Facile H/D exchange at (hetero)aromatic hydrocarbons catalyzed by a stable trans-dihydride n-heterocyclic carbene (NHC) iron complex

Article abstract of DOI:10.1021/jacs.0c07689

Earth-abundant metal pincer complexes have played an important role in homogeneous catalysis during the last ten years. Yet, despite intense research efforts, the synthesis of iron PCcarbeneP pincer complexes has so far remained elusive. Here we report the synthesis of the first PCNHCP functionalized iron complex [(PCNHCP)FeCl2] (1) and the reactivity of the corresponding trans-dihydride iron(II) dinitrogen complex [(PCNHCP)- Fe(H)2N2)] (2). Complex 2 is stable under an atmosphere of N2 and is highly active for hydrogen isotope exchange at (hetero)aromatic hydrocarbons under mild conditions (50 °C, N2). With benzene-d6 as the deuterium source, easily reducible functional groups such as esters and amides are well tolerated, contributing to the overall wide substrate scope (e.g., halides, ethers, and amines). DFT studies suggest a complex assisted σ-bond metathesis pathway for C(sp2)-H bond activation, which is further discussed in this study.

Full text of DOI:10.1021/jacs.0c07689

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Facile H/D Exchange at (Hetero)Aromatic Hydrocarbons Catalyzed by
a Stable Trans-Dihydride N-Heterocyclic Carbene (NHC) Iron Complex
Subhash Garhwal, Alexander Kaushansky, Natalia Fridman, Linda J.W. Shimon, and Graham de Ruiter
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07689 • Publication Date (Web): 09 Sep 2020
Downloaded from pubs.acs.org on September 9, 2020
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 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 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.
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 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Facile H/D Exchange at (Hetero)Aromatic Hydrocarbons Catalyzed by a
Stable Trans-Dihydride N-Heterocyclic Carbene (NHC) Iron Complex
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
Subhash Garhwal,† Alexander Kaushansky,† Natalia Fridman,† Linda J. W. Shimon,∥ and Graham de
Ruiter†*
†Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Technion City, 3200008 Haifa, Israel; ∥Department
of Chemical Research Support, Weizmann Institute of Science, Rehovot, 7610001, Israel
Supporting Information Placeholder
From the wide variety of available ligand
architectures, pincer-type ligands have contributed
tremendously to the development of earth-abundant metal
catalysis.8 The most commonly encountered structural
motifs within this set of ligands are those featuring an
XNX (X = NR, PR2, P(OR)2) pincer type geometry with
a central amino or pyridine donor.8 In contrast, earth-
abundant metal pincer complexes presenting a carbene as
central donor are virtually absent from the literature,9 in
particular those containing a PCNHCP type geometry
(Figure 1).10 Their absence is quite surprising as carbenes
often impart distinct electronic and steric properties to the
metal center.11 For instance, when comparing PCP versus
PNP pincer complexes of the 2nd and 3rd row transition
metals, the PCP complexes featuring a central N-
heterocyclic carbene (NHC) typically bind stronger to the
metal center,12 while simultaneously increasing its
electron density,13 benefitting catalyst stability and
reactivity.12a
ABSTRACT: Earth-abundant metal pincer complexes have
played an important role in homogenous catalysis during
the last ten years. Yet, despite intense research efforts, the
synthesis of iron PCcarbeneP pincer complexes has so far
remained elusive. Here we report the synthesis of the first
PCNHCP functionalized iron complex [(PCNHCP)FeCl2]
(1), and the reactivity of the corresponding trans-
dihydride
iron(II)
dinitrogen
complex
[(PCNHCP)Fe(H)2N2)] (2). Complex 2 is stable under an
atmosphere of N2 and is highly active for hydrogen
isotope exchange at (hetero)aromatic substrates under
mild conditions (50 °C, N2). With benzene-d6 as
deuterium source, easily reducible functional groups such
as esters and amides are well tolerated, contributing to the
overall wide substrate scope (e.g. halides, ethers, amines).
DFT studies suggest a complex assisted σ-bond
metathesis pathway for C(sp2)–H bond activation, which
is further discussed in this study.
Base-Metal PCcarbeneP Pincer Complexes
INTRODUCTION
N
N
Driven by their pre-eminent two-electron chemistry,
the predictable reactivity and selectivity of precious
metals have made them the premier choice as catalysts in
many synthetic processes.1 The growing environmental,
economic, and geopolitical concerns associated with
using precious metals, in conjunction with their limited
availability, are strong incentives to rethink current
strategies and establish more environmental friendly
alternatives.2 One such methodology relies on using
earth-abundant metals such as cobalt,3 manganese4 and in
particular iron,5 as catalyst for a variety of organic
transformations.6 Indeed, during the past decade we have
seen a resurgence of using earth-abundant metals in
homogenous catalysis. One of the main reasons behind
this resurgence is our ability to utilize the unique
properties of earth-abundant metals (e.g. spin-state
reactivity) via elaborate ligand designs.7
P(iPr)2
(iPr)2P
Ph2P
Ni
PPh2
PPh2
Ph2P
Me3P
Co
PMe3
Ni
H
PMe3
Piers, W. E.
Young, R. D.
Green, J.C. & Fryzuk, M. D.
J. Am. Chem. Soc., 2009, 131, 10461
J. Am. Chem. Soc. 2013, 135, 11776
Chem. Sci. 2018, 9, 8234
Our Work
tBu
Z
Hydrogen Isotope Exchange
or
PiPr2
R
D
R
Z
H
N
or
Fe
Fe
N2
R
D
N
N2, C6D6
R
H
PiPr2
[2]
>15 examples, >95% Deuteration, No H2/D2 required
tBu
Figure 1. Selected examples of first-row transition-metal
PCcarbeneP pincer complexes, and the herein reported
reactivity of [(PCNHCP)Fe(H)2N2)] (2).
Yet, despite these advantages no catalytic activity of
iron, cobalt or manganese PCNHCP pincer complexes have
been reported,14 while synthetic methodologies to access
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 11
these complexes for iron are currently lacking.10b
Addition of FeCl2·1.5THF (1.1 equiv.) to a stirred
1
2
3
4
5
6
7
8
Considering these limitations, developing NHC-centered
phosphine-functionalized pincer complexes could hold
great benefits for iron-based catalysis, especially when
containing metal-hydrides.15
Here we report the synthesis and characterization of
novel PCNHCP pincer complex [(PCNHCP)FeCl2)] (1), that
upon exposure to 2.2 equiv. of NaBHEt3 generates the
first example of a stable trans-dihydride iron(II)
dinitrogen complex [(PCNHCP)Fe(H)2N2)]. (Scheme 1;
2). Iron complex 2 is highly stable at room temperature
and does not readily reductively eliminate H2 upon
exposure to N2, which is a commonly observed
solution of A2 in THF (15 mL), resulted in the formation
of a new paramagnetic species (1) as judged by 1H NMR
spectroscopy (Figure S12). High-resolution mass
spectrometry (HRMS) is consistent with the assignment
of 1 as [(PCNHCP)FeCl2)] (Figure S13), which was also
confirmed by X-ray crystallography.
The solid-state structure of 1 is shown in Figure 2, and
features an iron metal center in a distorted trigonal
bipyramidal geometry. The axial phosphine donors are
only weakly bound to the iron metal center, which is
evident from the long iron phosphine distances of
2.782(2) Å (Fe–P1) and 2.765(2) Å (Fe–P2). The iron
carbene (Fe–C1) distance of 2.062(6) and the NCN angle
of 102.3(5)° are typical for other iron NHCs reported in
the literature.18
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
deactivation pathway for other trans-dihydride iron(II)
16
complexes lacking π-acidic CO ligands.15b,
The
equatorial N2 ligand in 2 is readily displaced under
catalytic conditions enabling hydrogen/deuterium (H/D)
exchange at (hetero)aromatic hydrocarbons with
benzene-d6 as deuterium source. Generally, the reaction
occurs under mild conditions (N2, 50 °C), and is tolerant
of a variety of functional groups including, ethers, esters,
amides, halides, and heterocycles. To the best of our
knowledge, complex 2 is one of the very few iron-based
catalysts capable of catalytic H/D exchange at hetero-
aromatics using a readily available deuterium source.
RESULTS AND DISCUSSION
Synthesis of iron PCNHCP pincer complexes
Figure 2. Solid state structures of [(PCNHCP)FeCl2] (1, left)
and [(PCNHCP)Fe(H)2N2] (2, right). Thermal ellipsoids are
shown at the 30% probability level. Hydrogen atoms and
co-crystallized solvent molecules are omitted for clarity.
Realizing the lack of current synthetic methodologies
for preparing earth-abundant metal PCNHCP pincer
complexes, we became interested in a ligand platform
known as dipyrido[1,2-c;2′,1′-e]imidazolin-6-ylidenes,17
whose rigid framework might allow for strong binding of
earth-abundant metals. We commenced our studies by
synthesizing azolium salt A1 via a modification of a
known literature procedure.17a Subsequent deprotonation
of A1 with potassium tert-butoxide (KOtBu) in THF,
resulted in the formation of free carbene A2 (Scheme 1).
With iron PCNHCP pincer complex 1 in hand, we
investigated its reactivity towards a variety of hydride
donors, because of the wide applicability of transition-
metal hydrides in catalysis.8b, 19 Addition, of two equiv.
of NaBHEt3 to a THF solution of complex 1 at −110° C,
afforded a new diamagnetic species (2) that is stable for
several days in solution at room temperature (Scheme 1).
1
The H NMR spectrum of complex 2, exhibits a single
2
characteristic triplet at −8.79 ppm (2H), whose JP-H
Scheme 1. Synthesis of PCNHCP iron complexes 1 and
2, and the observed H/D exchange in benzene-d6.
values of 43.0 Hz are consistent with a tentative
assignment of 2 as the trans-dihydride iron complex
[(PCNHCP)Fe(H2)N2)]. Additional T1 measurements (at
298K) support such a trans-dihydride assignment where
the decay time of 420 ms is similar to those reported for
other transition-metal trans-dihydride complexes.15b, 16
Definite structural assignment of 2 was provided by X-
ray crystallography (Figure 2). Although the crystals
were not of sufficient quality to allow comparison of the
bond metrics, it does allow for identification of complex
2 as [(PCNHCP)Fe(H)2N2)] with the coordinated N2
opposite to the PCNHCP carbene, forcing the two hydrides
in a trans geometry. As a result, the combined
spectroscopic (NMR) and crystallographic data confirm
the formation of a stable classical iron(II) trans-
dihydride, which is unprecedented.20
ACS Paragon Plus Environment

Page 3 of 11
Journal of the American Chemical Society
which is promising for allowing catalytic HIE with other
Hydrogen isotope exchange (HIE) at (hetero)aromatics
hydrocarbons.25b, 29 As evident from Table 1, complex 2
indeed efficiently catalyzes the H/D exchange between
the solvent (benzene-d6) and a variety of (hetero)aromatic
hydrocarbons. The reaction occurs under mild conditions
(N2, 50-80 °C) and typically requires less than three hours
for high levels of deuterium incorporation. For example,
toluene is exclusively deuterated at the meta-, and para-
position (>95%), which are the sterically most accessible
positions. (Table 1; [d3]-4). Likewise, for m-xylene, the
meta-position was preferentially deuterated (98%). In
both substrates, deuteration of the ortho-position was not
observed. These data suggest that for toluene and m-
xylene, the observed regioselectivity is primarily dictated
by steric factors. Computational studies (vide infra)
corroborated these findings and showed that for toluene
C–H bond activation at the meta- and para-positions is
energetically more favorable than at the ortho-position
(Table 2). Note however, that by using elevated
temperatures and longer reaction times different
regioselectivities can be observed (Figure S20 and S21).
Notwithstanding, these results are akin to those obtained
by Chirik,27f and Leitner,24a whose iron and ruthenium
1
The ability to selectively exchange hydrogen for either
deuterium or tritium is important for understanding many
fundamental processes in organometallic,21 medicinal,22
and biological chemistry.23 Classically, HIE is catalyzed
by noble metals such as ruthenium,24 rhodium,25 and
iridium.26 In contrast, only a few studies report on the HIE
with earth-abundant metals.27 Given the importance of
earth-abundant metal-hydride species in hydrogen
isotope exchange (HIE) reactions,28 we reasoned that iron
complex 2 could be a straightforward entry towards facile
H/D exchange at aromatic hydrocarbons.
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
Our studies into H/D exchange started with the
observation that the hydride resonance at −8.79 ppm (t,
2JP-H = 43.0 Hz) in complex 2 slowly disappeared after
1
dissolving 2 in benzene-d6. No other changes in the H
NMR spectrum of 2 were observed. Analysis of the
2
solution by H and 31P NMR spectroscopy revealed the
appearance of a triplet (2H) at -8.68 ppm (2JP-D = 6.6 Hz),
and a quintet (31P) at 133.27 ppm (2JD-P = 6.2 Hz), which
is consistent with the formation of the di-deuteride
iron(II) complex 3 (Figure S3) Similarly, dissolving 3 in
benzene results to the reformation of complex 2 in
quantitative yields.
pincer
complexes;
[H4-iPrCNC)Fe(N2)2]
and
[(PNP)Ru(H)2(H2)] showed comparable regioselectivity.
The reversible H/D exchange between the solvent and
complex 2 indicates reversible C(sp2)–H activation,
Table 1. Substrate scope for hydrogen isotope exchange at (hetero)aromatic hydrocarbons, catalyzed by 3.a, b
D
5 mol %
Z
Z
or
or
Fe
R
R
D
C6D6, N2
R
R
F
(98%)
F
Cl
OMe
(98%)
(95%)
(98%)
(85%)
(85%)
(98%)
(98%)
(98%)
(95%)
(95%)
(98%)
(95%)
(98%)
(90%)
(98%)
(98%)
(98%)
OMe
[d3]– 4
80 °C, 3h
[d1]– 5
80 °C, 3h
[d5]– 6
50 °C, 3h
[d1]– 7
50 °C, 3h
[d8]– 8
80 °C, 3h
[d2]– 9
50 °C, 3h
O
NMe2
O
CF3
O
(98%)
(0%)
(0%)
(60%)
(30%)
(95%)
(90%)
(30%)
(95%)
(0%)
(0%)
OEt
NMe2
(98%)
(98%)
(90%)
(0%)
F
N
(60%)
(98%)
(95%)
(90%)
[d3]– 13
[d5]– 10
50 °C, 3h
[d3]– 11
50 °C, 3h
[d2]– 12
50 °C, 3h
[d1]– 15
50 °C, 3h
[d0]– 14
50 °C, 3h
50 °C, 5h
(60%)
(90%)
(85%)
N
O
(85%)
(85%)
(60%)
(60%)
(91%)
O
N
(50%)
(98%)
(98%)
(98%)
(98%)
N
(85%)
(96%)
(80%)
(80%)
(94%)
(90%)
(98%)
N
(90%)
[d2]– 16
50 °C, 4h
[d3]– 17
50 °C, 3h
[d3]– 18
50 °C, 1.5h
[d2]– 19
50 °C, 3h
[d7]– 21
50 °C,3h
[d4]– 20
50 °C, 3h
aSee supporting information for experimental details. bYields were determined by 1H NMR spectroscopy in the presence of an internal
standard (tetraethylsilane).
Encouraged by these initial results, we sought to
increase the substrate scope to include a variety of
electronically and sterically differentiated substrates
(Table 1). For example, fluorobenzene was completely
deuterated within three hours (Table 1, [d5]-6).
Monitoring the reaction by 1H and 19F NMR spectroscopy
revealed that the ortho- and meta-position are
preferentially deuterated (Figures S71 and S72). Only
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 11
after 30 minutes deuteration of the para-position is deuteration of the methyl substituent was also observed
1
observed, while complete deuteration of the para-
positions takes nearly three hours. These results reflect
the level of deuteration in the order of ortho (98%) > meta
(95%) > para (90%) as shown in Table 1. Interestingly,
for the related chlorobenzene deuterium incorporation
was only observed at the para-position, whereas for 4-
fluoroanisole incorporation was observed at the ortho-
position (Table 1; [d1]-7 and [d2]-9). Clearly, besides the
established steric effects, electronic effects are important
contributors to the observed regioselectivity (vide infra).
More detailed computational studies regarding the
observed regioselectivity and mechanism for H/D
exchange are presented in Figure 3 and Table 2, and are
further discussed in the computational section of this
manuscript. Nonetheless, the ability of 2 to efficiently
deuterate chlorobenzene demonstrates that the complex 2
is stable towards reductive elimination of H2 and
subsequent oxidative addition of the aryl halide.
Besides aryl halides, arenes bearing other electron
withdrawing substituents were efficiently deuterated as
well, albeit primarily at sterically accessible C(sp2)–H
bonds (Table 1; [d5]-10). In a similar manner, electron
rich arenes were also efficiently deuterated.
Dimethylaniline showed near quantitative incorporation
of deuterium (>98%) at the meta- and para-positions,
whereas for anisole complete deuteration was observed to
yield anisole-d8 within the course of 3 hours (Table 1).
Substrates containing reducible substituents such as
esters ([d2]-12) and amides ([d3]-13) are tolerated as well.
For instance, ethyl 4-fluorobenzoate is selectively
deuterated at the ortho position (60%), while N,N-
dimethylbenzamide is selectively deuterated at the meta-
and para position (Table 1). The difference in
regioselectivity between [d2]-12 and [d3]-13 is due to
different steric requirements of the directing group,
although electronic effects from the fluorine atom cannot
be excluded (vide infra). Unfortunately, substrates
containing ketones (e.g. acetophenone, benzophenone,
and/or cyclohexyl phenyl ketone) are not susceptible for
catalytic H/D exchange. It is known that iron-dihydride
complexes are good ketone hydrogenation catalysts.30 In
the absence of a suitable proton donor, the iron-hydride is
nucleophilic enough to attack the ketone to generate an
alkoxide intermediate,31 incapable of performing HIE.
However, catalyst decomposition to form inactive Fe(I)
or Fe(0) species cannot be excluded.32 Nonetheless, these
results do not negate the fact that complex 2, tolerates
several functional groups (e.g. halides, ethers, esters,
amides, and/or heterocycles).
to a large extend (50%). Because of the vastly different
physicochemical and electronic properties of pyrroles,
imidazoles, and furans, it is difficult to rationalize the
regioselectivity for each substrate individually. In
general, H/D exchange of hydrogen atoms ortho to a
heteroatom is highly favorable and is most-likely directed
by pre-coordination of the heteroatom to the metal center.
Pre-coordination also explains the deuteration of the
C(sp3)–H bonds in 2-methyl furan (Table 1; [d3]-18).
However, for 2,5-dimethylfuran ([d2]-19) and 2,6-
dimethylpyridine ([d1]-15) coordination to the metal
center is hampered due to steric crowding and deuteration
of the C(sp3)–H bonds is not observed. Furthermore, for
5-membered heterocycles, deuteration of C–H bonds
adjacent to methyl substituents is more feasible because
they are sterically more accessible compared to their 6-
membered counterparts (e.g. compare [d3]-16–[d2]-19
with ([d1]-15). The exception appears to be N-
methylpyrrole (Table 1), whose lack of ortho reactivity
we are not able to explain at this stage. For 6-membered
aromatic heterocycles such as 2,6-lutidine deuteration
was regioselective for the sterically most accessible para
proton (Table 1, [d1]-15). For quinoline all aromatic C–
H bonds were deuterated to yield quinoline-d7 (Table 1,
[d7]-21). The different degree of deuteration in quinoline
reflects the different bond dissociation energies of the
various C(sp2)–H bonds.33
Comparing these results to the state-of-the-art, it was
realized that despite the tremendous progress in
homogeneous catalysis, earth-abundant metal catalyzed
HIE at aromatic C(sp2)-H bonds remains extremely rare.27
For example, the cobalt catalyzed H/D exchange reported
by Zou and co-workers is only applicable to indoles,27b
while the cobalt catalysts developed by Chirik and co-
workers primarily catalyze H/D exchange at (benzylic)
C(sp3)-H bonds.27e For iron related studies, the seminal
work of Chirik and co-workers is important as it describes
the first example of the iron catalyzed HIE at aromatic
C(sp2)-H bonds including those of pharmaceuticals.27f
However, due to the instability of the in-situ formed
dihydride, hydrogen or deuterium gas is always required
to ensure catalyst stability and efficiency as shown in a
recent study.27a The herein reported results, however,
demonstrate for the first time that such trans-dihydrides
can be stable, ultimately leading to the deuteration of
wide variety of aromatic hydrocarbons at lower
temperatures with shorter reaction times and greater
efficiencies,27f even when compared to PNP ruthenium
dihydride complexes reported by Milstein and Leitner.24a
However, it must be mentioned that comparison to the
state-of-the-art is challenging due to the different nature
of (i) the used solvents (e.g. benzene vs. THF), (ii) the
deuterium source (D2, D2O, or C6D6), and (iii) the used
catalyst loadings.
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
In addition to the various substituted aromatic
hydrocarbons, heteroaromatic compounds are also good
substrates for HIE with catalyst 2. For instance, in 5-
membered heterocyclic compounds such as, N-methyl-
pyrrole, 1-methylimidazole, 2-methylfuran, and 2,5-
dimethylfuran, most aromatic protons were deuterated
with incorporation levels ranging from 80 to 98% (Table
1, [d2]-16–[d2]-19). In addition, for 2-methylfuran
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
century.37 On the other hand, Eisenstein and co-workers
Computational mechanistic investigations.
1
have shown that, for iron, σ-CAM is also a plausible
mechanistic pathway for H/D exchange at aromatic
hydrocarbons.38 Our computational studies also indicates
that H/D exchange with benzene-d6 most likely occurs via
a σ-CAM based mechanism (Figure 3). Starting from 3,
labeled A in Figure 3, formation of the σ-complex C is a
two-step process and energetically uphill by 18.4
kcalꢀmol−1. The structure of intermediate C is shown in
Figure 3, and features in an η2C–H interaction of benzene
with the iron metal center resulting in elongation of the
C–H bond by 0.032 Å. Such intermediates have also been
implied for aromatic C(sp2)–H activation with ruthenium
and iridium.39 The C(sp2)-carbon atom engaged in the
η2C–H interaction is located 0.125 Å above the plane of the
PCNHCP pincer ligand, while the Cb–Hb bond is rotated
To further understand the regioselectivity, and to gain
more insight into the mechanism of the H/D exchange
between benzene-d6 and (hetero)aromatic hydrocarbons,
we used density functional theory (DFT) to obtain more
detailed information about the relevant intermediates and
transition states (Figures 3). To reduce the computational
load, calculations were performed on a model system
with R1=Me (Figure 3). Additional computational details
are reported in the supporting information.
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
Before going into the details of the herein reported
H/D exchange and C–H bond activation, there are several
mechanisms by which C–H bonds can be activated that
include (i) oxidative addition, (ii) σ-bond metathesis, or
other types of mechanisms.34 Low valent (late) transition
metals generally activate C(sp2)–H bonds via oxidative
addition. High valent (early) transition metals – on the
other hand – prefer a σ-bond metathesis pathway, because
of their general lack of available d-electrons. A variant of
σ-bond metathesis, σ‐complex‐assisted metathesis or σ-
CAM, has also been developed for late transition metals
to explain the facile hydrogen exchange at bound E–H (E
= B, C, or Si) σ -complexes.35 For example, Leitner,24a
Lau,24b and others,36 have used σ-CAM to explain metal-
catalyzed H/D exchange at aliphatic and aromatic
hydrocarbons.
upward by 27.0° and located 0.420 Å above the PCNHC
P
plane. The slight upward rotation, might indicate an
attractive interaction between the axial deuteride (D1)
and Hb as their calculated distance of 2.098 Å is slightly
shorter than the sum of their van der Waals radii (2.200
Å).38 The attractive interaction between D1 and the Cb–
Hb bond is somewhat reminiscent of the hydride “cis
effect” proposed by Eisenstein and Caulton,40 which
describes the interaction between a metal-hydride and a
coordinated dihydrogen molecule en-route towards
dynamic hydrogen atom exchange. As such the “cis-
effect” demonstrates important concepts that are also
observed in the herein described σ-CAM (vide infra).35
For iron, oxidative addition of C(sp2)–H bonds is well
known and has been established for nearly half a
1
1
R
R
P(Pr)2
P(Pr)2
D
D
N
Fe
N
22.4
26.0
22.5
25.9
Fe
N
D
N
H
TS3
TS1
P(Pr)2
P(Pr)2
14.5
18.9
1
1
15.1
18.6
15.1
18.6
R
16.1
18.4
R
15.3
17.7
26.7
16.9
25.8
16.1
1
1
R
R
TS2
E
C
D
F
P(Pr)2
D
P(Pr)2
D
B
G
N
N
N
N
1
1
1
1
Fe
Fe
N
N
2
R
R
R
R
2
D
P(Pr)2
D
P(Pr)2
D
H
P(Pr)2
D
P(Pr)2
D
P(Pr)2
P(Pr)2
N
N
N
N
N
N
N
N
1
1
Fe
Fe
H
Fe
Fe
R
R
D
D
H
D
P(Pr)2
H
P(Pr)2
−0.8
−0.7
H
D
0.0
P(Pr)2
P(Pr)2
1
1
1
1
A
R
R
R
R
H
Cb– Hb 1.118 Å
Fe– Hb
Cb– Hb 1. 447 Å
D1– Hb
Fe– D1 1.614 Å
Fe– Hb
D1– Hb 0.838 Å
Fe– Hb
1.781 Å
1.193 Å
1.600 Å
1.611 Å
Fe– D1 1.612 Å
Fe– Cb 2.455
Å
Fe– Cb 2.106 Å
Fe– Cb 2.007 Å
Fe– Cb
1.998 Å
P2
P2
Hb
P2
Cb
D1
Hb
D1
D1
P2
Hb
D1
D2
Hb
Fe
CNHC
CNHC
CNHC
CNHC
Ca
Ca
Cb
Fe
Fe
Fe
Ca
D2
Cb
Cb
D2
D2
P1
Ca
P1
P1
P1
TS2
∠
∠
∠
∠
D1-Fe-Cb-Ca: 40.1°
D1-Fe-Cb-Ca: 43.0°
TS1
D1-Fe-Cb-Ca: 16.8°
D
D1-Fe-Cb-Ca: 0.3°
C
Figure 3. Calculated free energy profiles (ΔH/ΔG) in kcalꢀmol−1 and plausible mechanistic pathways for hydrogen isotope
exchange (HIE) of 3 with benzene. Hydrogen atoms (except Hb) are omitted for clarity. For computational details, see the
supporting information
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
The critical C–H activation step occurs via a which is slightly lower than for TS1, due to isotope
effects.43 Overall, as our calculations will show, the
observed regioselectivity is combination of steric and
electronic effects (vide infra). As expected strong steric
effects are observed for toluene (R = Me; Table 2). The
energy barrier for ortho C–H bond activation (30.4 kcal
mol−1) is significantly higher than for activation at the
meta- and para-positions (ΔG = 25.9/25.2 kcal mol-1).
Similar effects are observed for dimethylaniline, where
C–H bond activation at the ortho-position has an energy
barrier of 31.3 kcal mol-1 (Table 2). These results are in-
line with our experimental results (Table 1)
Because for anisole no strong steric effects are
expected and pre-coordination of the heteroatom is
commonly invoked in C–H bond activation strategies,
there are no clear differences in the energies for ortho,
meta, or para C–H bond activation. As a result, complete
deuteration of all C–H bonds is observed, including those
present in the –OMe substituent (Tables 1 and 2).
1
2
3
4
5
6
7
8
σ‐complex‐assisted metathesis pathway and leads to the
formation of the non-classical hydride isotopologue (D)
with an overall energy barrier (ΔG) of 25.9 kcalꢀmol−1.
The transition state structure (TS1) is shown in Figure 3
(bottom), and features an iron complex with a distorted
pentagonal bipyramidal geometry. Obviously, starting
from C, further distortion of the Fe···C axis is necessary
to access the planar four-center transition state in TS1 that
is typically observed for σ-CAM based mechanisms. In
TS1, the calculated D1···Hb and Fe···Cb distances of
1.193 and 2.106 Å are significantly shorter than those
found by Leitner and Milstein,24a and are indicative of a
σ-CAM based mechanism with a late transition-state
structure exhibiting very little oxidative addition
character as shown by Eisenstein and co-workers.41
Overall, the barrier going from C to D is 7.5 kcal mol−1,
indicating that H/D exchange occurs quite readily once
the σ-complex is formed and that the slightly elevated
temperatures (50 °C) are necessary to facilitate
dissociation of the N2 ligand (Figure 3).
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
Table 2. Relative energies (ΔG) in kcalꢀmol−1 of the
transition state (TS1-R) for C–H exchange at the ortho,
meta, and para positions of toluene, fluorobenzene, anisole,
and dimethylaniline.a,b
The formation of non-classical hydride isotopologue
D is also supported by NMR studies. Monitoring a
solution of 2 in benzene-d6 shows the formation of a
1
triplet at -8.79 ppm (1JH-D = 21.1 Hz) in the H{31P}
NMR spectrum after 15 min (Figures S1–S4). The
large value of the H–D coupling constant is indicative
for the formation of
a non-classical hydride
Position
Meta
25.2
intermediate, as cis/trans HD couplings are general
small or negligible.42 In this process, oxidative addition
from an Fe(0)/Fe(II) complex was not observed
experimentally and computationally.
Substituent
Ortho
25.2
Para
25.2
R = H
Rotation around the iron H–D bond (Figure 3, D→E)
is essentially barrierless and the transition state structure
TS2 is shown in Figure 3 (bottom). The calculated bond
lengths in TS2 do not differ significantly from those
calculated for D and the complex remains essentially
octahedral. After rotation, the first stage of the H/D
exchange is complete (Figure 3, A→E). Hereafter, a
nearly identical, but reverse, pathway follows that start
with σ-CAM to yield the σ-bonded deuterated benzene
adduct (F). Final two-step ligand exchange between the
substrate and N2 regenerates an isotopologue of the
starting catalyst (H). In general, the herein presented
mechanism is similar to that proposed by Leitner and
Milstein, whose ruthenium PNP complex also catalyzes
H/D exchange between aromatic hydrocarbons and
benzene-d6.24a Besides the mechanism outlined in Figure
3, a modified version is also energetically accessible
(Figure S76; Path B). In this mechanism, instead from
the trans-dideuteride, σ-CAM is initiated from the
iron(II) cis-dideuteride with a very similar transition state
that is only 5.2 kcal mol−1 higher in energy.
R = Me
R = NMe2
R = OMe
R = F
30.4
31.3
25.6
23.9
25.9
25.2
24.5
23.6
25.2
27.5
25.7
25.1
aEnergies are reported relative to structure A (Figure 3). bSee
supporting information for computational details.
Besides the obvious steric effects, electronic effects
are also important. This is particularly evident in
fluorinated substrates [d5]-6 and [d2]-9. We begin by
noting that the overall transition barriers TS1-F for
C(sp2)–H activation in fluorinated substrates are lower
than those calculated for their non-fluorinated
counterparts (Table 2). Despite having the strongest C–H
bond, the more facile activation of fluoroarenes is well-
known and is due to the larger increase of the M–CAr bond
strength relative to that of the CAr–H bond.44, 45 This is
particularly true when fluorine substituents are
introduced at the ortho-position as demonstrated by Jones
and Perutz.46 This pronounced ortho-fluorine effect is
clearly seen in [d2]-9, which shown nearly exclusive
deuteration (~85%) at ortho-position. Similarly, for
fluorobenzene ([d5]-6), the highest level of deuteration is
observed at ortho-position (98%). In contrast, the para-
We also used computational studies to gain more
insight into the observed regioselectivity. For a series of
substituted benzenes, we calculated the energy barriers of
TS1-R (Table 2; R = H, Me, NMe2, OMe, and F). For
benzene (R = H) the calculated barrier is 25.2 kcal mol−1
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
Notes
position shows a lower level of deuteration (~90%),
1
2
3
4
5
6
7
8
consistent with a transition state barrier that is 1.2 kcal
mol-1 higher than that calculated for the ortho-position
(Table 2). Besides the electronic of fluorine, other
electronic effects are observed as well. To illustrate, we
calculated the natural charges on the aromatic carbons
and hydrogen atom Hb (Figure S79). As expected upon
C–H bond activation, additional negative charges develop
on aromatic carbon atoms (incl. Cb), while a positive
charge develops on Hb. Consequently, π-donation of the
coplanar NMe2 substituent effectively destabilizes this
negative charge, resulting in an overall higher activation
energy for C–H bond activation (Table 2).
Overall, these computational studies show that for the
majority of substrates the observed regioselectivity can be
explained by a combination of steric and electronic
factors (Table 2) and that a σ-CAM based mechanism is
able to explain the observed HIE (Figure 3).
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Research was supported by the Azrieli Foundation (Israel),
and the Technion EVPR Fund – Mallat Family Research
Fund. G.de.R is an Azrieli young faculty fellow and a Horev
Fellow supported by the Taub Foundation.
9
REFERENCES
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
1. (a) Cornils, B.; Herrmann, W. A.; Beller, M.; Paciello, R., Applied
Homogeneous Catalysis with Organometallic Compounds: A
Comprehensive Handbook in Four Volumes. 3 ed.; Wiley-VCH
Verlag GmbH & Co: Weinheim, Germany, 2017; (b) Hartwig, J.
F., Organotransition Metal Chemistry: From Bonding to Catalysis.
University Science Books: 2010.
2. (a) Ludwig, J. R.; Schindler, C. S., Catalyst: Sustainable Catalysis.
Chem 2017, 2, 313-316; (b) Nakamura, E.; Sato, K., Managing the
Scarcity of Chemical Elements. Nat. Mater. 2011, 10, 158-161.
3. Hapke, M.; Hilt, G., Cobalt Catalysis in Organic Synthesis:
Methods and Reactions. Wiley-VCH Verlag GmbH & Co:
Weinheim, Germany, 2020.
4. (a) Carney, J. R.; Dillon, B. R.; Thomas, S. P., Recent Advances of
Manganese Catalysis for Organic Synthesis. Eur. J. Org. Chem.
2016, 2016, 3912-3929; (b) Liu, W.; Ackermann, L., Manganese-
Catalyzed C–H Activation. ACS Catal. 2016, 6, 3743-3752.
5. (a) Fürstner, A., Iron Catalysis in Organic Synthesis: A Critical
Assessment of What It Takes To Make This Base Metal a
Multitasking Champion. ACS Cent. Sci. 2016, 2, 778-789; (b)
Bauer, I.; Knölker, H.-J., Iron Catalysis in Organic Synthesis.
Chem. Rev. 2015, 115, 3170-3387.
6. Gebbink, R. J. M. K.; Moret, M. E., Non-Noble Metal Catalysis:
Molecular Approaches and Reactions. Wiley-VCH Verlag GmbH
& Co: Weinheim, Germany, 2019.
7. (a) Fritz, M.; Schneider, S., The Renaissance of Base Metal
Catalysis Enabled by Functional Ligands. In The Periodic Table
II: Catalytic, Materials, Biological and Medical Applications,
Mingos, D. M. P., Ed. Springer International Publishing: Cham,
2019; pp 1-36; (b) Holland, P. L., Reaction: Opportunities for
Sustainable Catalysts. Chem 2017, 2, 443-444.
8. (a) Junge, K.; Papa, V.; Beller, M., Cobalt–Pincer Complexes in
Catalysis. Chem. Eur. J. 2019, 25, 122-143; (b) Alig, L.; Fritz, M.;
Schneider, S., First-Row Transition Metal (De)Hydrogenation
Catalysis Based On Functional Pincer Ligands. Chem. Rev. 2019,
119, 2681-2751; (c) Wen, H.; Liu, G.; Huang, Z., Recent Advances
in Tridentate Iron and Cobalt Complexes gor Alkene and Alkyne
Hydrofunctionalizations. Coord. Chem. Rev. 2019, 386, 138-153;
(d) Mukherjee, A.; Milstein, D., Homogeneous Catalysis by Cobalt
and Manganese Pincer Complexes. ACS Catal. 2018, 8, 11435-
11469; (e) Gorgas, N.; Kirchner, K., Isoelectronic Manganese and
Iron Hydrogenation/Dehydrogenation Catalysts: Similarities and
Divergences. Acc. Chem. Res. 2018, 51, 1558-1569; (f) Bauer, G.;
Hu, X., Recent Developments Of Iron Pincer Complexes For
Catalytic Applications. Inorg. Chem. Front. 2016, 3, 741-765; (g)
Farrell, K.; Albrecht, M., Late Transition Metal Complexes with
Pincer Ligands that Comprise N-Heterocyclic Carbene Donor
Sites. In The Privileged Pincer-Metal Platform: Coordination
Chemistry & Applications, van Koten, G.; Gossage, R. A., Eds.
Springer International Publishing: Cham, 2016; pp 45-91.
9. (a) Jiang, Y.; Gendy, C.; Roesler, R., Nickel, Ruthenium, and
Rhodium NCN-Pincer Complexes Featuring a Six-Membered N-
Heterocyclic Carbene Central Moiety and Pyridyl Pendant Arms.
Organometallics 2018, 37, 1123-1132; (b) Harris, C. F.; Bayless,
M. B.; van Leest, N. P.; Bruch, Q. J.; Livesay, B. N.; Bacsa, J.;
Hardcastle, K. I.; Shores, M. P.; de Bruin, B.; Soper, J. D., Redox-
Active Bis(phenolate) N-Heterocyclic Carbene [OCO] Pincer
Ligands Support Cobalt Electron Transfer Series Spanning Four
Oxidation States. Inorg. Chem. 2017, 56, 12421-12435; (c) Brown,
Conclusions
In summary, we have reported the synthesis and
characterization of a rare trans-dihydride iron(II)
dinitrogen complex (2) that is based on a novel PCNHC
P
pincer type motif. This compound is stable under N2 for
several days and can be used for selective H/D exchange
at (hetero)aromatic hydrocarbons with benzene-d6 as
deuterium source. Deuterium incorporation typically
exceeds 90% and is generally regioselective for sterically
accessible C(sp2)–H bonds unless overriding electronic
effects are present. Computational studies indicate that a
σ-bond metathesis pathway is mainly responsible for the
observed hydrogen isotope exchange (HIE), which is
accessible under mild conditions (N2, 50 oC). Overall, the
herein reported results convey a convenient and
straightforward method for H/D exchange that displays a
wide functional group tolerance (e.g. esters, amides,
halides, ethers, etc.). Furthermore, the robustness and
stability of the herein reported catalyst holds great
potential for other organic transformations that rely on
hydride transfer or those that focus on small molecule
activation. Current efforts are directed towards
synthesizing the corresponding manganese, cobalt, and
nickel complexes and exploring their reactivity in a
variety of organic transformations.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge at
the ACS website.
Crystal data (CIF)
xyz-coordinate files (ZIP)
Synthetic procedures, characterization data, catalysis, and
computational studies (PDF)
AUTHOR INFORMATION
Corresponding Author
* Email: graham@technion.ac.il
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
R. M.; BorauꢁGarcia, J.; Valjus, J.; Roberts, C. J.; Tuononen, H.
Coordinate Iron−Hydride Complexes. J. Am. Chem. Soc. 2008,
130, 6624-6638.
16. Trovitch, R. J.,
M.; Parvez, M.; Roesler, R., Ammonia Activation by a Nickel
NCN-Pincer Complex featuring a Non-Innocent N-Heterocyclic
Carbene: Ammine and Amido Complexes in Equilibrium. Angew.
Chem. Int. Ed. 2015, 54, 6274-6277; (d) Kaplan, H. Z.; Li, B.;
Byers, J. A., Synthesis and Characterization of a Bis(imino)-N-
heterocyclic Carbene Analogue to Bis(imino)pyridine Iron
Complexes. Organometallics 2012, 31, 7343-7350.
1
2
3
4
5
6
7
8
J.;
Lobkovsky,
E.;
Chirik,
P.
Bis(diisopropylphosphino)pyridine Iron Dicarbonyl, Dihydride,
and Silyl Hydride Complexes. Inorg. Chem. 2006, 45, 7252-7260.
17. (a) Fuku-en, S.-i.; Yamamoto, J.; Kojima, S.; Yamamoto, Y.,
Synthesis and Application of New Dipyrido-Annulated N-
heterocyclic Carbene with Phosphorus Substituents. Chem. Lett.
2014, 43, 468-470; (b) Fuku-en, S.-i.; Yamamoto, J.; Minoura, M.;
Kojima, S.; Yamamoto, Y., Synthesis of New Dipyrido-Annulated
N-Heterocyclic Carbenes with Ortho Substituents. Inorg. Chem.
2013, 52, 11700-11702; (c) Gierz, V.; Seyboldt, A.; Maichle-
Moessmer, C.; Froehlich, R.; Rominger, F.; Kunz, D.,
Straightforward Synthesis of Dipyrido-Annelated NHC-
palladium(II) Complexes by Oxidative Addition. Eur. J. Inorg.
Chem. 2012, 2012, 1423-1429; (d) Nonnenmacher, M.; Kunz, D.;
Rominger, F., Synthesis and Catalytic Properties Of Rhodium(I)
and Copper(I) Complexes Bearing Dipyrido-Annulated N-
Heterocyclic Carbene Ligands. Organometallics 2008, 27, 1561-
1568; (e) Nonnenmacher, M.; Kunz, D.; Rominger, F.; Oeser, T.,
X-Ray Crystal Structures of 10 π - and 14 π -Electron Pyrido-
Annelated N-Heterocyclic Carbenes. Chem. Commun. 2006, 1378-
1380; (f) Nonnenmacher, M.; Kunz, D.; Rominger, F.; Oeser, T.,
First Examples of Dipyrido[1,2-C:2',1'-E]Imidazolin-7-Ylidenes
Serving as NHC-Ligands: Synthesis, Properties and Structural
Features of their Chromium and Tungsten Pentacarbonyl
Complexes. J. Organomet. Chem. 2005, 690, 5647-5653.
18. (a) Schremmer, C.; Cordes, C.; Klawitter, I.; Bergner, M.;
Schiewer, C. E.; Dechert, S.; Demeshko, S.; John, M.; Meyer, F.,
Spin-State Variations of Iron(III) Complexes with Tetracarbene
Macrocycles. Chem. Eur. J. 2019, 25, 3918-3929; (b) Schneider,
H.; Schmidt, D.; Eichhöfer, A.; Radius, M.; Weigend, F.; Radius,
U., Synthesis and Reactivity of NHC-Stabilized Iron(II)–Mesityl
Complexes. Eur. J. Inorg. Chem. 2017, 2017, 2600-2616; (c)
Liang, Q.; Janes, T.; Gjergji, X.; Song, D., Iron Complexes of a
Bidentate Picolyl-NHC Ligand: Synthesis, Structure and
Reactivity. Dalton Trans. 2016, 45, 13872-13880; (d) Ouyang, Z.;
Du, J.; Wang, L.; Kneebone, J. L.; Neidig, M. L.; Deng, L., Linear
and T-Shaped Iron(I) Complexes Supported by N-Heterocyclic
Carbene Ligands: Synthesis and Structure Characterization. Inorg.
Chem. 2015, 54, 8808-8816; (e) Zlatogorsky, S.; Muryn, C. A.;
Tuna, F.; Evans, D. J.; Ingleson, M. J., Synthesis, Structures, and
Reactivity of Chelating Bis-N-Heterocyclic-Carbene Complexes
of Iron(II). Organometallics 2011, 30, 4974-4982.
19. (a) Wiedner, E. S.; Chambers, M. B.; Pitman, C. L.; Bullock, R.
M.; Miller, A. J. M.; Appel, A. M., Thermodynamic Hydricity of
Transition Metal Hydrides. Chem. Rev. 2016, 116, 8655-8692; (b)
Wang, D.; Astruc, D., The Golden Age of Transfer Hydrogenation.
Chem. Rev. 2015, 115, 6621-6686; (c) Larionov, E.; Li, H.; Mazet,
C., Well-Defined Transition Metal Hydrides in Catalytic
Isomerizations. Chem. Commun. 2014, 50, 9816-9826; (d)
Pospech, J.; Fleischer, I.; Franke, R.; Buchholz, S.; Beller, M.,
Alternative Metals for Homogeneous Catalyzed Hydroformylation
Reactions. Angew. Chem. Int. Ed. 2013, 52, 2852-2872; (e) Recent
Advances in Hydride Chemistry. Peruzzini, M.; Poli, R., Eds.
Elsevier: Amsterdam, 2001; pp 1-578.
20. Trans-dihydride iron complexes lacking stabilizing carbonyl
ligands, readily reductively eliminate H2 when exposed to an
atmosphere N2. The resulting Fe(0) complexes are either (I)
inactive for HIE, see for example: Yu, R. P.; Darmon, J. M.;
Semproni, S. P.; Turner, Z. R.; Chirik, P. J., Synthesis of Iron
Hydride Complexes Relevant to Hydrogen Isotope Exchange in
Pharmaceuticals. Organometallics 2017, 36, 4341-4343; or (ii)
they are very sluggish catalysts for HIE exchange see: Corpas, J.;
Viereck, P.; Chirik, P. J., C(sp2)–H Activation with Pyridine
Dicarbene Iron Dialkyl Complexes: Hydrogen Isotope Exchange
of Arenes Using Benzene-d6 as a Deuterium Source. ACS Catal.
2020, 10, 8640-8647.
10. (a) Subramaniyan, V.; Dutta, B.; Govindaraj, A.; Mani, G., Facile
Synthesis of Pd(II) and Ni(II) Pincer Carbene Complexes by the
Double C–H Bond Activation of a New Hexahydropyrimidine-
Based Bis(Phosphine): Catalysis of C–N Couplings. Dalton Trans.
2019, 48, 7203-7210; (b) Sung, S.; Wang, Q.; Krämer, T.; Young,
R. D., Synthesis and Reactivity of a PCcarbeneP Cobalt(I)
Complex: The Missing Link in the Cobalt PXP Pincer Series (X =
B, C, N). Chem. Sci 2018, 9, 8234-8241; (c) Gutsulyak, D. V.;
Piers, W. E.; Borau-Garcia, J.; Parvez, M., Activation of Water,
Ammonia, and Other Small Molecules by PCcarbeneP Nickel
Pincer Complexes. J. Am. Chem. Soc. 2013, 135, 11776-11779; (d)
Steinke, T.; Shaw, B. K.; Jong, H.; Patrick, B. O.; Fryzuk, M. D.;
Green, J. C., Noninnocent Behavior of Ancillary Ligands:
Apparent Trans Coupling of a Saturated N-Heterocyclic Carbene
Unit with an Ethyl Ligand Mediated by Nickel. J. Am. Chem. Soc.
2009, 131, 10461-10466.
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. Dröge, T.; Glorius, F., The Measure of All Rings—N-Heterocyclic
Carbenes. Angew. Chem. Int. Ed. 2010, 49, 6940-6952.
12. (a) Eizawa, A.; Arashiba, K.; Tanaka, H.; Kuriyama, S.; Matsuo,
Y.; Nakajima, K.; Yoshizawa, K.; Nishibayashi, Y., Remarkable
Catalytic Activity of Dinitrogen-Bridged Dimolybdenum
Complexes Bearing NHC-Based PCP-Pincer Ligands Toward
Nitrogen Fixation. Nat. Commun. 2017, 8, 14874; (b) Plikhta, A.;
Pöthig, A.; Herdtweck, E.; Rieger, B., Toward New
Organometallic Architectures: Synthesis of Carbene-Centered
Rhodium and Palladium Bisphosphine Complexes. Stability and
Reactivity of [PCBImPRh(L)][PF6] Pincers. Inorg. Chem. 2015,
54, 9517-9528.
13. Baker, T. M.; Mako, T. L.; Vasilopoulos, A.; Li, B.; Byers, J. A.;
Neidig, M. L., Magnetic Circular Dichroism and Density
Functional Theory Studies of Iron(II)-Pincer Complexes: Insight
into Electronic Structure and Bonding Effects of Pincer N-
Heterocyclic Carbene Moieties. Organometallics 2016, 35, 3692-
3700.
14. (a) Harris, C. F.; Kuehner, C. S.; Bacsa, J.; Soper, J. D.,
Photoinduced Cobalt(III)−Trifluoromethyl Bond Activation
Enables Arene C−H Trifluoromethylation. Angew. Chem. Int. Ed.
2018, 57, 1311-1315; (b) Manna, C. M.; Kaplan, H. Z.; Li, B.;
Byers, J. A., High Molecular Weight Poly(Lactic Acid) Produced
by an Efficient Iron Catalyst Bearing a Bis(Amidinato)-N-
Heterocyclic Carbene Ligand. Polyhedron 2014, 84, 160-167.
15. (a) Morris, R. H., Mechanisms of the H2- and Transfer
Hydrogenation of Polar Bonds Catalyzed by Iron Group Hydrides.
Dalton Trans. 2018, 47, 10809-10826; (b) Yu, R. P.; Darmon, J.
M.; Semproni, S. P.; Turner, Z. R.; Chirik, P. J., Synthesis of Iron
Hydride Complexes Relevant to Hydrogen Isotope Exchange in
Pharmaceuticals. Organometallics 2017, 36, 4341-4343; (c)
Gorgas, N.; Alves, L. G.; Stöger, B.; Martins, A. M.; Veiros, L. F.;
Kirchner, K., Stable, Yet Highly Reactive Nonclassical Iron(II)
Polyhydride Pincer Complexes: Z-Selective Dimerization and
Hydroboration of Terminal Alkynes. J. Am. Chem. Soc. 2017, 139,
8130-8133; (d) Gorgas, N.; Stöger, B.; Veiros, L. F.; Kirchner, K.,
Highly Efficient and Selective Hydrogenation of Aldehydes: A
Well-Defined Fe(II) Catalyst Exhibits Noble-Metal Activity. ACS
Catal. 2016, 6, 2664-2672; (e) Langer, R.; Diskin-Posner, Y.;
Leitus, G.; Shimon, L. J. W.; Ben-David, Y.; Milstein, D., Low-
Pressure Hydrogenation of Carbon Dioxide Catalyzed by an Iron
Pincer Complex Exhibiting Noble Metal Activity. Angew. Chem.
Int. Ed. 2011, 50, 9948-9952; (f) Langer, R.; Leitus, G.; Ben-
David, Y.; Milstein, D., Efficient Hydrogenation of Ketones
Catalyzed by an Iron Pincer Complex. Angew. Chem. Int. Ed. 2011,
50, 2120-2124; (g) Yu, Y.; Sadique, A. R.; Smith, J. M.; Dugan, T.
R.; Cowley, R. E.; Brennessel, W. W.; Flaschenriem, C. J.; Bill, E.;
Cundari, T. R.; Holland, P. L., The Reactivity Patterns of Low-
21. (a) Parkin, G., Applications of Deuterium Isotope Effects for
Probing Aspects of Reactions Involving Oxidative Addition and
Reductive Elimination of H–H and C–H Bonds. J. Label. Compd.
Radiopharm. 2007, 50, 1088-1114; (b) Jones, W. D., Isotope
ACS Paragon Plus Environment

Page 9 of 11
1
2
3
Journal of the American Chemical Society
Effects in C−H Bond Activation Reactions by Transition Metals.
Acc. Chem. Res. 2003, 36, 140-146.
L‘ = Olefin or L−L‘ = Bipyridine. Organometallics 2000, 19, 1247-
1254.
22. (a) Katsnelson, A., Heavy Drugs Draw Heavy Interest From
Pharma Backers. Nat. Med. 2013, 19, 656-656; (b) Elmore, C. S.,
The Use of Isotopically Labeled Compounds in Drug Discovery.
In Annu. Rep. Med. Chem., Macor, J. E., Ed. Academic Press:
2009; Vol. 44, pp 515-534.
28. (a) Yang, H.; Hesk, D., Base Metal-Catalyzed Hydrogen Isotope
Exchange. J. Label. Compd. Radiopharm. 2020, 63, 296-307; (b)
Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J., The Renaissance
of H/D Exchange. Angew. Chem. Int. Ed. 2007, 46, 7744-7765.
29. (a) Zhou, J.; Hartwig, J. F., Iridium-Catalyzed H/D Exchange at
Vinyl Groups without Olefin Isomerization. Angew. Chem. Int. Ed.
2008, 47, 5783-5787; (b) Feng, Y.; Lail, M.; Foley, N. A.; Gunnoe,
T. B.; Barakat, K. A.; Cundari, T. R.; Petersen, J. L.,
Hydrogen−Deuterium Exchange between TpRu(PMe3)(L)X (L =
PMe3 and X = OH, OPh, Me, Ph, or NHPh; L = NCMe and X =
Ph) and Deuterated Arene Solvents:ꢀ Evidence for Metal-Mediated
Processes. J. Am. Chem. Soc. 2006, 128, 7982-7994; (c) Giunta,
D.; Hölscher, M.; Lehmann, C. W.; Mynott, R.; Wirtz, C.; Leitner,
W., Room Temperature Activation of Aromatic C–H Bonds by
Non-Classical Ruthenium Hydride Complexes Containing
Carbene Ligands. Adv. Synth. Catal. 2003, 345, 1139-1145; (d)
Golden, J. T.; Andersen, R. A.; Bergman, R. G., Exceptionally
4
5
6
7
8
23. Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M., Deuterium- and
Tritium-Labelled Compounds: Applications in the Life Sciences.
Angew. Chem. Int. Ed. 2018, 57, 1758-1784.
24. (a) Prechtl, M. H. G.; Hölscher, M.; Ben-David, Y.; Theyssen, N.;
Loschen, R.; Milstein, D.; Leitner, W., H/D Exchange at Aromatic
and Heteroaromatic Hydrocarbons Using D2O as the Deuterium
Source and Ruthenium Dihydrogen Complexes as the Catalyst.
Angew. Chem. Int. Ed. 2007, 46, 2269-2272; (b) Ng, S. M.; Lam,
W. H.; Mak, C. C.; Tsang, C. W.; Jia, G.; Lin, Z.; Lau, C. P., C−H
Bond Activation by a Hydrotris(pyrazolyl)borato Ruthenium
Hydride Complex. Organometallics 2003, 22, 641-651.
25. (a) DiꢁGiuseppe, A.; Castarlenas, R.; Pérez-Torrente, J. J.; Lahoz,
F. J.; Oro, L. A., Hydride-Rhodium(III)-N-Heterocyclic Carbene
Catalysts for Vinyl-Selective H/D Exchange: A Structure–Activity
Study. Chem. Eur. J. 2014, 20, 8391-8403; (b) Lenges, C. P.;
White, P. S.; Brookhart, M., Hydrogen/Deuterium Exchange
Reactions and Transfer Hydrogenations Catalyzed by
[C5Me5Rh(olefin)2] Complexes:ꢀ Conversion of Alkoxysilanes to
Silyl Enolates. J. Am. Chem. Soc. 1999, 121, 4385-4396; (c) Blake,
M. R.; Garnett, J. L.; Gregor, I. K.; Hannan, W.; Hoa, K.; Long, M.
A., Rhodium Trichloride as a Homogeneous Catalyst for Isotopic
Hydrogen Exchange. Comparison with Heterogeneous Rhodium in
the Deuteriation of Aromatic Compounds and Alkanes. J. Chem.
Soc., Chem. Commun. 1975, 930-932.
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
Low-Temperature
Carbon−Hydrogen/Carbon−Deuterium
Exchange Reactions of Organic and Organometallic Compounds
Catalyzed by the Cp*(PMe3)IrH(ClCH2Cl)+ Cation. J. Am. Chem.
Soc. 2001, 123, 5837-5838.
30. (a) Smith, S. A. M.; Lagaditis, P. O.; Lüpke, A.; Lough, A. J.;
Morris, R. H., Unsymmetrical Iron P-NH-P′ Catalysts for the
Asymmetric Pressure Hydrogenation of Aryl Ketones. Chem. Eur.
J. 2017, 23, 7212-7216; (b) Sonnenberg, J. F.; Wan, K. Y.; Sues,
P. E.; Morris, R. H., Ketone Asymmetric Hydrogenation Catalyzed
by P-NH-P′ Pincer Iron Catalysts: An Experimental and
Computational Study. ACS Catal. 2017, 7, 316-326; (c) Yang, X.,
Unexpected Direct Reduction Mechanism for Hydrogenation of
Ketones Catalyzed by Iron PNP Pincer Complexes. Inorg. Chem.
2011, 50, 12836-12843.
31. Morello, G. R.; Hopmann, K. H., A Dihydride Mechanism Can
Explain the Intriguing Substrate Selectivity of Iron-PNP-Mediated
Hydrogenation. ACS Catal. 2017, 7, 5847-5855.
32. After addition of the ketone, the reaction mixture turns from
yellow/brown to dark green, which might indicate formation of an
iron(0) species. Other iron(0) species have been isolated by us,
which are all green. However, formation of a metal-enolate species,
or stoichiometric reduction of the ketone cannot be exclusively
excluded.
33. (a) Wren, S. W.; Vogelhuber, K. M.; Garver, J. M.; Kato, S.; Sheps,
L.; Bierbaum, V. M.; Lineberger, W. C., C–H Bond Strengths and
Acidities in Aromatic Systems: Effects of Nitrogen Incorporation
in Mono-, Di-, and Triazines. J. Am. Chem. Soc. 2012, 134, 6584-
6595; (b) Luo, Y. R., Handbook of Bond Dissociation Energies in
Organic Compounds. CRC Press: 2002.
34. (a) Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.;
Ackermann, L., 3d Transition Metals for C–H Activation. Chem.
Rev. 2019, 119, 2192-2452; (b) Balcells, D.; Clot, E.; Eisenstein,
O., C—H Bond Activation in Transition Metal Species from a
Computational Perspective. Chem. Rev. 2010, 110, 749-823; (c)
Labinger, J. A.; Bercaw, J. E., Understanding and Exploiting C–H
Bond Activation. Nature 2002, 417, 507-514; (d) Shilov, A. E.;
Shul'pin, G. B., Activation of C−H Bonds by Metal Complexes.
Chem. Rev. 1997, 97, 2879-2932.
35. Perutz, R. N.; Sabo-Etienne, S., The σ -CAM Mechanism: σ ꢁ
Complexes as the Basis of σ-Bond Metathesis at Late-Transition-
Metal Centers. Angew. Chem. Int. Ed. 2007, 46, 2578-2592.
36. Di Giuseppe, A.; Castarlenas, R.; Oro, L. A., Mechanistic
Considerations on Catalytic H/D Exchange Mediated by
Organometallic Transition Tetal Complexes. Compt. Rend. Chimie
2015, 18, 713-741.
37. (a) Dombray, T.; Werncke, C. G.; Jiang, S.; Grellier, M.; Vendier,
L.; Bontemps, S.; Sortais, J.-B.; Sabo-Etienne, S.; Darcel, C., Iron-
Catalyzed C–H Borylation of Arenes. J. Am. Chem. Soc. 2015, 137,
4062-4065; (b) Azizian, H.; Morris, R. H., Photochemical
26. (a) Nilsson, G. N.; Kerr, W. J., The Development and use of Novel
Iridium Complexes as Catalysts for Ortho-Directed Hydrogen
Isotope Exchange Reactions. J. Label. Compd. Radiopharm. 2010,
53, 662-667; (b) Corberán, R.; Sanaú, M.; Peris, E., Highly Stable
Cp*−Ir(III) Complexes with N-Heterocyclic Carbene Ligands as
C−H Activation Catalysts for the Deuteration of Organic
Molecules. J. Am. Chem. Soc. 2006, 128, 3974-3979; (c) Yung, C.
M.; Skaddan, M. B.; Bergman, R. G., Stoichiometric and Catalytic
H/D Incorporation by Cationic Iridium Complexes:ꢀ A Common
Monohydrido-Iridium Intermediate. J. Am. Chem. Soc. 2004, 126,
13033-13043; (d) Klei, S. R.; Golden, J. T.; Tilley, T. D.; Bergman,
R. G., Iridium-Catalyzed H/D Exchange into Organic Compounds
in Water. J. Am. Chem. Soc. 2002, 124, 2092-2093; (e) Ellames, G.
J.; Gibson, J. S.; Herbert, J. M.; McNeill, A. H., The Scope and
Limitations of Deuteration Mediated by Crabtree's Catalyst.
Tetrahedron 2001, 57, 9487-9497; (f) Heys, R., Investigation of
[IrH2(Me2CO)2(PPh3)2]BF4 as a Catalyst of Hydrogen Isotope
Exchange of Substrates in Solution. J. Chem. Soc., Chem.
Commun. 1992, 680-681.
27. (a) Corpas, J.; Viereck, P.; Chirik, P. J., C(sp2)–H Activation with
Pyridine Dicarbene Iron Dialkyl Complexes: Hydrogen Isotope
Exchange of Arenes Using Benzene-d6 as a Deuterium Source.
ACS Catal. 2020, 10, 8640-8647; (b) Zhang, J.; Zhang, S.; Gogula,
T.; Zou, H., Versatile Regioselective Deuteration of Indoles via
Transition-Metal-Catalyzed H/D Exchange. ACS Catal. 2020,
7486-7494; (c) Zarate, C.; Yang, H.; Bezdek, M. J.; Hesk, D.;
Chirik, P. J., Ni(I)–X Complexes Bearing a Bulky α -Diimine
Ligand: Synthesis, Structure, and Superior Catalytic Performance
in the Hydrogen Isotope Exchange in Pharmaceuticals. J. Am.
Chem. Soc. 2019, 141, 5034-5044; (d) Yang, H.; Zarate, C.;
Palmer, W. N.; Rivera, N.; Hesk, D.; Chirik, P. J., Site-Selective
Nickel-Catalyzed Hydrogen Isotope Exchange in N-Heterocycles
and Its Application to the Tritiation of Pharmaceuticals. ACS Catal.
2018, 8, 10210-10218; (e) Palmer, W. N.; Chirik, P. J., Cobalt-
Catalyzed Stereoretentive Hydrogen Isotope Exchange of C(sp3)–
H Bonds. ACS Catal. 2017, 7, 5674-5678; (f) Pony Yu, R.; Hesk,
D.; Rivera, N.; Pelczer, I.; Chirik, P. J., Iron-Catalysed Tritiation
of Pharmaceuticals. Nature 2016, 529, 195-199; (g) Lenges, C. P.;
White, P. S.; Marshall, W. J.; Brookhart, M., Synthesis, Structure,
and Reactivity of [C5Me5CoLL‘] Complexes with L = Pyridine and
Synthesis
and
Reactions
of
FeH(C6H4PPhCH2CH2PPh2)(PPh2PCH2CH2PPh2). Inorg. Chem.
1983, 22, 6-9; (c) Tolman, C. A.; Ittel, S. D.; English, A. D.; Jesson,
J. P., Chemistry of 2-Naphthyl Bis[bis(dimethylphosphino)ethane]
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
Hydride Complexes of Iron, Ruthenium, and Osmium. 3. Cleavage
respective potential energy surfaces (PESs) will be nearly identical
of sp2 Carbon-Hydrogen Bonds. J. Am. Chem. Soc. 1979, 101,
1742-1751; (d) Hata, G.; Kondo, H.; Miyake, A.,
Ethylenebis(Diphenylphosphine) Complexes of Iron And Cobalt.
Hydrogen Transfer between the Ligand and Iron Atom. J. Am.
Chem. Soc. 1968, 90, 2278-2281.
except for their relative energies. Typically, PESs that include
deuterium are slightly higher in energy (ca. 0.4 kcal/mol). For more
information see the supporting information for additional
computational details.
1
2
3
4
5
6
7
8
44. (a) Clot, E.; Mégret, C.; Eisenstein, O.; Perutz, R. N., Exceptional
Sensitivity of Metal−Aryl Bond Energies to ortho-Fluorine
Substituents: Influence of the Metal, the Coordination Sphere, and
the Spectator Ligands on M−C/H−C Bond Energy Correlations. J.
Am. Chem. Soc. 2009, 131, 7817-7827; (b) Evans, M. E.; Burke,
C. L.; Yaibuathes, S.; Clot, E.; Eisenstein, O.; Jones, W. D.,
Energetics of C−H Bond Activation of Fluorinated Aromatic
Hydrocarbons Using a [Tp′Rh(CNneopentyl)] Complex. J. Am.
Chem. Soc. 2009, 131, 13464-13473; (c) Clot, E.; Besora, M.;
Maseras, F.; Mégret, C.; Eisenstein, O.; Oelckers, B.; Perutz, R. N.,
Bond Energy M–C/H–C Correlations: Dual Theoretical and
Experimental Approach to the Sensitivity of M–C Bond Strength
to Substituents. Chem. Commun. 2003, 490-491.
45. For M−C/H−C bond energy correlations in non-fluorinated
systems see: (a) Clot, E.; Mégret, C.; Eisenstein, O.; Perutz, R. N.,
Validation of the M−C/H−C Bond Enthalpy Relationship through
Application of Density Functional Theory. J. Am. Chem. Soc.
2006, 128, 8350-8357; (b) Jones, W. D.; Hessell, E. T., Photolysis
of Tp’Rh(Cn-Neopentyl)( η2-PhN:C:N-Neopentyl) in Alkanes and
Arenes: Kinetic and Thermodynamic Selectivity ff [Tp’Rh(Cn-
Neopentyl)] for Various Types of Carbon-Hydrogen Bonds. J. Am.
Chem. Soc. 1993, 115, 554-562.
38. Mantina, M.; Chamberlin, A. C.; Valero, R.; Cramer, C. J.; Truhlar,
D. G., Consistent van der Waals Radii for the Whole Main Group.
J. Phys. Chem. A. 2009, 113, 5806-5812.
39. Ben-Ari, E.; Cohen, R.; Gandelman, M.; Shimon, L. J. W.; Martin,
J. M. L.; Milstein, D., Ortho C−H Activation of Haloarenes and
Anisole by an Electron-Rich Iridium(I) Complex:ꢀ Mechanism and
Origin of Regio- andꢀChemoselectivity. AnꢀExperimental
andꢀTheoreticalꢀStudy. Organometallics 2006, 25, 3190-3210.
40. Van der Sluys, L. S.; Eckert, J.; Eisenstein, O.; Hall, J. H.;
Huffman, J. C.; Jackson, S. A.; Koetzle, T. F.; Kubas, G. J.;
Vergamini, P. J.; Caulton, K. G., An Attractive cis-Effect of
Hydride on Neighbor Ligands: Experimental and Theoretical
Studies on the Structure and Intramolecular Rearrangements of
Fe(H)2(η2-H2)(PEtPh2)3. J. Am. Chem. Soc. 1990, 112, 4831-4841.
41. Lam, W. H.; Jia, G.; Lin, Z.; Lau, C. P.; Eisenstein, O., Theoretical
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
Studies on the Metathesis Processes, [Tp(PH3)MR(
η2-H–
CH3)]ꢀ→ꢀ[Tp(PH3)M(CH3)( η2-H–R)] (M=Fe, Ru, and Os; R=H
and CH3). Chem. Eur. J. 2003, 9, 2775-2782.
42. (a) Crabtree, R. H., Dihydrogen Complexation. Chem. Rev. 2016,
116, 8750-8769; (b) Morris, R. H., Dihydrogen, Dihydride and in
Between: NMR and Structural Properties of Iron Group
Complexes. Coord. Chem. Rev. 2008, 252, 2381-2394; (c) Jessop,
P. G.; Morris, R. H., Reactions of Transition Metal Dihydrogen
Complexes. Coord. Chem. Rev. 1992, 121, 155-284.
46. Selmeczy, A. D.; Jones, W. D.; Partridge, M. G.; Perutz, R. N.,
Selectivity in the Activation of Fluorinated Aromatic
Hydrocarbons by Rhodium Complexes [(C5H5)Rh(PMe3)] and
[(C5Me5)Rh(PMe3)]. Organometallics 1994, 13, 522-532.
43. Computationally, the only difference between hydrogen and
deuterium atoms are in the vibrational modes, as a result the
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
TOC
1
2
tBu
D
Z
Z
PiPr2
Fe
or
or
3
4
5
6
R
R
D
H
N
N
N2, C6D6
R
R
Å
Fe
N2
High-level of deuterium incorporation
H
>15 Examples
PiPr2
[2]
Wide substrate scope
tBu
Mild Conditions (N2, 50 °C)
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
11
ACS Paragon Plus Environment