Double Dehydrogenation of Primary Amines to Nitriles by a Ruthenium Complex Featuring Pyrazole Functionality

Article abstract of DOI:10.1021/jacs.8b05009

A ruthenium(II) complex bearing a naphthyridine-functionalized pyrazole ligand catalyzes oxidant-free and acceptorless selective double dehydrogenation of primary amines to nitriles at moderate temperature. The role of the proton-responsive entity on the ligand scaffold is demonstrated by control experiments, including the use of a N-methylated pyrazole analogue. DFT calculations reveal intricate hydride and proton transfers to achieve the overall elimination of 2 equiv of H₂.

Full text of DOI:10.1021/jacs.8b05009

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Communication
Double Dehydrogenation of Primary Amines to Nitriles by
a Ruthenium Complex Featuring Pyrazole Functionality
Indranil Dutta, Sudhir Yadav, Abir Sarbajna, Subhabrata
De, Markus Hoelscher, Walter Leitner, and Jitendra K. Bera
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jun 2018
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Double Dehydrogenation of Primary Amines to Nitriles by a Ruthe-
nium Complex Featuring Pyrazole Functionality
Indranil Dutta,† Sudhir Yadav,† Abir Sarbajna,† Subhabrata De,† Markus Hölscher,*,‡ Walter
Leitner‡,§ and Jitendra K. Bera*,†
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†Department of Chemistry and Center for Environmental Science and Engineering, Indian Institute of Technology
Kanpur, Kanpur 208016, India.
‡Institut für Technische und Makromolekulare Chemie, RWTH Aachen University, Worringerweg 2, 52074 Aachen,
Germany.
,
‡ §Max Planck Institute for Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mülheim an der Ruhr, Germany.
Supporting Information Placeholder
activation is reliant on the basicity of the proton responsive
ABSTRACT:
naphthyridine-functionalized pyrazole ligand catalyzes
oxidant-free and acceptorless selective double
dehydrogenation of primary amines to nitriles at moderate
temperature. The role of the proton responsive entity on the
ligand scaffold is demonstrated by control experiments
including the use of a N-methylated pyrazole analogue. DFT
calculations reveal intricate hydride and proton transfers to
achieve the overall elimination of two H2 equivalents.
A
ruthenium(II)
complex
bearing
unit.12 Kuwata and Ikariya have exploited metal-ligand coop-
eration strategy utilizing metal/pyrazole systems for bifunc-
tional substrate activation.13 An intramolecular hydroamina-
tion reaction proceeds via nucleophilic attack of the amine to
an iridium-coordinated olefin promoted by a pyrazolato lig-
and through secondary interactions (Scheme 1a).13c,e This
prompted us to incorporate a β-protic pyrazole moiety on a
naphthyridine scaffold. A ruthenium complex containing a
naphthyridine-pyrazole ligand was synthesized that was
found to be an excellent catalyst for selective dehydrogena-
tion of various primary amines to nitriles, without requiring
oxidant or acceptor. The essential role of the β-protic center
is demonstrated by using an analogous N-methylated pyra-
zole complex. In contrast to direct amine deprotonation
(Scheme 1b) that one may initially envision, DFT calculations
suggest that Nβ facilitates intricate proton/hydride transfer
in the catalytic double dehydrogenation pathway.
Nitrile is an important functionality in organic synthesis.
Natural products, bio-active molecules, and industrially rele-
vant compounds have abundant presence of nitriles.1 Com-
mon methodologies for nitrile syntheses include Sandmeyer
reaction, ammoxidation, oxidation using hypervalent iodine-
based compounds and transition metal catalyzed oxidations,
among others.2,3 However, these conventional methods often
suffer from limited reactivity, poor atom economy, harsh
reaction conditions and narrow functional group tolerance.
Scheme 1. β-Protic Pyrazole for Amine Activation.
An alternative nitrile synthesis protocol involves transition
metal catalyzed double dehydrogenation of primary amines.
Brookhart reported an Ir pincer catalyst for amine dehydro-
genation in the presence of stoichiometric hydrogen accep-
tor.4 Other known catalysts are either low yielding5 or require
exogenous additives under harsh conditions.6 Further, com-
petition between second dehydrogenation and transamina-
tion pathway invariably leads to the loss of selectivity.7 We
are aware of only one report from Szymczak group who em-
ployed a NNN-Ru(II) hydride complex for oxidant-free and
acceptorless selective conversion of primary amines to ni-
triles.8 An inner-sphere mechanism involving proton transfer
from a coordinated amine (or imine) to Ru-hydride followed
by H2 release was proposed.9 Although alcohols are readily
dehydrogenated by numerous bifunctional catalysts,9,10 lig-
and-promoted amine dehydrogenation remains a difficult
task to accomplish. The higher nucleophilic character of the
amines and energetically unfavorable β-H elimination step
are the principal challenges to be overcome for amine dehy-
drogenation.11 Designing a bifunctional catalyst for amine
A pyrazole unit was attached to 1,8-naphthyridine (NP)
scaffold by
a
multistep synthesis starting from 2-
aminonicotinaldehyde (Scheme S1). Treatment of pzH-NP
(L1) with [Ru(p-cymene)Cl2]2 (2:1 molar ratio) in 2-propanol
afforded [Ru(p-cymene)(L1)(Cl)]Cl (1) in 81% yield. The mo-
lecular structure of 1 is shown in Figure 1. The pyrazole NH
shows interaction with the counter anion chloride
(N4H4A···Cl2 = 2.123 Å) implying the Brønsted acidic nature
of the pyrazole proton.13d ESI–MS revealed a signal at m/z
523.1200 for [1–Cl]+ (Figure S7). The pyrazole hydrogen ap-
pears downfield at δ 10.19 ppm.
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termediate is preferred over a competitive transamination
1
[Ru(p-cymene)Cl2]2
+
L
1
2
3
4
5
6
7
8
reaction (Scheme S8, Figure S25). Conversion of primary
amines to nitriles is accompanied by the release of two mole-
cules of hydrogen, which was identified by GC (thermal de-
tector) and quantified on a gas buret set up (Figures S21-23).
Styrene hydrogenation to ethylbenzene in the presence of
Wilkinson catalyst further confirmed molecular hydrogen as
the by-product.15,16
iPrOH, rt
Cl
N
N
NH
N
Ru
Cl
1
Table 1. Amine Dehydrogenation Catalyzed by 1.a,b
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Figure 1. Synthesis of 1. Molecular structure of 1 is depicted
in the inset.
Initial attempt towards acceptorless dehydrogenation of p-
methylbenzylamine (p-MBA) using 2 mol% catalyst 1 in the
presence of 10 mol% KOtBu at 70°C afforded p-
methylbenzonitrile exclusively in 89% yield after 24 h (Table
1). A slow stream of nitrogen gas was allowed to pass through
the reaction vessel to drive away the produced hydrogen
gas.8 Performing the reaction in a sealed tube (closed system)
led to a substantial reduction in the yield (42%). The reaction
was hindered in the absence of base (Table S2). Optimization
studies showed that KOtBu and toluene were the best
combinations among a variety of bases and solvents. The
reaction temperature was maintained at 70°C to achieve op-
timized yields. The homogeneity of the reaction medium was
confirmed by mercury addition experiments.14
9 R = H (42%)
1 R = H (84%)
10 R = 4–OCH3 (49%)
2 R = 4–OCH3 (92%)
11 R = 4–NO2 (37%)
3 R = 4–CH3 (89%)
4 R = 4–Cl (80%)
5 R = 4–NO2 (78%)
6 R = 3,5–NO2 (72%)
12 (73%) 13 (76%) 14 (52%)
7 R = 2–CN (76%)
8 R = 4–CN (77%)
Substrate scope for various amines was examined under
optimized reaction conditions (Table 1). Benzylamine and its
electron rich derivatives afforded the corresponding nitriles
(84-92%, entries 1-3) in excellent yields. Electron deficient
benzylamines gave slightly lower yields (72-80%, entries 4-6).
Position of substituent (o- or p-) on the aromatic ring did not
show any significant effect on the product formation (entries
7-8). Dehydrogenation of 2-phenethylamine afforded
moderate yield of 2-phenylacetonitrile (42%, entry 9), an
important precursor for pharmaceuticals.1c For p-substituted
phenethylamines, electron-donating methoxy group gave
relatively higher yield (49%, entry 10) than an electron with-
drawing nitro derivative (37%, entry 11). Heterocyclic amines
afforded the corresponding nitriles in good to moderate
yields (52-76%, entries 12-14). The scope of 1 was further
extended for aliphatic amines. Long chained amines afforded
the corresponding nitriles in excellent yields (87-93%, entries
15, 16). Oleylamine gave oleonitrile in 76% yield (entry 17)
where the double bond remained unaffected. Cyclohex-
anecarbonitrile (81%, entry 18) and butyronitrile (65%, entry
19) were also obtained from their amine derivatives. Aliphatic
diamines were employed to access the corresponding dini-
triles (54-72%, entries 20-22). p-Aminobenzylamine was
converted to p-aminobenzonitrile (85%, entry 23) keeping
the aromatic amino group intact, which demonstrates
chemoselectivity of 1. Oxidative dehydrogenation of second-
ary amines affords a mixture of products that include imine,
aldehyde and alcohol.3j-m Catalyst 1, to our delight, afforded
the selective imine products for dibenzylamine and bis(4-
methylbenzyl)amine (53-57%, entries 24, 25). Heterocyclic
amine indoline was converted to indole in high yield (88%,
entry 26).
15 x=11 (93%)
18 (81%)
23 (85%)
16 x=14 (87%)
19 (65%)
17 (76%)
20 x=1 (54%), 21 x=2
(58%), 22 x=6, (72%)
24 R = H (53%), 25 R = CH3 (57%)
26 (88 %)
aReaction conditions: 0.5 mmol amine, 1 (2 mol%), KOtBu
(10 mol%), toluene, 70°C, 24 h. bYields are determined by GC–
MS using dodecane as internal standard.
Scheme 2. Modified Catalysts and Their Activities for
p-MBA Dehydrogenation.
Cl
Cl
N
N
N
N
N
N
N
N
N
NH
N
CH3
Ru
Ru
Ru
Cl
Cl
Cl
4
3
2
Additive: KOtBu
Yield: 19%
Additive: TlPF6
Yield: 84%
Additive: KOtBu
Yield: 61%
Catalyst 1 was designed to exploit proton responsive β-NH
for dehydrogenation. To verify its participation, the perfor-
mance of an analogous N-methyl complex [Ru(p-
cymene)(L2)(Cl)]Cl (2) was examined.17 Complex 2 showed
Since imine or imine derivatives were not detected during
primary amine dehydrogenation, it can be safely assumed
that a second dehydrogenation of short-lived aldimine in-
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poor activity (19% p-methylbenzonitrile) (Scheme 2) for the
defining the lowest point in the catalytic cycle (TDI 1). A di-
rect amine deprotonation by Nβ was attempted but a rele-
vant intermediate within a realistic energy span could not be
obtained. Instead, one of the amine molecules rearranges
from N− to C−H type coordination (IV) to ruthenium, which
necessitates the dissociation of the second amine.21 The ru-
thenium centre receives the hydride to form VI with an acti-
vation barrier of 27.1 kcal/mol. The protonated aldimine then
transfers a proton to a molecule of p-MBA through the in-
volvement of pyrazolato β-N (VII) to give IX. Computing a
pathway from VI to IX without involving a second amine
either results in energy barriers far too high to make such a
pathway realistic or the appropriate transition states could
not be localized. In principle, the first dehydrogenative
pathway could involve proton transfer to the Nβ of the ligand
backbone and H2 could be eliminated from XIX (Scheme
S10). However, the Gibbs free energy of the corresponding
transition state (XX, 41.0 kcal/mol) is way too high (67.7
kcal/mol relative to III) to be overcome.22 Instead, the first
dehydrogenation occurs from XII via ammonium-mediated
protonation of the Ru-H moiety (TS XIII, 4.0 kcal/mol; over-
all barrier height relative to III = 30.7 kcal/mol, TDTS 1). As
the reaction is conducted in an open flask, liberated H2 is
driven away from the system resulting in complex III, which
can be considered as the starting point for the second dehy-
drogenation. The imine hydrogen and carbon-bound hydro-
gen of the cis-aldimine23 are transferred to an amine mole-
cule and Ru (XIV), respectively, through a concerted transi-
tion state (XV, 11.1 kcal/mol, TDTS 2) generating the nitrile
with an activation barrier of 28.0 kcal/mol.
1
2
3
4
5
6
7
8
model reaction strongly suggesting the vital role of the β-NH
in the dehydrogenation process. To further check the in-
volvement of the pyrazolato complex in the catalytic path-
way, a neutral complex 3 was synthesized by the treatment of
1 with Et3N in benzene.17 Under base-free condition, and in
the presence of 5 mol% TlPF6, catalyst 3 showed comparable
activity (84% vs 89% for 1).18 The pyrazolato form of 1, there-
fore, is most likely the active catalyst. An analogous pyridine
complex [Ru(p-cymene)(L3)(Cl)]Cl (4) was also synthesized.17
Even with increased catalyst loading (5 mol%), 4 showed
reduced activity compared to 1 (61% vs 89%). Hence, we pur-
sued the amine dehydrogenation reactions with 1.19
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The initial rate of the dehydrogenative oxidation reaction
was monitored (up to ~10-15% conversion) to determine the
reaction order with respect to amine. Increasing the concen-
tration of p-MBA results in an increase in rate with a linear
dependency, up to a certain point, after which increase in [p-
MBA] shows zero-order dependency (Figure S26). The ob-
served saturation kinetics implies a pre-equilibrium step, and
the overall reaction is driven forward in the presence of ex-
cess amine.9
The effect of temperature on the reaction rate was studied,
and activation parameters were determined from ln(k/T) vs
1/T plots (Figure S27-28). A high negative ΔS⧧ value (−20.03 ±
0.56 cal mol–1 K–1) is indicative of an organized and associa-
tive transition state involving substrates and the catalyst. The
Gibbs energy of activation (ΔG⧧) was estimated to be 26.2
kcal/mol at reaction temperature. Further, a Hammett plot
was constructed using electronically disparate amine deriva-
tives (Figure S29). A plot of the relative rates (log(KX/KH))
against the substituent constant σ yielded a fairly good linear
relationship following the reactivity trend p-OMe>p-CH3 >p-
H >p-Cl >p-NO2. An observed negative ρ value of −1.22 sug-
gests that the reaction should be favored by electron rich
substrates, which is in agreement with substrate activities
(Table 1).20 However, when log(KX/KH) was plotted against
standard σ+ values, linearity could not be obtained.20a,b These
observations indicate that the turnover limiting transition
state of the reaction has a partial positive charge deployment
over the entire system which points to a concerted mecha-
nism.
NH2
+
Ru Nβ
+
Nβ
+
tBu
N Nβ
NH2
Nβ
+
Nβ
Ru
Ru
H
N
H2N
NH2
N
Ru
+
Ru
H
NH2
NH2
NH2
II
III
-26.7
TDI 1
IV
-2.4
-20.5
I
+
Nβ
0.0
Ru
H
Ru Nβ
H
+
+
trans-aldimine
N
H
Nβ
NH2
Ru Nβ
Ru
β
+
Ru
H
N
NH3
TS
H
H
H
H
N
H
+
H
IX
+
-8.4
NH2
N
H
NH2
VI
-5.9
V
0.4
VII
-9.5
See Scheme S10
NH2
+
Ru
Nβ
X
H
H
cis-aldimine
XIX -2.6
H
H
N
NH2
N
H
+
Ru Nβ
+
Nβ
H
Comparing the reaction rate of PhCH2NH2 in toluene and
PhCD2NH2 in toluene-d8 showed a kinetic isotope effect
(KIE) of kC–H/kC–D = 1.52 ± 0.04 (Figure S30). When
PhCD2ND2 was used as a substrate, the rate of reaction was
3.91 ± 0.02 times slower than with PhCH2NH2 and 2.57 ± 0.03
times than with PhCD2NH2. These data indicate that cleav-
age of the N−H bond during the hydrogen elimination has a
transition state with more direct influence on the overall rate
than cleavage of the C-H bond.
H2
TS
Ru
H
Ru Nβ
H
+
H
H2
N
NH2
H
2N
H3
N
H2N
NH2
dimine
to cis-al
trans
See
XIII
4.0
TDTS 1
III
XII
-10.4
S11
Scheme
-16.9
TDI 2
+
Nβ
H2
+
+
Ru
H
Nβ
Ru Nβ
Ru
TS
H
N
H
H
H
H2N
NH2
H
N
N H
NH2
N
N
H
XIV
10.7
III
-12.3
XV
11.1
TDI 1
TDTS 2
To further obtain insight about the reaction mechanism, a
DFT study (B97D3-BJ/def2-TZVP, IEF-PCM(SMD)) was car-
ried out for substrate p-MBA. Computed reaction pathway is
shown in Figure 2 (see Scheme S9 for complete cycle). Given
the experimentally used activation method for 1 (KOtBu),
and comparable activity of 3/TlPF6 as well, it is plausible to
assume the species available in solution prior to enter the
catalytic cycle to be the dechlorinated (at Ru) and
deprotonated (Nβ) cationic complex I, which exergonically
can bind one (II, ꢀG = −20.5 kcal/mol, Table S7) and even
two (III, ꢀG = −26.7 kcal/mol) molecules of p-MBA, with III
Figure 2. Computed reaction mechanism showing double
dehydrogenation of p-MBA. For full cycle, see Scheme S9.
Gibbs free energy values are in kcal/mol.
In conclusion, we herein report a cooperative Ru/pyrazole
system for selective dehydrogenation of a wide range of pri-
mary and secondary amines to nitriles and imines, respec-
tively, at a moderate temperature, without requiring oxidant
or hydrogen acceptor. Catalyst 1 exhibits wider substrate
scope, operates under milder reaction condition and displays
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dy, B.; G. F. Shoair, A.; Suriaatmaja, M.; J. P. White, A.; J. Williams,
higher activity compared to other known systems. The poor
yield obtained for a related N-methylated pyrazole complex
confirms the vital role of the protic ligand in the dehydro-
genation reaction. Kinetic isotope studies suggest that N−H
bond cleavage during the hydrogen elimination has a direct
influence on the overall rate. DFT calculations reveal intri-
cate hydride and proton transfer aided by the pyrazolato β-
N. Insights gained in this work should pave the way to devel-
op new generation dehydrogenation catalysts based on pro-
ton responsive pyrazole ligands.
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ASSOCIATED CONTENT
Supporting Information
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AUTHOR INFORMATION
Corresponding Author
jbera@iitk.ac.in
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work is financially supported by the DST and DAE,
India. I.D. and S.Y. thank CSIR, India and S.D. thanks IIT
Kanpur for fellowships. This work is dedicated to Professor
Vadapalli Chandrasekhar on the occasion of his 60th birth-
day.
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ethylbenzene in the second flask after the completion of the reaction
demonstrates that hydrogen gas is generated during the ADD of
amine (Figure S24).
(17) See ESI for detailed synthesis and X-ray characterization of 2, 3
and 4.
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(18) The use of TlPF6 was warranted to remove the chloride from
metal coordination sphere, without which the conversion was only
14%.
(19) The rationale to use naphthyridine-functionalized ligand was to
introduce a free N atom on the ligand architecture, situated close to
the metal center, to promote hydration reaction. We envisaged that
the product nitrile could be subsequently hydrated to the amide by
the same catalyst utilizing naphthyridine-N8 via a tandem dehydro-
genation-hydration. See ESI for details.
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(20) (a) Hansch, C.; Gao, H. Chem. Rev. 1997, 97, 2995–3059. (b)
Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195. (c) Daw,
P.; Petakamsetty, R.; Sarbajna, A.; Laha, S.; Ramapanicker, R.; Bera, J.
K. J. Am. Chem. Soc. 2014, 136, 13987−13990. (d) Michel, B. W.;
Steffens, L. D.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 8317−8325.
(21) While the formation of III is inevitable energetically at this stage
of the reaction, one of the two amines of III must dissociate to create
the necessary spatial requirements needed to travel to transition
state V from IV.
(22) Even when tunneling corrections are applied, barrier height is
53.2 kcal/mol.
(23) Computed pathway for barrier-less trans- to cis−aldimine is
shown in Scheme S11.
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