Borrowing Hydrogen-Mediated N-Alkylation Reactions by a Well-Defined Homogeneous Nickel Catalyst

Article abstract of DOI:10.1021/acscatal.9b02977

We report herein a well-defined and bench-stable azo-phenolate ligand-coordinated nickel catalyst which can efficiently execute N-alkylation of a variety of anilines by alcohol. We demonstrate that the redox-active azo ligand can store hydrogen generated during alcohol oxidation and redelivers the same to an in-situ-generated imine bond to result in N-alkylation of amines. The reaction has wide scope, and a large array of alcohols can directly couple to a variety of anilines. Mechanistic studies including deuterium labeling to the substrate establishes the borrowing hydrogen method from alcohols and pinpoints the crucial role of the redox-active azo moiety present on the ligand backbone. Isolation of the ketyl intermediate in its trapped form with a radical quencher and higher k_H/k_D for the alcohol oxidation step suggest altogether a hydrogen-atom transfer (HAT) to the reduced azo backbone to pave alcohol oxidation as opposed to the conventional metal-ligand bifunctional mechanism. This example clearly demonstrates that an inexpensive base metal catalyst can accomplish an important coupling reaction with the help of a redox-active ligand backbone.

Full text of DOI:10.1021/acscatal.9b02977

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Article
Borrowing Hydrogen Mediated N-Alkylation Reactions
by a Well-Defined Homogeneous Nickel Catalyst
Amreen K Bains, Abhishek Kundu, Sudha Yadav, and Debashis Adhikari
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02977 • Publication Date (Web): 19 Aug 2019
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Borrowing Hydrogen Mediated N-Alkylation Reactions by a Well-
Defined Homogeneous Nickel Catalyst
Amreen K. Bains, Abhishek Kundu, Sudha Yadav, Debashis Adhikari*†
†Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, SAS
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Nagar-140306, India.
emission. The N-alkylation of amines using alcohols could be
ABSTRACT: We report herein a well-defined and bench- stable
envisaged as the successful merger of three different steps: an
alcohol oxidation by borrowing hydrogen method, in situ
azo-phenolate ligand coordinated nickel catalyst which can
efficiently execute N-alkylation of a variety of anilines by
imine formation from the resulting carbonyl species in
alcohol. We demonstrate that the redox-active azo ligand can
presence of an amine, and finally hydrogenation of the imine
store hydrogen generated during alcohol oxidation and
redelivers the same to an in situ generated imine bond to result
by the borrowed hydrogen from alcohol.15, 16
N-alkylation of amines. The reaction has wide scope and a large
array of alcohols can directly couple to a variety of anilines.
Mechanistic studies including deuterium-labelling to the
substrate establishes borrowing hydrogen method from alcohols
and pinpoints the crucial role of the redox active azo moiety
present on the ligand backbone. Isolation of the ketyl
intermediate in its trapped form with a radical quencher, higher
kH/kD for the alcohol oxidation step suggest altogether a
hydrogen atom transfer (HAT) to the reduced azo backbone to
pave alcohol oxidation as opposed to conventional metal-ligand
bifunctional mechanism. This example clearly demonstrates that
an inexpensive base metal catalyst can accomplish an important
coupling reaction with the help of a redox-active ligand
backbone.
Several reports disclose single-site catalytic system
comprising 4d, 5d transition metals towards effective N-
alkylations,17-23 but cost-effective and environment-friendly
base metal representatives24-29 for this class of catalysts are
relatively rare and sought-after synthetic goals. A thorough
literature survey further reveals that nickel for N-alkylation
reactions are extremely sparse. Some examples report
heterogeneous Raney nickel systems for N-alkylation using
HB, but often the system works in combination of a second
metal whose role is not clearly defined.30-32 In the
heterogeneous front, Yus has extensively worked on
hydrogen transfer reactions using nickel nanoparticles.33, 34
Barta and coworkers recently reported the use of Ni(COD)2
to develop a N-alkylation protocol via heterogeneous nickel
oxide cluster.35 In contrast, to our knowledge, there are only
two examples of nickel based homogeneous catalyst for N-
alkylation reactions.36, 37Recently, a nickel bromide and 1,10-
phenanthrolene combination has been reported that can
effectively N-alkylate a large group of amine substrates.36
Interestingly, asymmetric version of N-alkylation has also
been investigated to furnish chiral N-benzylamine, utilizing
Ni(OTf)2 and chiral phosphine, following HB technique.37
KEYWORDS: hydrogen-borrowing catalysis, N-alkylation,
Ni(Azo-phenolate)2 complex, Base metal, Redox active ligand
The C–N bond formation maintaining atom economy
represents an extremely important goal in contemporary
catalysis research, owing to the ubiquitous presence of
nitrogenated products in chemistry, biology and
pharmaceuticals.1 Powerful older methods toward this target
3
are hydroamination,2, Buchwald-Hartwig coupling,4 and
Ullmann reactions5 which despite their efficiency are either
based on precious metals or generate considerable amount of
side-products. In this context, a significant impetus has been
propelled for N-alkylation reactions to furnish new C–N bond
using alcohols as the cheap and abundant source of alkyl
groups following hydrogen borrowing (HB) or hydrogen
autotransfer.6-11 This atom-economic transformation appeals
further since water is the sole by-product, that is
environmentally benign. As an alkyl source, alcohol draws
great attention due to its abundant supply from indigestible
lignocellulose biomass degradation that is very important to
make the chemistry sustainable.12-14 Hence, alcohol re-
functionalization can immensely contribute towards
protecting earth’s fossil fuel reserve and abating CO2
Scheme 1. N-Alkylation Reaction of Anilines via
Hydrogen Borrowing using Earth-abundant Ni Catalyst
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Though effective, the synthetic protocols have problems of
slightly lower (75%) with 5% catalyst loading. The
using expensive phosphine and operational difficulty
associated with the putative ligand. Henceforth, single-site
nickel catalyst is still scarce and highly coveted in base metal
catalyzed HB-based N-alkylation reactions. To this end, we
are intrigued by the development of a well-defined,
phosphine free homogeneous nickel catalyst which can be
effective in N-alkylation reactions utilizing a wide variety of
alcohols (Scheme 1). Moreover, starting with a well-defined,
bench-stable molecule will greatly assist unraveling the
reaction mechanism which will potentially be useful for
further catalyst discovery.
catalytic system is attractive owing to moderate loading (7
mol%) of an inexpensive, air-stable, well-defined nickel
molecule. It is noteworthy that few reported systems
utilizing phosphine ligands are very efficient for N-
alkylation reactions. Notable examples are Kempe’s PN5P
ligand with triazine backbone44 or Shafir’s phosphino
amine ligands.45 However, our azo phenolato ligand is
considerably cheaper compared to any phosphine based
ligands without sacrificing any efficiency.
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The broad substrate scope and functional group tolerance
of the reaction is highlighted with respect to both amine and
alcohol components. As displayed in the Table 1, a wide
variety of benzyl alcohol was used for the purpose of N-
alkylation to aniline. An array of diverse functionalities
such as methyl (2d, 2f), naphthyl (2g), different halides on
the benzyl alcohols were well tolerated and gave products
in high yield. Furthermore, sterically encumbering o-bromo
(2i), o-methoxy (2h) effectively converted the benzyl
alcohols to expected secondary amines in great yield (86-
89%). Similarly, highly electron donating p-OMe (2c), –
NMe2 (2e) group present in benzyl alcohol afforded good
yield of the corresponding aminated products. Notably,
electron withdrawing groups such as Cl, Br, F, NO2 (2b, 2i,
2l, 2m, 2n) present in the benzyl alcohol furnished the
similar N-alkylated product in very good yield.
Having this target in mind, we searched for an appropriate
ligand backbone which can help dehydrogenation of alcohol
and simultaneously store the borrowed hydrogen for further
delivery. The known redox activity of the azo38, 39 group
suggests that this could be suitable for both redox-driven
alcohol dehydrogenation and hydrogen storage.40-42 To test
this conjecture, we designed a bidentate ligand, 3,5-di(tert-
butyl)-2-hydroxy azobenzene (L), and two of the ligands can
coordinate nickel in a square planar environment. This
complex, 1 being diamagnetic, offers further advantage of
tracking the key catalytic steps by 1H, 13C NMR
spectroscopies, which can shed significant insight on the
mechanistic aspect of alcohol dehydrogenation as well as
imine hydrogenation reactions. We also posit that using the
redox activity of the azo group for the alcohol oxidation
circumventing the nickel-hydride formation can make the
protocol more rewarding with respect to functional group
tolerance.
Furthermore, the scope of the reaction methodology was
expanded to variety of substituted anilines. In this case also
highly electron withdrawing groups present on aniline such
as nitro (3d), trifluoro methyl (3h, 3i), cyano (3k) resulted
excellent yield of aminated products.
The complex was prepared by adding a methanolic solution
of L to anhydrous Ni(OAc)2 and refluxing the mixture for 30
minutes. The isolated dark brown colored complex 1 is
diamagnetic, and its C2 symmetry affirms the Ni(II) is
confined in a square-planar environment via trans N,O-
coordination of the azo-phenolic ligands. It is noteworthy
that this class of complex was synthesized earlier to establish
basic coordination chemistry of the azo-phenolate ligand but
the utility of these molecules to catalytic reactions were
never tested.43
Table 1. Substrate Scope for Alcohols
NH2
1 (7mol%), KOtBu
Toluene, 130 oC, 24 h
+
Ar
OH
Ar
N
H
2a-2n
3a
4a-4n
N
H
N
N
H
H
Cl
MeO
4a (92%)
4b (82%)
4c (86%)
Our preliminary investigation of tandem acceptorless
dehydrogenation and imine hydrogenation started with
oxidizing benzyl alcohol and coupling with aniline,
followed by hydrogenation of imine to obtain N-benzyl
aniline. In a typical reaction, 1 mmol of benzyl alcohol was
mixed with 0.25 mmol of aniline in presence of 7 mol% of
catalyst 1 (wrt aniline) and 0.25 mmol of KOtBu, and the
N
H
N
H
N
H
N
4d (76%)
4e (73%)
4f (89%)
Br
OMe
N
H
N
H
N
H
4g (86%)
4h (86%)
4ia (89%)
o
reaction was heated to 130 C for 24 h. Monitoring the
reaction by 1H NMR spectroscopy and thin layer
chromatography typically reveals the full consumption of
benzyl alcohol, remnant aldehyde (from excess substrate
alcohol) and the desired aminated product. Although, the
oxidation of alcohols by the same catalyst can be finished
in shorter time span, the imination and subsequent
hydrogenation takes longer period of time (vide infra).
Standard work up of the reaction mixture under optimized
reaction conditions provides the desired aminated product
(86%) exclusively (see SI, Table S1). The yield could be
N
H
N
N
H
H
N
Br
4ja (79%)
4k (74%)
4l (80%)
N
H
N
H
F
O2N
4mb (92%)
4nb (80%)
Reaction conditions: 1 (7 mol%, w.r.t. aniline), 2 (1 mmol), 3a (0.25 mmol),
KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield); a30 h;
b36 h
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Simultaneously, presence of electron donating groups on pyridyl amine gave respective amines in good yield (66-
1
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8
the aniline (Table 2) component also efficiently
transformed it to the respective amine in very high yield (3b
and 3g in 80 and 90% respectively). Gratifyingly, the
protocol is very chemoselective, since presence of hydroxy
(3j), cyano, trifluoromethyl groups in the aniline did not
cause any detrimental reaction or reduction of yield.
81%), as well as pyridine dimethanol was easily dialkylated
with two equivalents of aniline to furnish 7d in excellent
yield (87%).
Next, we attempted to N-alkylate the diamines. Under the
optimized protocol, 1,8-napthelene diamine smoothly
transformed to N-alkylated product (8a) in 78% yield.
Table 2. Substrate Scope for Amines
Table 3. Substrate Scope for Aliphatic Alcohols
NH2
1 (7mol%), KOtBu
H
9
N
NH2
OH
Toluene, 130 oC, 24 h
H
+
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1 (7mol%), KOtBu
Toluene, 130 oC, 24 h
Aliphatic
N
R
+
OH
R
Aliphatic
2a
3b-3m
5b-5m
2'
3a
6a-6h
H
H
N
H
N
N
MeO
Cl
O2N
5da (78%)
N
N
N
H
5c (75%)
N
5b (80%)
H
H
H
iPr
6b (68%)
6c (79%)
6d (85%)
6a (75%)
H
N
H
N
H
N
Br
iPr
5f (86%)
5g (90%)
5e (82%)
N
H
N
H
N
H
N
H
H
N
H
H
N
tBu
6e (55%)
6h (89%)
6g (58%)
N
F3C
6f (78%)
Reaction conditions: 1 (7 mol%, w.r.t. aniline), 2' (1 mmol), 3a (0.25
F3C
OH
5j (80%)
5ia (82%)
mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield)
5ha (87%)
H
N
H
N
H
N
Table 4. Substrate Scope for Heteroaromatic Amines or
Alcohols
NH
CN
5m (75%)
1 (7mol%), KOtBu
Toluene, 130 oC, 24 h
OH
+
NH2
5k (92%)
5l (90%)
Ar
Ar
N
Ar(het)
Ar(het)
H
Reaction conditions: 1 (7 mol%, w.r.t. amine), 2a (1 mmol), 3 (0.25 mmol),
2''
3'
7a-7d
KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield); a30 h
N
N
Succeeding with the diverse range of benzylic alcohols and
substituted anilines, we turned our attention to aliphatic
alcohols (Table 3). To examine whether our homogeneous
catalyst can also span the scope of aliphatic alcohols, we
screened a diverse range of this substrate. Encouragingly,
aminated products from isopropyl alcohol, cyclohexanol,
cyclopentanol, octanol and heptanol (6b-6d, 6f-6g) all were
successfully isolated in good to excellent yield. Additionally,
citronellol that is a renewable terpenoid and contains
unsaturation, smoothly alkylated aniline to give the aminated
product (6h) in 89% yield. This result is very inspiring since
it further supports the chemoselective nature of the
transformation. This methodology affords the presence of
reducible groups in the substrate and hints that nickel hydride
formation during β-hydride elimination from a nickel bound
alkoxide might not be happening (vide infra). Moreover, this
synthetic protocol is highly attractive since multiple noble
metal catalysts cannot be tolerant to unsaturated alcohols,24,
46that may be attributed to metal hydride generation during
the reaction.47, 48
N
N
H
N
N
H
H
7a (81%)
7b (66%)
7c (72%)
H
H
N
N
N
7da (87%)
Reaction conditions: 1 (7 mol%, w.r.t. mono-amine), 2'' (1 mmol), 3' (0.25
mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield);
a2'' (0.5 mmol), 36 h
Similarly, o- and p-phenylene diamine (Table 5) both were
converted to the respective product (8b-8c) in slightly lower
yield (52-53%). Intriguingly, when diols (8d, 8f) and even
triols (8e) were used as an alkylating agent the multiple
motifs were alkylating the respective amine in commendable
yields (74-92%). In essence, the screening of the substrate
scope can easily span the multifunctional amines and
alcohols resulting secondary amine products in good yield.
To diversify the scope of this N-alkylation protocol, we
further screened heteroaromatic amine and heteroaromatic
alcohol as substrates (Table 4). Interestingly, o-, m- and p-
Table 5. N-Alkylation of Diamines and Diol, Triol as Alkyl
Sources
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NH2
signal at g = 2.004. Simulation of the experimental EPR
1 (7mol%), KOtBu
Toluene, 130 oC, 24 h
OH
1
Aminated Product
8a-8f
spectrum suggests the triplet signal for a nitrogen centered
radical results from hyperfine coupling (15 Hz) with the
nitrogen nucleus. Coupling with the second nitrogen is very
small (~1-2 Hz), and we expect that the localized character of
the radical helps in hydrogen atom transfer (HAT) step during
alcohol oxidation. In essence, the g value and hyperfine
features of the EPR signal affirm that the reduction is fully
azo-based and a nitrogen centric radical is generated without
affecting the preferable oxidation state of Ni (+2).
NH2
+
2
3
2"'
3"
HO
4
5
H
N
NH HN
6
7
NH
HN
N
H
8
8b (53%)
8a (78%)
8c (52%)
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H
H
N
N
H
NH
N
H
N
8fa (92%)
8da (74%)
H
H
N
N
8eb (86%)
Reaction conditions: 1 (7 mol%, w.r.t. mono-amine), 2''' (1 mmol), 3''
(0.125 mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated
Figure 1. a) The LUMO of pre-catalyst 1 depicting
predominantly the π* of N=N, isosurface value is set to 0.02
(e.bohr-3)1/2 b) X-band EPR signal obtained from the singly
reduced product of 1
yield); 2''' (0.5 mmol) 3'' (0.25 mmol), 30 h; b 2''' (0.33 mmol) 3'' (0.25
a
mmol), 36 h
Mechanistic Consideration
Intuitively, the borrowed hydrogen from an alcohol will
remain stored in 1, and convert the azo to a hydrazo
functionality. To substantiate our claim that the azo motif,
when reduced, can be converted to hydrazo, we did a
stoichiometric control experiment. Reducing 1 in presence of
1 equivalent KOtBu and exposing the mixture to substrate
alcohol for 4 hours clearly evinced new proton resonance at
4.14 ppm. The integration of the peak is consistent with both
the nitrogen being hydrogenated resulting a hydrazo species.
As it will be proved later, this is an important intermediate
along the catalytic cycle and its isolation (IV’ in Figure 4,
We assume that the development of a well-defined
homogenous system will inarguably help to delineate the
mechanism for this N-alkylation reaction by HB. At first, to
prove homogeneous nature of the catalyst we performed
mercury drop test, and observed no inhibition of the reaction
or reduction of product yield. The redox non-innocence of the
azo motif is known for a long time which can undergo two-
electron redox in a reversible fashion.49 Our choice of the
ligand was motivated by the proximity of the azo
functionality to nickel, which can supposedly help in alcohol
dehydrogenation without the intermediacy of the relatively
unstable nickel hydride. In our HB protocol, KOtBu is
indispensable, and the same can reduce the azo-motif in the
backbone. Notably, role of KOtBu as a reductant has been
documented in earlier literature reports.50-52 An array of
control reactions proved that the reduced azo backbone is
extremely crucial for the success of the catalyst (see SI). In
agreement with the above proposition, use of reductant (Zn)
and base (KOH) in combination, can convert primary alcohol
to corresponding aldehyde and N-alkylated product catalyzed
by 1.
1
vide infra) and characterization by H, 13C NMR and IR
spectroscopies add valuable support to the postulated
mechanistic course.
To further understand the nature of intermediate formation
and to quantify the progress of reaction over time, the reaction
was stopped after 6 h and clear imine formation was observed
which conclusively prove that the species is a true
intermediate en route to subsequent hydrogenation. This
NMR experiment is additionally supported by GC/MS
probation during the reaction (Table S5, SI). After 6 h, imine
formation remains 36% while the amine is only slightly
formed (20%). Growth of the aminated product is lot higher
after 12 h, 52% which reaches a completion providing 86%
yield after 24 h. Thus, the reaction can be clearly dissected in
the sequence of alcohol dehydrogenation- condensation-
imine hydrogenation steps.
To investigate the most reduction-prone motif in the catalyst
molecule, we resorted on preliminary DFT calculations to
validate that the LUMO of 1 is π* orbital of N=N
functionality (Figure 1). Interestingly, one electron reduction
of 1 generated a burgundy colored paramagnetic material
which under X-band EPR analysis exhibited an isotropic
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Figure 2. Kinetic time profile of the alcohol oxidation (substrate equivalence variation). a) growth of oxidized product by UV-
Vis spectroscopy. b) rate constant calculation for a first order kinetics. (Reaction conditions: 1 (7 mol%), 2a (variable
concentration w.r.t. catalyst), KOtBu (0.25 mmol), toluene (10 mL), 130 oC.
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To examine the dependence of reaction rate on the catalyst
and substrate during benzyl alcohol oxidation, we studied the
rate of benzaldehyde formation as a function of both catalyst
loading and substrate equivalence variation. Increasing the
concentration of 1 over the range from (2.5 to 10 mol% with
respect to benzyl alcohol) displayed a linear increase in the
rate, kobs for the oxidation of alcohol (Figure S18). Moreover,
similar study to figure out the dependence of rate on the
substrate loading over a range of 80-140 times (with respect
to catalyst) further exhibits same linear dependence (Figure
2). From these set of experiments the rate law for the alcohol
dehydrogenation can be derived as rate = k[1][benzyl
alcohol] which further suggests the substrate remains bound
to the catalyst at the rate determining step.
Focusing only the hydrogenation step with a pre-synthesized
imine, shows the ratio of products 4a: 4a-d1: 4a-d2 as
25:44:31 (Scheme 2). The formation of some amount of 4a-
d2 strongly indicates the reversibility in the imine formation,
which can be partly responsible for the slower kinetics of
imination and imine hydrogenation reactions. In essence, the
obtained ratio of deuterated products starting from a
deuterium labelled alcohol is in consonance with the HB
method for N-alkylation step.23
4a
4a-d1
4a-d2
H/H = 16 %
H/D = 51 %
D/D = 33 %
H/D H/D
Ph
D
D
Optimized
condition
H2N
+
Ph
Ph
N
Ph OH
H/D
4a
4a-d1
4a-d2
H/H = 25 %
H/D = 44 %
D/D = 31 %
H/D H/D
Ph
D
D
H
Optimized
condition
+
Ph
N
Ph
Ph OH
Ph
N
H/D
To shed light on the imine hydrogenation step, we further
performed the kinetic run on a previously synthesized imine
in the presence of catalyst 1 and alcohol, and monitored the
growth of secondary amine by UV-Visible spectroscopy.
Likewise, amount of catalyst variation disclosed similar first
order dependence of the hydrogenated amine formation on
catalyst loading (Figure S20). As examined by the kinetic
studies for the entire reaction, imine hydrogenation step is
much slower compared to the alcohol oxidation part of the
reaction. Rate calculation of these steps with 7.5 mol % of 1
loading revealed the kobs = 2.5 x 10-3 s-1 for alcohol oxidation,
whereas the rate for imine hydrogenation was 5.5 x 10-5 s-1.
The rate comparison clearly corroborates with faster alcohol
oxidation and lot slower subsequent imine hydrogenation
step. The imine hydrogenation rate was also measured earlier
Scheme 2. Deuterium Labeling Experiments
To generate deeper insight regarding the mechanistic course,
we analyzed some of the key steps by preliminary DFT
computation (M06/Ni(Lanl2dz) and 6-31G* for C, H, N,
O).55 Interestingly, the alkoxide binding to the four-
coordinate nickel failed to reach convergence due to the
strong propensity of nickel for square planar geometry. We
realized during optimization of the intermediate, that one of
the phenolate arm of the ligand can be protonated, and
consequently be detached to reduce coordination, facilitating
substrate binding. Notably, a zinc-bound water has been
shown to protonate a phenolate arm augmenting detachment
of the ligand earlier.56 The incoming alkoxide now can bind
the nickel maintaining a slightly distorted square planar
geometry, where one of the azo ligand is mono-reduced. As
expected, in this intermediate (I, Figure 3) significant spin
density is observed on the nitrogen which is connected to the
phenolic ring (Figure S23). Computational isolation of the
intermediate I and subsequent HAT is fully consistent with
the 1st order dependence of the substrate from kinetic
experiments. Encouragingly, in I the β-hydrogen of the
bound alkoxide is properly oriented towards the nitrogen-
centric azo radical maintaining a distance of 2.58 Å.
by Bäckvall to be slow for Ru-based Shvo catalyst53, 54
.
To further unambiguously establish N-alkylation process as
HB, we conducted deuterium labeling experiments. Starting
from isotopically enriched PhCD2OH, deuterium
incorporation at N- benzylaniline product was evident. The
product distribution analysis by 1H NMR spectroscopy
uncovered the selective transformation to 4a-d1 along with
4a and 4a-d2 and displayed 51% deuterium incorporation at
the benzylic position of 4a-d1. Additional experiment with
imine hydrogenation with deuterated benzyl alcohol also
displays deuterium incorporation in the aminated product.
Notably, the distance between two termini during HAT has
a profound influence on the rate of hydrogen transfer, as has
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been revealed by Klinman during her study on enzymatic
computed N─H stretching values at 3301 and 3354 cm-1.60
models.57 Upon further search, we were able to locate the
Since radicals are involved in the reaction pathway, it is
expected that a radical quencher will inhibit the reaction.
Indeed, complete stoppage of the reaction was realized
when TEMPO was used in two equivalents. This fact also
strongly contradicts with any traditional metal-ligand
bifunctional mechanism in our system for alcohol oxidation
reaction, as radical intermediates are not to be invoked in
that case.
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transition state (TSI-II) for HAT that crosses an energy
ǂ
barrier (ΔG ) of 10.79 kcal mol-1 with respect to the
reference state, where all the reactants are infinitely apart.
In the TSI-II, the C---H and N---H distances (1.346 and
1.339 Å respectively) are almost similar (Figure 3b). When
the barrier is compared to the alkoxide-bound intermediate
I, the value is only 5.73 kcal mol-1. The low-energy barrier
associated with HAT suggests the process to be very
favorable once the reduced azo backbone finds the β-
hydrogen of nickel-bound alkoxide in the right alignment.
Inspired by this computational clue, we attempted further to
find experimental evidence for the HAT process. The
measured kH/kD for this step at 130 0C was found to be 6.8.
Such a large value implicates a tunneling of the hydrogen
atom might be operative and provides strong support for
HAT step during alcohol oxidation.58, 59 The resulting ketyl
radical upon this HAT is not stable on the potential energy
9
Intimate participation of the azo function in alcohol
oxidation reactions was first proposed by Markó using azo-
dicarboxylate as a cocatalyst61 and has been recently
scrutinized further by Sthal.62 Importantly, HAT from a
bound substrate to the reduced ligand backbone is a
hallmark of galactose oxidase (GO) chemistry and similar
events have been elegantly established in the synthetic
mimic of GO by Wieghardt et al.59 Our proposed
mechanism is significantly different from the traditional
metal-ligand bifunctionality observed in a large body of
systems. In such systems established by Shvo, Noyori,
Milstein, and Morris, a metal and nearby heteroatom work
in a cooperative fashion to primarily result a metal hydride
intermediate.63-66 In the present report, the strong
requirement of one-electron reduction of pre-catalyst,
isolation of the ketyl radical and IV’ along the catalytic
cycle, computational probation of the low-energy HAT
step, all oppose the conventional metal-ligand bifunctional
cooperative activation of a bond. This is a rare example
where a reduced ligand backbone plays a preponderant role
with some assistance from metal to accomplish this
important transformation and the azo-radical based HAT
contrasts the abundant examples of efficient catalysts for N-
alkylation reactions which largely involve metal hydride
generation.
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Figure 3. a) DFT optimized structure (tBu groups are
truncated to Me) of I, where the reduced azo group poses a
N---N bond length of 1.32 Å. b) Optimized TSI-II for HAT,
upon which a ketyl radical is transiently generated. All
hydrogens except chemically important ones are removed
for clarity.
Once the imine is formed by carbonyl and amine
condensation, the borrowed hydrogen from the alcohol
can hydrogenate it to result N-alkylated product. Likely,
the imine hydrogenation can follow a very similar
pathway to the alcohol oxidation process. A SET from IV
to the in situ generated imine is likely to form a benzylic
radical, which may undergo HAT from the hydrazo
fragment of the ligand. In close resemblance to the alcohol
oxidation component, detachment of the ligand phenoxide
arm to converting it to phenol is necessary to pave imine
binding to the nickel center. Imine binding to the nickel
center is crucial and also supported by the first order
dependence of this substrate from kinetic experiments
(Figure S20). Finally, protonation of the bound amide by
the phenolic arm engender the N-alkylated product, and
the resting state of the catalyst is back (Figure S21). Of
note, similar sequence of one-electron reduction followed
by HAT to reduce imine has been recently established by
Guo and Wenger.67 Although, we prefer the single-
electron reduction of the imine following HAT as a
plausible mechanistic scenario for imine hydrogenation,
under the current stage, hydrogen walk68 from the hydrazo
fragment to nickel cannot be fully discarded.
surface and an aldehyde formation was eminent, giving one
electron back to the unreduced azo-motif in the ligand, III.
In strong support to our conjecture that the ketyl radical
forms during catalytic cycle, we were able to trap the
intermediate in the form of a TEMPO adduct (Figure 4). In
our computation, the product aldehyde formation with
concomitant reduction of the second azo motif is
thermodynamically downhill by 12.73 kcal mol-1 with
respect to the reference state. So the presence of two redox-
active azo moieties ensure that nickel’s preferable oxidation
state (+2) is consistently preserved during the catalytic
cycle. Subsequently, the anionic azo motif is protonated by
the phenol, giving hydrazo intermediate IV, and nickel
regains the four-coordinate geometry from bis-
azophenolato ligand in a square planar environment. As
discussed earlier IV’ has been isolated and well
characterized with a battery of spectroscopic techniques. In
IR spectroscopic analysis, stretching frequency for the
N─H group was clearly observed at 3357 cm-1. This value
corroborates extremely well with the theoretically
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Figure 4. Plausible mechanistic scheme for the direct coupling of alcohol and amine to yield N-alkylated product
Conclusion
ASSOCIATED CONTENT:
In summary, we present a well-defined, homogeneous,
single-site catalyst comprising of a redox-active azo ligand
and base metal nickel which efficiently N-alkylate a variety
of amines with alcohols. As a distinct advantage, this
catalyst is highly stable and can be handled in aerobic
atmosphere. As an alkyl source, a diverse range of alcohol
has been used including aliphatic alcohols which are
challenging substrates even for noble metal catalysts. Our
catalytic protocol is tolerant to extensive functional groups
including cyano, nitro, hydroxy, methoxy, olefin and
efficiently perform N-alkylation in a chemoselective
manner. The ligand chosen for such base metal catalyst is
instrumental given its direct participation in the alcohol
oxidation step via HAT. Furthermore, azo to hydrazo
transformation is feasible which helps to store the borrowed
hydrogen and promotes its delivery to imines. Deuterium
labelling to the starting benzyl alcohol conclusively proves
the process to be classified as borrowing hydrogen method.
Isolation of some key intermediates along the catalytic cycle
unambiguously proves a radical is involved and the pathway
differs considerably from conventional metal-ligand
bifunctional mechanism in N-alkylation reactions. We
assume that the mechanistic understanding from such a well-
defined catalyst will further help in designing base-metal
catalysts for transfer hydrogenation reactions. Current
efforts in our laboratory focus on expanding the scope of N-
alkylation for other class of substrates and synthesizing
value-added heterocycles using this methodology.
Supporting Information:
The Supporting Information is available free of charge on
the ACS Publications website. Experimental procedure,
spectroscopic data, kinetic data, coordinates of computed
structures and NMR spectra for products.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for D.A.: adhikari@iisermohali.ac.in
NOTES
The authors declare no competing financial interests.
ACKOWLEDGEMENT
We thank SERB (DST), India (Grant No.
ECR/2017/001764) for financial support and IISER Mohali
for seed grant. AKB thanks IISER Mohali for a research
fellowship, AK thanks CSIR for junior research fellowship,
and SY thanks DST for an Inspire fellowship. The authors
sincerely thank Prof. Sanjay Singh for giving access to his
glove box.
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