7738-7748. (b) Fallis, A. G.; Brinza, I.
M. Tetrahedron 1997, 53, 17543-17594. (c) Gooßen, L. J.; Rauhaus,
J. E.; Deng, G. Angew. Chem., Int. Ed. 2005, 44, 4042-4045. (d)
Wang, X.; Widenhoefer, R. A. Organometallics 2004, 23, 1649-
1651. (e) LaLonde, R. L.; William, E.; Brenzovich, W. E., Jr.; Beni-
tez, D.; Tkatchouk, E.; Kelley, K.; Goddard, W. A., III; Toste, F. D.
Chem. Sci. 2010, 1, 226-233. (f) Komeyama, K.; Morimoto, T.;
Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938-2941. (g) Li, Z.;
Song, L.; Li, C. J. Am. Chem. Soc. 2013, 135, 4640-4643.
(5) (a) Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32,
1035-1038. (b) Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-Sire,
B.; Schiano, A. M.; Zard, S. Z. Tetrahedron 1995, 51, 6517-6528. (c)
Kemper, J.; Studer, A. Angew. Chem., Int. Ed. 2005, 44, 4914-4917.
(d) Guin, J.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed. 2008,
47, 779-782. (e) Chou, C. M.; Guin, J.; Muck-Lichtenfeld, C.;
Grimme, A.; Studer, A. Chem. Asian J. 2011, 6, 1197-1209. (f) Nico-
laou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.;
Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233-2244. (g)
Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229-3231. (h) Quinn, R. K.;
Konst, Z. A.; Michalak, S. E.; Schmidt, Y.; Szklarski, A. R.; Flores,
A. R.; Nam, S.; Horne, D. A.; Vanderwal, C. D.; Alexanian, E. J. J.
Am. Chem. Soc. 2016, 138, 696-702.
(6) Bordwell, F. G.; Harrelson, J. A.; Lynch, T. Y. J. Org. Chem.
1990, 55, 3337-3341.
(7) (a) Hammes-Schiffer, S. J. Am. Chem. Soc., 2015, 137, 8860-
8871. (b) Huynh, M. H. V.; Meyer, T. J. Chem. Rev. 2007, 107,
5004-5064. (c) Mayer, J. M. Ann. Rev. Phys. Chem. 2004, 55, 363-
390. (d) Reece, S. Y.; Nocera, D. G. Ann. Rev. Biochem. 2009, 78,
673-699.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) Bordwell BDFE Bordwell, F. G.; Cheng, J. P.; Harrelson, J.
A. J. Am. Chem. Soc. 1988, 110, 1229-1231.
(12) Warren, J. J.; Tronic, T. A.; Mayer, J. M. Chem. Rev. 2010,
110, 6961-7001.
(13) Waidmann, C. R.; Miller, A. J. M.; Ng, C. A.; Scheuermann,
M. L.; Porter, T. R.; Tronic, T. A.; Mayer, J. A. Energy Environ. Sci.
2012, 5, 7771-7780.
(14) (a) Turro, C.; Chang, C. K.; Leroi, G. E.; Cukier, R. I.; Noc-
era, D. G. J. Am. Chem. Soc. 1992, 114, 4013-4015. (b) Kirby, J.;
Roberts, J.; Nocera, D. G. J. Am. Chem. Soc. 1997, 119, 9230-9236.
(c) Young, E. R.; Rosenthal, J.; Hodgkiss, J. M.; Nocera, D. G. J.
Am. Chem. Soc. 2009, 131, 7678-7684. (d) Sjodin, M.; Irebo, T.;
Utas, J. E.; Lind, J.; Merenyi, G.; Akermark, B.; Hammarstrom, L.
J. Am. Chem. Soc. 2006, 128, 13076-13083. (e) Markle, T. F.; Mayer,
J. M. Angew. Chem., Int. Ed. 2008, 47, 738-740.
(15) (a) Mayer, J. M.; Rhile, I. J. Biochim. Biophys. Acta, Bioen-
erg. 2004, 1655, 51-58. (b) Schrauben, J. N.; Cattaneo, M.; Day, T.
C.; Tenderholt, A. L.; Mayer, J. M. J. Am. Chem. Soc. 2012, 134,
16635-16645. (c) Rosenthal, J.; Luckett, T. D.; Hodgkiss, J. M.;
Nocera, D. G. J. Am. Chem. Soc. 2006, 128, 6546-6547. (d) Yang, J.
Y.; Nocera, D. G. J. Am. Chem. Soc. 2007, 129, 8192-8198.
(16) Schrauben, J. N.; Cattaneo, M.; Day, T. C.; Tenderholt, A.
L.; Mayer, J. M. J. Am. Chem. Soc. 2012, 134, 16635-16645.
(17) Choi, G. C.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137,
9226-9229.
(18) For a brief review on photoredox catalysis, please see: (a)
Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785-9789. (b) Yoon,
T. P.; Ischay, M. A.; Du, J. Nature Chem. 2010, 2, 527-532. (c) Na-
rayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40,
102-113. (d) Xuan, J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51,
6828-6838. (e) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687-
7697. (f) Wallentin, C.-J.; Nguyen, J. D.; Stephenson, C. R. J.
Chimia 2012, 66, 394-398.
(8) (a) Meyer, T. J.; Huynh, M. H. V.; Thorp, H. H. Angew.
Chem., Int. Ed. 2007, 46, 5284-5304. (b) Stubbe, J.; Nocera, D. G.;
Yee, C.; Chang, M. Chem. Rev. 2003, 103, 2167-2202. (c) Kaila, V.
R. I.; Verkhovsky, M. I.; Wikström, M. Chem. Rev. 2010, 110,
7062-7081. (d) Hatcher, E.; Soudachov, A.; Hammes-Schiffer, S. J.
ACS Paragon Plus Environment

Page 11 of 12
ACS Catalysis
(19) (a) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem.
dor, M. M.; Quilez del Moral, J. F.; Barrero, A. F. J. Am. Chem.
Soc. 2010, 132, 254-259.
(29) Tarantino, K. T.; Miller, D. C.; Callon, T. A.; Knowles, R.
R. J. Am. Chem. Soc. 2015, 137, 6440-6443.
1
2
3
4
5
6
7
8
Soc. 1980, 102, 3583-3587. (b) Ney, J. E.; Wolfe, J. P. Angew.
Chem., Int. Ed. Engl. 2004, 43, 3605-3608. (c) Ney, J. E.; Wolfe, J.
P. J. Am. Chem. Soc. 2005, 127, 8644-8651. (d) Rosewall, C. F.;
Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc.
2009, 131, 9488-9489. (e) Zeng, W.; Chemler, S. R. J. Am. Chem.
Soc. 2007, 129, 12948-12949. (f) Liwosz, T. W.; Chemler, S. R. J.
Am. Chem. Soc. 2012, 134, 2020-2023. (g) Scarborough, C. C.;
Stahl, S. S. Org. Lett. 2006, 8, 3251-3254. (h) Yip, K. T.; Yang, M.;
Law, K. L.; Zhu, N. Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130-
3131.
(30) (a) Campana, A. G.; Estevez, R. E.; Fuentes, N.; Robles, R.;
Cuerva, J. M.; Bunuel, E.; Cardenas, D.; Oltra, J. E. Org. Lett.
2007, 9, 2195-2198. (b) Paradas, M.; Campaꢀa, A. G.; Jimꢁnez, T.;
Robles, R.; Oltra, J. E.; Buꢀuel, E.; Justicia, J.; Cꢂrdenas, D. J.;
Cuerva, J. M. J. Am. Chem. Soc. 2010, 132, 12748-12756. (c) Cuerva,
J. M.; Campana, A. G.; Justicia, J.; Rosales, A.; Oller-Lopez, J. L.;
Robles, R.; Cardenas, D. J.; Bunuel, E.; Oltra, J. E. Angew. Chem.,
Int. Ed. 2006, 45, 5522-5526.
(31) (a) Huang, K.; Waymouth, R. M. J. Am. Chem. Soc. 2002,
124, 8200-8201. (b) Huang, K.; Han, J. H.; Cole, A. P.; Musgrave,
C. B.; Waymouth, R. M. J. Am. Chem. Soc. 2005, 127, 3807-3816.
(c) Huang, K.; Han, J. H.; Musgrave, C. B.; Waymouth, R. M.
Organometallics 2006, 25, 3317-3323. For mechanistic studies
involving titanocene complexes, see: (d) Gansꢃuer, A.; Kube, C.;
Daasbjerg, K.; Sure, R.; Grimme, S.; Fianu, G. D.; Sadasivam, D.
V.; Flowers, R. A., II. J. Am. Chem. Soc. 2014, 136, 1663-1671. (e)
Gansꢃuer, A.; von Laufenberg, D.; Kube, C.; Dahmen, T.;
Michelmann, A.; Behlendorf, M.; Sure, R.; Seddiqzai, M.; Grim-
me, S.; Sadasivam, D. V.; Fianu, G. D.; Flowers, R. A., II. Chem.
Eur. J. 2015, 21, 280-289.
9
(20) Hanss, D.; Freys, J. C.; Bernardinelli, G.; Wenger, O. S.
Eur. J. Inorg. Chem. 2009, 32, 4850-4859.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(21) (a) Warren, J. J.; Menzeleev, A. R.; Kretchmer, J. S.; Miller,
T. F., III; Gray, H. B.; Mayer, J. M. J. Phys. Chem. Lett. 2013, 4,
519-523. (b) Warren, J. J.; Mayer, J. M. J. Am. Chem. Soc. 2011, 133,
8544-8551. (c) Hammes-Schiffer, S.; Soudackov, A. V. J. Phys.
Chem. B 2008, 112, 14108-14123. (d) Megiatto, J. D.; Méndez-
Hernández, D. D.; Tejeda-Ferrari, M. E.; Teillout, A.-L.; Llansola-
Portolés, M. J.; Kodis, G.; Poluektov, O. G.; Rajh, T.; Mujica, V.;
Groy, T. L.; Gust, D.; Moore, T. A.; Moore, A. L. Nature Chem.
2014, 6, 423-428. (e) Edwards, S. J.; Soudackov, A. V.; Hammes-
Schiffer, S. J. Phys. Chem. A 2009, 113, 2117-2126. (f) Bronner, C.;
Wenger, O. S. J. Phys. Chem. Lett., 2012, 3, 70-74.
(22) Prier, C. K.; Rankic, D. A.; Macmillan, D. W. C. Chem.
Rev. 2013, 113, 5322-5363.
(23) Miller, D. C.; Choi, G. J.; Orbe, H. S.; Knowles, R. R. J. Am.
Chem. Soc. 2015, 137, 13492-13495.
(32) DeBeer George, S.; Huang, K.-W.; Waymouth, R. M.; Sol-
omon, E. I. Inorg. Chem. 2006, 45, 4468-4477.
(24) (a) Gagliardi, C. J.; Murphy, C. F.; Binstead, R. A.; Thorp,
H. H.; Meyer, T. J. J. Phys. Chem. C 2015, 119, 7028-7038. (b) Me-
dina-Ramos, J.; Oyesanya, O.; Alvarez, J. C. J. Phys. Chem. C 2013,
117, 902-912. (c) KussPetermann, M.; Wenger, O. S. J. Phys. Chem.
Lett. 2013, 4, 2535-2539. (d) Bordwell, F. G.; Cheng, J. P.; Ji, G. Z.;
Satish, A. V.; Zhang, X. J. Am. Chem. Soc. 1991, 113, 9790-9795.
(25) (a) Chai, J. D.; Head-Gordon, M. Phys. Chem. Chem. Phys.
2008, 10, 6615-6620. (b) DiLabio, G. A.; Johnson, E. R.; Otero-de-
la-Roza, A. Phys. Chem. Chem. Phys. 2013, 15, 12821-12828.
(26) (a) Estes, D. P.; Grills, D. C.; Norton, J. R. J. Am. Chem.
Soc. 2014, 136, 17362-17365. (b) Roth, J. P.; Mayer, J. M. Inorg.
Chem. 1999, 38, 2760-2761. (c) Manner, V. W.; Mayer, J. M. J. Am.
Chem. Soc. 2009, 131, 9874-9875. (d) Jonas, R. T.; Stack, T. D. P. J.
Am. Chem. Soc. 1997, 119, 8566-8567. (e) Fang, H.; Ling, Z.; Lang,
K.; Brothers, P. J.; Bruin, B.; Fu, X. Chem. Sci. 2014, 5, 916-921. (f)
Miyazaki, S.; Kojima, T.; Mayer, J. M.; Fukuzumi, S. J. Am. Chem.
Soc. 2009, 131, 11615-11624. (g) Wu, A.; Mayer, J. M. J. Am. Chem.
Soc. 2008, 130, 14745-14754. (h) Milsmann, C.; Semproni, S. P.;
Chirik, P. J. J. Am. Chem. Soc. 2014, 136, 12099-12107. (i) Fang, H.;
Jing, H.; Ge, H.; Brothers, P. J.; Fu, X.; Ye, S. J. Am. Chem. Soc.
2015, 137, 7122-7127.
(27) (a) Semproni, S. P.; Milsmann, C.; Chirik, P. J. J. Am.
Chem. Soc. 2014, 136, 9211-9224. (b) Ribas, X.; Calle, C.; Poater,
A.; Casitas, A.; Gomez, L.; Xifra, R.; Parella, T.; Benet-Buchholz,
J.; Schweiger, A.; Mitrikas, G.; Sola, M.; Llobet, A.; Stack, T. D. P.
J. Am. Chem. Soc. 2010, 132, 12299-12306. (c) Pappas, I.; Chirik, P.
J. J. Am. Chem. Soc. 2015, 137, 3498-3501. (d) Wu, A.; Masland, J.;
Swartz, R. D.; Kaminsky, W.; Mayer, J. M. Inorg. Chem. 2007, 46,
11190-11201. (e) Chciuk, T. V.; Flowers, R. A. J. Am. Chem. Soc.
2015, 137, 11526-11531. (f) Warren, J. J.; Menzeleev, A. R.;
Kretchmer, J. S.; Miller, T. F.; Gray, H. B.; Mayer, J. M. J. Phys.
Chem. Lett. 2013, 4, 519-523.
(28) (a) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medei-
ros, M. R.; Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513-12515. (b)
Medeiros, M. R.; Schacherer, L. N.; Spiegel, D. A.; Wood, J. L.
Org. Lett. 2007, 9, 4427-4429. (c) Pozzi, D.; Scanlan, E. M.; Re-
naud, P. J. Am. Chem. Soc. 2005, 127, 14204-14205. (d) Dieguez, H.
R.; Lopez, A.; Domingo, V.; Arteaga, J. F.; Dobado, J. A.; Herra-
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Insert Table of Contents artwork here
12
ACS Paragon Plus Environment