CO2-Catalyzed Efficient Dehydrogenation of Amines with Detailed Mechanistic and Kinetic Studies

Article abstract of DOI:10.1021/acscatal.8b03059

CO₂-catalyzed dehydrogenation of amines has been achieved under photocatalytic conditions. With this concept, various amines have been selectively dehydrogenated to the corresponding imines in the presence of different functional groups such as nitrile, nitro, ester, halogen, ether, thioether, and carbonyl or carboxylic acid moieties. At the end, the CO₂-catalyzed synthesis of pharmaceutical drugs has been achieved. The CO₂ radical has been detected by EPR spectroscopy using DMPO, and the mechanism of this reaction is proposed on the basis of DFT calculations and experimental evidence.

Full text of DOI:10.1021/acscatal.8b03059

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Article
CO2-Catalyzed Efficient Dehydrogenation of Amines
with Detailed Mechanistic and Kinetic Studies
Daniel Riemer, Waldemar Schilling, Anne Goetz, Yu Zhang,
Sascha Gehrke, Igor Tkach, Oldamur Hollóczki, and Shoubhik Das
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03059 • Publication Date (Web): 29 Oct 2018
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ACS Catalysis
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CO2-Catalyzed Efficient Dehydrogenation of Amines with Detailed
Mechanistic and Kinetic Studies
Daniel Riemera, Waldemar Schillinga, Anne Goetza, Yu Zhanga, Sascha Gehrkeb, Igor Tkachc, Oldamur
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Hollóczkib, Shoubhik Dasa*
aInstitut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttin-
gen, Germany.
bMulliken Center for Theoretical Chemistry, Institut für Physikalische und Theoretische Chemie, Universität Bonn, Bering-
straße 4+6, 53115 Bonn, Germany.
cResearch Group EPR Spectroscopy, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen,
Germany.
ABSTRACT: CO2-Catalyzed dehydrogenation of amines has been achieved under photocatalytic conditions. With this concept,
various amines have been selectively dehydrogenated to the corresponding imines in the presence of different functional groups
such as nitrile, nitro, ester, halogen, ether, thioether, carbonyl or carboxylic acid moieties. At the end, the CO2-catalyzed synthesis
of pharmaceutical drugs has been achieved. The radical anion from CO2 has been detected by EPR spectroscopy using DMPO and
the mechanism of this reaction is proposed on the basis of DFT calculations and experimental evidences.
KEYWORDS: amines • imines • CO2 • dehydrogenation • photocatalysts • metal-free
INTRODUCTION
way of alcohol oxidation. High temperature or higher base
loadings and screening of different bases did not improve the
formation of imine. We rationalized that under operationally
simple photocatalytic conditions, CO2 can be transformed into
radical species (namely, carbon dioxide radical anion or
hydroxycarbonyl radical species) and that should enhance this
reaction.[8] In this regard, it should be noted that the generation
of these radical species from CO2 requires special equipment
or strict reaction conditions.[9] However, small organic
molecule such as pyridine trapped these radicals under mild
electrochemical and photochemical conditions and finally
were applied these into hydrocarbon-based fuel synthesis.[8]
Inspired by this, we became interested to use small organic
molecules (pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-
diazabicyclo[4.3.0] non-5-ene etc.) as trapping agents under
photocatalytic conditions.[10]
CO2 is an easily available and sustainable carbon resource that
is nontoxic, nonflammable and renewable.[1] However, its high
thermodynamic stability and kinetic inertness apply strict
conditions for further applications. So far, CO2 has been
thermally, electrochemically and photochemically reduced to
formic acid, formaldehyde, methane, CO etc.[2] Reactive
substrates such as epoxides, alcohols, amines, alkynes, alkenes
and others formed new C-O, C-N, and C-C bonds utilizing
CO2 as a C1 source.[1,3] Strong efforts are also paid to
synthesize carboxylic acids and their derivatives via C-H bond
functionalizations or C-X bond transformations.[4] Parallel to
these, utilizing CO2 as a catalyst or as a mediator for chemical
transformations is flourishing rapidly as toxic chemicals can
be replaced in this way. Using this concept catalytic
rearrangement of propargyl alcohols into α,β-unsaturated
ketones, C–H bond arylation reactions, allylation via cross-
coupling reactions, asymmetric allylation reactions of ketones,
oxidative dehydrogenation of alkanes and alkyl aromatics, etc.
have been achieved.[5]
Our main interest was to find a metal-free photocatalyst as
they have shown prior activity in CO2-based transformations
towards hydrocarbon fuels and indeed these catalysts are non-
toxic, cheaper in price and commercially available.[11]
Additionally, metal-free catalysts are more interesting for the
pharmaceutical industries due to the easier purifications and to
avoid toxic residues in the final product. Traditional methods
for the dehydrogenation of amines to imines usually rely on
(over-) stoichiometric amount of oxidants such as DDQ, sulfur
or peroxides, high temperature, expensive noble or rare earth
metals and exhibit poor functional group tolerances.[12]
Catalytic methods are also known however requires expensive
transition metals such as supported Au catalysts or
homogeneous Pd-, Rh-, Ru- or Co-based catalysts, and
(over)stoichiometric amount of additives.[7g,13] Considering all
Inspired by these, we have also discovered the CO2-catalyzed
oxidation of benzylic and allylic alcohols which replaced toxic
promoters known for alcohol oxidation by CO2.[6] To extend
this concept, we became keen on finding suitable catalysts for
the dehydrogenation of amines. In general, imines are highly
important functional groups and have shown wide applications
in organic syntheses, pharmaceutical chemistry, agrochemistry
and many more.[7] Moreover, imines can also be used as
intermediates for further syntheses of natural products and
others.
However,
our
efforts
for
CO2-catalyzed
dehydrogenation of amines to imines did not work in the same
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thsese facts and to develop our own interest to promote CO2- carboxylic acid ester (7a), boronic acid ester (8a), nitro (9a),
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catalyzed reactions, herein we describe metal-free CO2-
catalyzed dehydrogenation of amines to imines.[14]
nitrile (11a) and hydroxyl (12a) groups were well tolerated
and dehydrogenated with an excellent yield. In addition to
these, electron-donating (2–5a) and electron-withdrawing
groups (9–11a) or both of them in a single molecule (6a)
reacted excellently under the optimized reaction conditions.
Moreover, the catalyst was able to dehydrogenate an aliphatic
benzylic amine (13a) to the corresponding imine in an
excellent yield under optimized reaction conditions. It should
be noted that compound 4b and 6b have been used as
intermediates for the syntheses of pyrrolidinone and
piperidinone derivatives for urokinase receptor binding
studies.[15] Additionally, acyclic imines (13 b) can be used for
the synthesis of artificial amino acids.[16]
RESULTS AND DISCUSSION
At the outset of our investigations, different metal-free
photocatalysts were applied to optimize the reaction
conditions with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as
trapping agent and dimethyl sulfoxide (DMSO) as solvent for
the transformation of benzyl aniline to benzylidene aniline
(Table S1). The reaction took place under CO2 balloon and at
room temperature under 12 W LED blue visible-light
irradiation. Four different photocatalysts such as fluorescein,
rose bengal, 9,10-dicyanoanthracene and eosin Y were
investigated for this reaction and among them, eosin Y
exhibited 45% yield of the benzylidene aniline. Further
screening of different trapping agents resulted in 70% yield of
the desired product in the presence of 1,5-diazabicyclo
[4.3.0]non-5-ene (DBN). Increasing the DBN amount from 1.0
to 1.2 equivalents (eq.) finally raised the yield to 86% within
24 h. Expediently, this dehydrogenation reaction was also
possible in the presence of catalytic amount of CO2 (20 mol%)
with slightly lower yield compared to the optimized reaction
conditions.
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Reaction conditions: Substrate (0.134 mmol), eosin
Y
(3 mol%), DBN (1.2 eq), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, r.t., 48 h. All are isolated yields.
Scheme 2. Substrates scope for the CO2-catalyzed dehydro-
genation of cyclic amines
After successfully dehydrogenating the acyclic amines, we
became interested in cyclic amines (Scheme 2, 14a–23a). In
case of 1,2,3,4-tetrahydroisoquinoline derivatives, catalyst was
able to dehydrogenate substrates bearing electron-withdrawing
(15–16a) as well as electron-donating groups (17–18a) to the
corresponding 3,4-dihydroisoquinoline derivatives in high
yields. In case of 2-phenyl-2,3-dihydro-quinoxaline derivative
(20a), formation of the doubly dehydrogenated product was
observed in quantitative yield. We believed that the driving
force for this reaction was the aromatization to the conjugated
π-system of the product. In addition to these, different ring
size (19a) and condensed ring systems (21–22a) reacted in
good to high yields. Under this condition, an amide group was
also tolerated (Scheme 2, 23a). Finally, we became interested
to dehydrogenate 1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]
iso-quinolin-4-one (Scheme 3) and we were pleased to
observe the dehydrogenation of the C–C bond between 1- and
2-position in good yield. It is noteworthy that in none of the
cases any byproduct or further dehydrogenation to the
isoquinoline derivative was observed. Traditionally, these
imines can be synthesized by the Bischler-Napieralski reaction
employing toxic POCl3 in stoichiometric amount. Compared
Reaction conditions: Substrate (0.134 mmol), eosin
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, r.t., 48 h. All are isolated yields.
Y
Scheme 1. Substrates scope for the CO2-catalyzed dehydro-
genation of acyclic amines
With these optimized reaction conditions in hand, we
investigated a plethora of acyclic amines to dehydrogenate to
the corresponding imines (Scheme 1, 1a–13a). To our delight,
benzyl anilines bearing different functional groups were
successfully converted to their corresponding imines in good
to excellent yields. For example, thioether (3a), alkynyl (5a),
to this, CO2-catalysed methodology provide
a simple,
environment friendly and less toxic route with a metal-free
way to this widely applicable imines. Additionally, partially
dehydrogenated 3,4-dihydroisoquinoline derivatives have been
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ACS Catalysis
the formed 5- and 6-membered ring (Scheme 6). This
used for the syntheses of isoquinoline alklaoids such as 18b
has been used in the synthesis of berine.[17]
condensation reaction is known to proceed at room
temperature within 24-60 h.[20] However, under our reaction
conditions the condensation was not only proceeded within
16 h but was also able to attain high yields of the in situ
dehydrogenated products from 4-methylbenzaldehyde, furfural
and isonicotinaldehyde (36a – 38a).
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Reaction conditions: Substrate (0.134 mmol), eosin
Y
7
8
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, r.t., 48 h; isolated yield.
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Scheme 3. Dehydrogenation of 1,2,3,6,7,11b-hexahydro-4H-
pyrazino[2,1-a]isoquinolin-4-one
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Since indole derivatives are important structural motifs found
in many natural products (e.g. tryptophan and tryptamine
alkaloids) and drug molecules (e.g. indometacin), our efforts
were also paid to dehydrogenate a variety of indoline
derivatives to achieve corresponding indole derivatives
(Scheme 4, 25a–31a).[18] Unsubstituted indoline (25a) reacted
excellently and 79% of indole was isolated. In addition to this,
substituted indoline derivatives (26a–30a) gave excellent
yields of more than 90%. The catalyst was also tolerant
towards carboxylic acid group (29a) and heteroaromatic
indoline derivatives (30a–31a). No other by-products were
identified in these reactions and in case of 30a, we observed
the double dehydrogenation to attain the aromaticity in the
product.
Reaction conditions: Substrate (0.134 mmol), eosin
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, r.t., 16 h. All are isolated yields.
Y
Scheme 5. CO2-catalyzed syntheses of poly-substituted pyri-
dine derivatives
Reaction conditions: Substrate (0.134 mmol), eosin
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, r.t., 16 h. All are isolated yields.
Y
Reaction conditions: Substrate (0.134 mmol), eosin
Y
Scheme 6. Condensation of diamines and aldehydes and in
situ oxidation to the heteroaromatic derivatives
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, r.t., 48 h. All are isolated yields.
Scheme 4. Substrates scope for the dehydrogenation of indo-
line derivatives to indole derivatives
Finally, we became keen on finding applications of this CO2-
catalyzed metal-free dehydrogenation reactions towards
pharmaceutical molecules. For this purpose, we were
The aromatization of Hantzsch ester-type molecules is also
important to synthesize poly-substituted pyridine derivatives.
Ideally, these Hantzsch ester-type molecules can be
synthesized via condensation reactions and further
dehydrogenation to these should generate desired pyridine
derivatives (Scheme 5, 32a–35a).[19] Therefore, we examined
our catalyst for the dehydrogenation of these types of
molecules and to our delight, ethyl (32a) and tert-butyl ester
(33a) as well as others (34a–35a) have shown excellent
reactivity and quantitative products were isolated after 16 h of
the reaction.
interested to synthesize harmine (39b),
a well-known
monoamine inhibitor which also possesses anti-HIV and anti-
tumor active properties.[21] Our interest was also to synthesize
dehydronifedipine (40b), an active metabolite (metabolized by
the cytochrome P450 isomers CYP3A4 and CYP3A5) and the
actual active agent for anti-hypertensive treatment.[22] In fact,
our catalyst selectively synthesized these two drugs up to 74%
yield using catalytic amount of CO2 (20 mol%) (Scheme 7).
After developing excellent substrates scope, we investigated
the
reaction
mechanism
of
this
CO2-catalyzed
dehydrogenation reaction. Initially, we carried out control
experiments of the model substrate with radical quenchers
(Table 1). To our delight, the reaction showed lower activity
under oxygen and nitrogen atmosphere. The reaction did not
Additionally, the catalyst was able to show the condensation
of aromatic diamines with aldehydes under our optimized
conditions with an in situ dehydrogenation/aromatization of
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show any activity without the presence of light source, base or
the catalyst which clearly depicted distinct role of CO2,
catalyst, base and light source in this reaction. Inactivity under
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Reaction conditions: Substrate (0.134 mmol), eosin
Y
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), 12 W blue LED, r.t.,
16–40 h. All are isolated yields: aCO2 balloon, b20 mol% CO2.
Scheme 7. CO2-catalyzed synthesis of harmine and dehydroni-
fedipine drug molecules
Description of different spectra: (a) N2 atmosphere,
O2 atmosphere ruled out that traces of oxygen in the reaction
could be the actual oxidant. Furthermore, different radical
quenchers such as butylated hydroxytoluene (BHT) and
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) showed low
to no activity (Table 1, entries 6–9) which indicated a radical
pathway. The reaction was also quenched in the presence of
benzoquinone which could be because of the presence of
carbon dioxide radical anion as there was no presence of
oxygen in the system.[23]
DMPO/DMSO (54 mM), no light; (b) N2 atmosphere,
DMPO/DMSO (54 mM), eosin Y (3 mol%), DBN (1.2 eq.), sub-
strate (0.134 mmol), blue LED light (18 h); (c) 12CO2 atmosphere
(balloon), DMPO/DMSO (54 mM), eosin Y (3 mol%), DBN
(1.2 eq.), substrate (0.134 mmol), no light; (d) 12CO2 atmosphere
(balloon), DMPO/DMSO (54 mM), eosin Y (3 mol%), substrate
(0.134 mmol), DBN (1.2 eq.), blue LED light for 18 h; (e) 13CO2
atmosphere, DMPO/DMSO (54 mM), eosin Y (3 mol%), sub-
strate (0.134 mmol), DBN (1.2 eq.), blue LED light for 18 h. The
distinctive hf-lines of 12CO2- and 13CO2-centered subspectra in d)
and e) are marked by stars. Experimental conditions: Bruker
ElexSys E500 CW/Transient X-band EPR spectrometer equipped
with the Bruker SHQ (ER4122 SHQE-W1) resonator, microwave
frequency 9.87 GHz, microwave power 20 mW, field modulation
1 G, receiver gain 60 dB; conversion time 5.18 ms, number of
averaged scans 400 and 81 for (a)-(c) and (d)-(e), respectively.
Table 1. Mechanistic experiments: different CO2 amounts and
control experiments
Chart 1. X-band EPR and background spectra of DMPO+CO2
adducts measured under different conditions using DMPO as a
trapping agent
Entry Changed reaction parameter Yield [%]
1
O2 balloon*
N2 atmosphere*
no light
5
This result triggered us to detect the radical by EPR
spectroscopy using DMPO as radical trap. Indeed, after a blue
LED light irradiation under reaction conditions (Chart 1),
several DMPO adducts were created and observed by EPR.
Their spectral lines overlap and make up the observed EPR
spectra (Chart 1 (d, e)). The radical spectra were only
detected if the reaction conditions were fulfilled (compare
Chart 1 (a-c)). All species exhibited partially resolved
hyperfine (hf) patterns mainly due to an internal interaction of
the electron spin with the 14N (I = 1) and β-1H (I = ½)
magnetic nuclei, which is typical for most DMPO adducts.[24]
However, decay times of the contributing spectra were
different, therefore systematic studies were obscured.
Furthermore, due to an increased viscosity of the reaction
mixture, correlation times of the observed adducts were
prolonged, hence anisotropic contributions were visible and
led to a deviation from isotropic-limit values. This feature
further complicated the analysis of the contributing
(sub)spectra. Thus, the exact assignment of the adducts is still
ambiguous and should be a matter of further special studies.
2
1
3
0
4
no Eosin Y
0
5
no base
0
6
0.2 eq. BHT
1.0 eq. BHT
0.2 eq. TEMPO
1.0 eq. TEMPO
Benzoquinone
12
0
7
8
0
9
0
10
2
Reaction conditions: Substrate (0.134 mmol), eosin
Y
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, rt, 48 h. Yields were determined by GC using n-
dodecane as internal standard. *No CO2 was present in this reac-
tion.
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However, the initial examination revealed that the hf structure
way in order to determine the reaction order and it was found
that the order of the reaction was 1st order with respect to
DBN, benzyl aniline and 0th order with respect to the catalyst.
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3
4
5
6
7
8
of one of the subspectra (Chart 1 (d), marked by stars) is in
close agreement with the previously reported data for CO2-
centered DMPO radical adduct.[25] Furthermore, performing the
reaction under 13CO2 atmosphere led to an additional splitting
of the hf-lines (Chart 1 (e), stars), as expected due to an
internal hf interaction with the magnetic 13C isotope (I = ½).
The effect should further support the CO2 nature of the
observed subspectrum contributing to the total EPR signal.
Further investigation by Stern-Volmer fluorescence quen-
ching experiments revealed that the excited state of the
photocatalyst was not quenched by carbon dioxide but rather
by the amine (Chart 3).[26] Fluorescence intensity decreased
with the increase of amine concentration and no change was
observed with saturated carbon dioxide solution which clearly
showed that the catalyst after excitation reacted with the
starting material first but not with CO2.
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1,35
1,30
1,25
1,20
1,15
1,10
1,05
1,00
0,95
Reaction conditions: Substrate (0.134 mmol), eosin
Y
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, 35 °C, 48 h. Yield of 23b was determined by GC using
n-dodecane as internal standard; amount of (n-Bu)2S was deter-
mined via GC-MS.
E quation
Adj. R -S quare
y = a + b*x
0,9558
--
N-B enzyl-aniline
C O 2
Scheme 8. Reaction of benzyl aniline in dibutyl sulfoxide as
solvent
0,90
0,85
0,80
0,75
0,70
Value S td E rr.
Intercept 1,01246
0,01334
N-Benzyl-anilin
e
S lope
Intercept
61,6056
1
5,89764
--
F it N-B enzyl-a.
F it C O 2
Additionally, no reduced products from CO2 such as CO,
C O2
S lope
4,0172
--
-
HCO2H or HCO2 were detected either by gas-phase GC
analysis (see Supporting Information, Chart S2) or NMR
spectroscopy and only CO2 was observed in gas phase GC
measurements. In order to find the actual oxidant and to
quantify the reduced product in this reaction, dibutyl sulfoxide
was chosen as solvent instead of DMSO (Scheme 8). The
reduced product from dibutyl sulfoxide was dibutyl sulfide
which was easier to quantify due to its high boiling point
compared to DMS (188 °C and 37 °C, respectively). Analysis
of the reaction mixture via GC and GC-MS clearly showed the
evidence of the solvent being the actual oxidant and forming
the corresponding dibutyl sulfide.
0,000
0,001
0,002
0,003
0,004
0,005
cquencher [mol L -1
]
Chart 3. Stern-Volmer plot for eosin Y with benzyl aniline
and CO2 as potential quenchers
In order to find the rate-determining step, we also carried out
KIE experiments (result of three independent runs each;
Scheme 9) with mono- and di-deuterated 1a which resulted in
an average KIE of 1.3 for this reaction. This value clearly
implied that the C–H bond cleavage of the starting material
was the rate-determining step in this reaction. Additionally,
D2O peak was observed as the by-product in H NMR spectra
recorded from the reaction mixture of 1a-d2 in non-deuterated
DMSO (see Supporting Information, Chart S3).
100
(B)
(A)
ln (c(base))
80
60
40
20
0
2
-4,5 -4,0 -3,5 -3,0 -2,5 -2,0
Ad. R.Sq 0,90552
Value Std. Err.
Intercept -3,6691 0,43319
-5,5
-6,0
-6,5
-7,0
-7,5
Benzylidene aniline
Benzyl aniline
Slope
0,89504 0,1427
ti2m0e [3h0]
0
10
40 50
ln (c(cat))
(D)
(C)
ln (c(SM))
-7,5 -7,0 -6,5 -6,0 -5,5 -5,0
-4.0 -3.5 -3.0 -2.5 -2.0 -1.5
-3,5
Adj. R-Sq 0,294
Value Std. Err.
Intercept -4,157 0,54148
Slope 0,137 0,0841
-5.0
-5.5
-6.0
-6.5
-7.0
-7.5
-8.0
-4,0
-4,5
-5,0
-5,5
-6,0
-6,5
Adj. R-Square 0.87585
Value
Std. Err.
Reaction conditions: Substrate (0.134 mmol), eosin
(3 mol%), DBN (1.2 eq.), DMSO (2.5 mL), CO2 (balloon), 12 W
blue LED, rt, 6 h. All are isolated yields.
Y
Intercept
Slope
-3.26692 0.55662
1.02505 0.18963
Chart 2. Reaction of benzyl aniline under optimized reaction
conditions: Reaction was monitored over 48 h (A), plots for
determination of reaction order with respect to DBN (B),
benzyl aniline (C) and eosin Y (D)
Scheme 9. KIE experiment with mono- and di-deuterated
substrate 1a
Since the presence of CO2 is necessary for the reaction to
occur, we focused on the possible role of this molecule. CO2
should be involved in the reductive part of the reaction
mechanism, identifying the species, which is the energetically
most favorable in the reaction mixture to be reduced should
reveal the reaction mechanism and the role of the gas within.
Furthermore, we monitored the process of the model reaction
over 48 h (Chart 2, A) and carried out experiments with
different concentrations of DBN (Chart 2, B), benzyl aniline
(Chart 2, C) and eosin Y (Chart 2, D). The concentrations
were plotted against the observed rate constants in logarithmic
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Hence, we performed density functional theory and ab initio
experimentally.[3c] These species may have some role in the
mechanism which is a matter of further studies.
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calculations with the COSMO-RS solvent model for DMSO to
calculate the standard redox potential of five different species
(Chart 4, for the description of the methods see the
experimental section). The reduction of CO2 to its radical
anion exhibits a substantial redox potential of –2.79 V, which
is in reasonable agreement the data of –2.21 V in literature.[4i]
Since eosin Y has been shown to overcome only an
approximately –1.06 V potential to reduce any molecule, it is
difficult to interpret the reactions above through a free CO2
radical anion.[27] Another possible species in the solution is the
base, which was found to have an even higher redox potential,
rendering the corresponding reduction also unlikely to play
any role in the reaction. However, the strong base DBN can be
protonated in the solution, which introduces a positive charge
into the molecule. The charge decreases the redox potential
significantly, and in the light of the overestimation of the
redox potential for CO2 above, it seems possible, although not
likely that the protonated base is reduced by the eosin Y.
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Scheme 10. Proposed reaction mechanism
Combining all the mechanistic experiments and calculations of
the redox processes above, a complete mechanistic picture can
be compiled (Scheme 10). First, the catalyst reaches the
excited state by the irradiation of light. In the subsequent
single electron transfer (SET) from the amine substrate an
amine radical cation results, while the catalyst becomes a
radical anion. The radical cation is then deprotonated by the
base, and subsequently reacts with the DMSO to give an oxo
radical species, and a DMS side product, in agreement with
the observed reduction of the S=O bond in the control
experiments with dibutyl sulfoxide. Although this step of the
reaction was found to be endothermic in the calculations
(ΔG = 26.6 kcal mol-1), the evaporation of DMS from the
reaction mixture clearly shifts the energetics of this step in a
manner that it becomes more favorable, which is in agreement
with the longer reaction time necessary when dibutyl sulfoxide
is used. Since the reaction needs at least 16 h to generate the
product in considerable yields it is more likely to overcome
this energetic barrier.
Chart 4. Calculated redox potentials of the species that may
occur in the reaction mixture and the values are given for the
reduction by a single electron
Being a Lewis acid, CO2 is generally prone to react with bases.
With DBN, we obtained a ΔG = –0.5 kcal mol-1 reaction Gibbs
free energy to form from free CO2 and DBN a DBN-CO2
adduct. For the resulting structure a somewhat less negative
potential was found than for CO2 or for free DBN, but notably
more negative than for the protonated DBN. The DBN-CO2
adduct is however possible to undergo protonation, resulting
in structure DBN-CO2H. This structure was found to have a
redox potential of –1.17 V, which is the lowest value obtained
here. The difference between this value and the literature data
for eosin Y’s reducing ability is well within the expected error
of the applied computational methods. Accordingly, the
reduction of the CO2 to a radical anion is apparently aided by
the DBN, which is in good agreement with the experimental
results that the base is necessary for the reaction to occur.
Since DBN is a stronger base than DBN-CO2, it is reasonable
to question the accessibility of DBN-CO2H in the excess of
DBN. The Gibbs free energy difference for the proton transfer
from the protonated DBN to DBN-CO2 was found to be only
ΔG = 8.2 kcal mol-1, which is an energy demand that is
possible to overcome at room temperature. This energy
demand is easily compensated at the reduction process, which
results in a ΔG = –9.9 kcal mol-1 more stable product in case
of DBN-CO2H as compared to protonated DBN. This DBN-
CO2H adducts should be prone to degrade under reaction
conditions when water is present. In fact, the product
formation was increased using dry DBN (see Table S1).
Additionally, formation of DBN-bicarbonate salt in the
presence of water (which is apparent in commercial DBN) and
the formation of carbamate anions from the respective starting
material under CO2 atmosphere were confirmed
The catalyst radical anion reduces the DBN-CO2H adduct,
which yields the corresponding radical and the catalyst. The
former species, which can be rationalized as a stabilized CO2
radical anion, can recombine with the oxo radical derivative
by transferring the ·CO2H (hydroxycarbonyl radical) unit to
the oxygen atom from the DBN-CO2H radical to yield an alkyl
carbonate in
a
highly exothermic reaction (ΔG = ‒
67.4 kcal mol-1). This energetically downhill step also helps to
overcome the energetic barrier in the previous step
(ΔG = 26.6 kcal mol-1) to shift the reaction equilibrium to the
product side. This structure can decompose to CO2, water and
the product in a thermodynamically favorable step (ΔG = ‒
0.8 kcal mol-1). In fact, the water and CO2 were both detected
experimentally by 2H NMR and gas GC measurements,
respectively.
CONCLUSION
In conclusion, we have described the CO2-catalyzed
dehydrogenation of amines to imines. This metal-free catalytic
system has shown broad substrates scope and excellent
functional group tolerances. The application of this
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[2]
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methodology has been also described for the syntheses of
pharmaceuticals. The generation of hydroxycarbonyl radical
was confirmed by EPR spectroscopy. Several experiments
have been done to have clear role of the catalyst and CO2 in
this reaction. Finally, detail mechanistic, kinetic and DFT
calculations revealed the mechanism of this reaction.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information contains
technical details of the quantum chemical calculations, experi-
mental details, characterization data and spectra of the synthesized
compounds. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
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and N-methylation of amines using metal-free N-heterocyclic carbene cata-
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AUTHOR INFORMATION
Corresponding Author
* Dr. Shoubhik Das (shoubhik.das@chemie.uni-goettingen.de)
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
Funding Sources
We thank Fonds der Chemischen Industrie (FCI, Liebig-
Fellowship to S.D.) and Chinese Scholarship Council (CSC fel-
lowship to Y.Z.) for the financial support.
ACKNOWLEDGMENTS
We are thankful to Prof. Dr. Lutz Ackermann for his support.
Support from Prof. Dr. Inke Siewert for GC measurements is also
acknowledged. We are also thankful to Prof. Dr. Marina Bennati
for the support behind EPR spectroscopy.
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(a) Luo, J.; Larrosa, I. C–H Carboxylation of Aromatic Compounds through
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219.
ABBREVIATIONS
BHT,
butylated
hydroxytoluene;
DBU,
DBN,
1,5-
1,8-
diazabicyclo[4.3.0]non-5-ene;
diazabicyclo[5.4.0]undec-7-ene; DMS, dimethyl sulfide; DMSO,
dimethyl sulfoxide; GC, gas chromatography; GC-MS, gas-
chromatography-coupled mass spectroscopy; NMR, nuclear mag-
netic resonance; SET, single electron transfer; TBD, 1,5,7-
triazabicyclo[4.4.0]dec-5-ene;
tetramethylpiperidin-1-yl)oxyl.
TEMPO,
2,2,6,6-
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R
R
N
N
R
R
NH
CO2 (1 atm)
Eosin Y, DBN
N
Visible-light mediated
40 substrates, pharmaceuticals
EPR signal for the radical anion
Detail mechanistic studies
R1
R1
DMSO, Visible-light
25-30 °C
R2
R2
R2
R2
N
O
N
N
O
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N
H
N
N
H
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