Development and mechanistic investigation of the manganese(iii) salen-catalyzed dehydrogenation of alcohols

Article abstract of DOI:10.1039/c8sc03969k

The first example of a manganese(iii) catalyst for the acceptorless dehydrogenation of alcohols is presented. N,N′-Bis(salicylidene)-1,2-cyclohexanediaminomanganese(iii) chloride (2) has been shown to catalyze the direct synthesis of imines from a variety of alcohols and amines with the liberation of hydrogen gas. The mechanism has been investigated experimentally with labelled substrates and theoretically with DFT calculations. The results indicate a metal-ligand bifunctional pathway in which both imine groups in the salen ligand are first reduced to form a manganese(iii) amido complex as the catalytically active species. Dehydrogenation of the alcohol then takes place by a stepwise outer-sphere hydrogen transfer generating a manganese(iii) salan hydride from which hydrogen gas is released.

Full text of DOI:10.1039/c8sc03969k

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Development and mechanistic investigation of the
manganese(III) salen-catalyzed dehydrogenation of
Cite this: DOI: 10.1039/c8sc03969k
alcohols†
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Simone V. Samuelsen,a Carola Santilli,a Marten S. G. Ahlquistb and Robert Madsen
a
*
˚
The first example of a manganese(III) catalyst for the acceptorless dehydrogenation of alcohols is presented.
N,N0-Bis(salicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (2) has been shown to catalyze the
direct synthesis of imines from a variety of alcohols and amines with the liberation of hydrogen gas. The
mechanism has been investigated experimentally with labelled substrates and theoretically with DFT
calculations. The results indicate a metal–ligand bifunctional pathway in which both imine groups in the
salen ligand are first reduced to form a manganese(III) amido complex as the catalytically active species.
Dehydrogenation of the alcohol then takes place by a stepwise outer-sphere hydrogen transfer
generating a manganese(III) salan hydride from which hydrogen gas is released.
Received 6th September 2018
Accepted 12th November 2018
DOI: 10.1039/c8sc03969k
rsc.li/chemical-science
withdrawing CO ligand is necessary for stabilizing the low
oxidation state of manganese. The mechanism for the dehy-
Introduction
drogenation with these complexes is believed to involve a cata-
lytic cycle with different manganese(I) species3,4b,e,5b and no
catalytic activity is observed without the CO ligands or with the
corresponding manganese(II) dihalide complexes.5d Although
manganese is an Earth-abundant and cheap metal, man-
ganese(I) complexes are not inexpensive since they are prepared
in several steps from Mn2(CO)10. This carbonyl complex is quite
expensive due to its difficult preparation by a carbonylation
reaction.7 As a result, there is a need for identifying a new and
more abundantly available class of manganese complexes for
alcohol dehydrogenations. Especially, it would be attractive to
catalyze the dehydrogenations by higher valent complexes
where stabilization by CO ligands is not necessary.
Metal-catalyzed dehydrogenation of alcohols gives rise to alde-
hydes and ketones, which can be further transformed into
imines, amides, esters, carboxylic acids and various heterocy-
cles in the same pot.1 The acceptorless dehydrogenation
constitutes an attractive synthetic protocol since it does not
require any stoichiometric oxidants and only releases hydrogen
gas as a co-product. The dehydrogenative transformations are
usually catalyzed by complexes of the platinum-group metals
such as ruthenium and iridium.1 Recently, however, non-noble
metal complexes based on iron, cobalt and manganese have
also been shown to catalyze alcohol dehydrogenations.2 Espe-
cially manganese-catalyzed dehydrogenations have been a hot
research area since the rst catalyst was introduced in 2016.3
Since then several research groups have presented different
manganese complexes for preparing various functional groups
and heterocyclic frameworks (Fig. 1).4 These complexes have
also been used to catalyze the hydrogenation of carbonyl
compounds.5 The signicance of the discoveries is exemplied
by the large number of works published on this topic over the
past two years3–6 including several reviews.2a–d
This prompted the question whether manganese(III)
complexes would be able to catalyze the same acceptorless
alcohol dehydrogenations? Manganese(III) complexes such as
Notably, the developed complexes are all manganese(I)
compounds with CO ligands and a pincer ligand. The electron-
aDepartment of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby,
Denmark. E-mail: rm@kemi.dtu.dk
bDepartment of Theoretical Chemistry & Biology, School of Engineering Sciences in
Chemistry Biotechnology and Health, KTH Royal Institute of Technology, 10691
Stockholm, Sweden
† Electronic supplementary information (ESI) available: Experimental procedures,
kinetic and compound characterization data, copies of 1H and 13C NMR spectra as
well as coordinates and energies from DFT calculations. See DOI:
10.1039/c8sc03969k
Fig. 1 Manganese(I) complexes for alcohol dehydrogenation.3,4
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the Jacobsen's catalyst8 are widely known for catalyzing oxida-
tion reactions in the presence of a stoichiometric oxidant. This
includes epoxidation of olens, oxidation of alcohols as well as
hydroxylation and halogenation of alkanes.9 The reactions
proceed through catalytic cycles with different manganese(III),
(IV) and (V) species.9
Herein, we describe the rst example of an acceptorless
alcohol dehydrogenation catalyzed by a manganese(III) complex.
An easily available manganese(III) salen catalyst has been shown
to liberate hydrogen gas from alcohols and the transformation
has been applied to the synthesis of imines from alcohols and
amines.10 The mechanism has been investigated by experi-
mental and theoretical methods which indicates a metal–ligand
bifunctional pathway11 for the removal of hydrogen gas from the
alcohol.
Fig. 2 Manganese(III) salen/salan complexes used in the investigation.
Results and discussion
The transformation was discovered while attempting to develop
a more convenient in situ-formed catalyst system (Table 1).
Benzyl alcohol was treated with an equimolar amount of
cyclohexylamine in the presence of Mn2(CO)10 and different
ligands. The most promising result was obtained with N,N0-
bis(salicylidene)ethylenediamine (H2salen) as the ligand (entry
1). Since this is a common ligand for manganese(III) complexes,
an experiment was also performed with the Jacobsen's catalyst
(1, Fig. 2). Interestingly, this increased the yield to 79% with
some unreacted benzyl alcohol remaining (entry 2).12 This
observation shows that the acceptorless dehydrogenation of
alcohols can also be catalyzed by manganese(III) complexes and
a number of experiments were now performed to optimize the
reaction. First, several derivatives of Jacobsen's catalyst were
prepared to investigate the inuence of the aryl substituent, the
axial group on manganese, the scaffold and the Schiff base
functionality (Fig. 2). Essentially the same result was obtained
with the unsubstituted analogue 2 (entry 3) and the tert-butyl
group can therefore be omitted. The axial substituent on
manganese, on the other hand, needs to be chloride since both
the bromide 3 and the acetate 4 gave signicantly lower
conversion and yield (entries 4 and 5). The same was observed
when the trans-1,2-diaminocyclohexane scaffold was changed to
either the cis (i.e. 5), the ethylene (i.e. 6) or the benzene (i.e. 7)
analogue (entries 6–8). Notably, the corresponding salan
complex 8 also furnished some conversion into the imine
(entry 9) which may indicate that the Schiff base functionality
in the salen ligand plays an important role in the mechanism
(vide infra). In the end, trans-N,N0-bis(salicylidene)-1,2-
cyclohexanediamine was selected as the salen ligand for the
transformation and thus complex 2 as the catalyst.
Table 1 Dehydrogenation with manganese salen/salan complexesa
For further optimization, the inuence of additives and the
solvent were investigated (Table 2). A number of common
additives13 were included in the reaction, but they all led to
lower imine yields due to a moderate conversion of benzyl
alcohol (results not shown). We have previously used nitride
salts as a basic additive for alcohol dehydrogenations,14 but
lower yields and conversion were also observed when Li3N and
Mg3N2 were added to the reaction (entries 1 and 2). However,
with Ca3N2 a complete transformation of benzyl alcohol and
a high yield of the imine was now obtained (entry 3). The
optimum amount of Ca3N2 was 16.7% since both higher and
lower quantities decreased the yield of the imine (entries 4–7).
We observed the same optimum percentage in our earlier
work14 and 16.7% is an intriguing number since one equiv. of
Ca3N2 can theoretically react as a base with 6 equiv. of either the
alcohol or water.
Entry
1
Catalyst
BnOH conversionb (%)
Imine yieldc (%)
38
5% Mn2(CO)10
10% H2salen
,
—
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
81
86
70
66
83
60
27
47
79
81
65
64
74d
58
25
12e
a
Conditions: BnOH (1 mmol), CyNH2 (1 mmol), catalyst (0.1 mmol),
˚
A
tetradecane (0.5 mmol, internal standard),
mesitylene (4 mL), reux, 48 h. Determined by GC using the internal
standard. GC yield based on the internal standard. 6% of N-
cyclohexylbenzamide was also formed. Traces of benzyl benzoate
4
MS (150 mg),
b
The inuence of the solvent was then investigated and
a slightly improved outcome was observed upon conducting the
reaction in toluene (entry 8). Dioxane and heptane gave lower
c
d
e
was also detected.
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Table 2 Optimization of dehydrogenation with complex 2a
imine was obtained in 70% yield (entry 7). A p-uoro and a p-
chloro substituent was also tolerated giving 73 and 85% yield
(entries 8 and 9). The analogous bromo substrate reacted
slightly slower although no competing dehalogenation was
observed (entry 10). In addition, the two isomeric naph-
thalenemethanols gave the corresponding imines in 71 and
60% yield (entries 11 and 12). Full conversion of the alcohol was
observed in all cases in Table 3 except for entries 5, 6, 10 and 12
where 5–10% of the alcohol remained and thus accounts for the
isolated ꢀ60% yield.
Entry
X
Additive
Solvent
Conversionb (%) Yieldc (%)
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
5
20% Li3N
20% Mg3N2
20% Ca3N2
Mesitylene 66
Mesitylene 54
Mesitylene 100
12d
48
92
93
84
90
88
98
62
18
96
73
66
77
79
97
95
The inuence of the amine was then investigated by reacting
benzyl alcohol with different primary amines (Table 4). Octyl-
amine gave essentially the same result as cyclohexylamine
(entry 1). The more hindered amines tert-octylamine and 1-
adamantylamine also gave full conversion of benzyl alcohol and
furnished the imine in 69 and 88% yield, respectively (entries 2
and 3). Similar yields were obtained with the two optically pure
amines (R)-1-phenylethylamine and (R)-1-(1-naphthyl)ethyl-
amine although 10–15% of benzyl alcohol remained in both
cases (entries 4 and 5). No sign of any racemization was
observed in the two transformations indicating that dehydro-
genation of the amine is not occurring under the reaction
conditions. Benzhydrylamine gave the imine in 73% yield while
tritylamine only furnished 19% yield (entries 6 and 7). In the
latter case, 48% of the intermediate benzaldehyde was also
observed indicating a poor conversion into the imine with the
16.7% Ca3N2 Mesitylene 100
33% Ca3N2
10% Ca3N2
5% Ca3N2
16.7% Ca3N2 Toluene
16.7% Ca3N2 Dioxane
16.7% Ca3N2 Heptane
16.7% Ca3N2 Toluene
Mesitylene 100
Mesitylene 100
Mesitylene 100
100
65
20
100
76
69
9
10
11
12
13
14
15
16e
17e
2.5 16.7% Ca3N2 Toluene
1.25 16.7% Ca3N2 Toluene
5
5
5
5
20% MgSO4
Toluene
80
20% Na2SO4 Toluene
16.7% Ca3N2 Toluene
20% Ca(OH)2 Toluene
81
100
99
a
Conditions: BnOH (1 mmol), CyNH2 (1 mmol), 2 (X/100 mmol),
˚
additive, tetradecane (0.5 mmol, internal standard), 4 A MS (150 mg),
solvent (4 mL), reux, 48 h. Determined by GC using the internal
standard. GC yield based on the internal standard. 4% of N- very hindered amine. The inferior reactivity is most likely
cyclohexylbenzamide was also formed. Without 4 A MS.
caused by Ca3N2 since a control experiment with benzaldehyde,
b
c
d
e
˚
tritylamine and Ca3N2 also showed incomplete imine forma-
tion.15 Furthermore, the imination could be performed with
yields due to incomplete conversion of benzyl alcohol (entries 9
and 10). Under the reaction conditions, complex 2 is fully
soluble at reux in mesitylene, toluene and dioxane, but not in
heptane. The catalyst loading could be adjusted to 5% without
affecting the imine yield while 2.5% or 1.25% gave lower
conversion of the alcohol (entries 11–13). The role of Ca3N2 is
probably to act as both a base and a desiccant (no byproducts
were observed from a potential release of NH3). Replacing Ca2N3
with MgSO4 or Na2SO4 led to a slower reaction (entries 14 and
15) while molecular sieves had no inuence on the trans-
formation (entry 16). Ca3N2 reacts with water to form Ca(OH)2
and interestingly this salt gave almost the same result as Ca3N2
(entry 17). Eventually, 5% of 2 and 16.7% of Ca3N2 in reuxing
toluene were chosen as the optimum conditions for conversion
of equimolar amounts of alcohol and amine.
With the optimized catalyst system in place, the substrate
scope of the imination reaction could now be investigated.
Cyclohexylamine was rst reacted with different alcohols and
the imines were isolated by ash chromatography (Table 3).
This produced 89% yield for the parent reaction with benzyl
alcohol while the p-methyl analogue furnished 70% yield
(entries 1 and 2). The p- and o-methoxy substituted substrates
afforded 83 and 90% yield, respectively, while p-phenyl- and
p-methylthiobenzyl alcohol both gave 60% yield (entries 3–6).
p-Nitrobenzyl alcohol is oen a challenging substrate in dehy-
drogenative transformations due to an accompanying reduction
of the nitro group,1 but this was not observed here and the
anilines where 74%, 63% and 62% yield were obtained with
aniline, p-anisidine and p-triuoromethylaniline, respectively
(entries 8–10). In entries 9 and 10 as well as in entries 5 and 6
about 10–30% of unreacted benzyl alcohol was also detected.
The reaction could be extended to the synthesis of pyrroles
by reacting cis-but-2-ene-1,4-diol with primary amines.16 The
transformation could be carried out with both aniline and
cyclohexylamine to afford the desired product in moderate
yield17 (Scheme 1).
The gas evolution was measured in a separate experiment
under the optimized conditions in Table 2, entry 16, but without
adding Ca3N2 (resulting in a slightly lower 78% imine yield).
One equivalent was collected and the gas was identied as
dihydrogen, which conrms the acceptorless dehydrogenative
pathway. Essentially no imine was formed when the reaction
was conducted in the absence of complex 2. The possibility for
trace metal impurities is a serious concern in the development
of reactions with new metal catalysts18 and studies have shown
that some coupling reactions with manganese catalysts are
most likely mediated by traces of other elements.19 For that
reason, complex 2 was analyzed by inductively coupled plasma
mass spectrometry (ICP-MS) for traces of other metals known to
perform alcohol dehydrogenations. However, none of these
elements could be detected beyond their detection limit and it
is therefore highly unlikely that another metal is responsible for
the observed results.
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Table 3 Imination of alcohols with cyclohexylaminea
Table 3 (Contd.)
Entry
1
Alcohol
Imine
Yieldb (%)
89
Entry
Alcohol
Imine
Yieldb (%)
12
60
a
Conditions: alcohol (1 mmol), CyNH2 (1 mmol), 2 (0.05 mmol), Ca3N2
2
3
4
5
6
7
70
83
90
60
60
70
b
c
(0.167 mmol), toluene (4 mL), reux, 48 h. Isolated yield. Reaction
time 72 h.
As mentioned above, complex 2 dissolves completely in
toluene upon heating the mixture to reux. However, aer the
imination has gone to completion and the reaction is cooled to
room temperature, complex 2 precipitates out again and 95%
can be recovered aer addition of a small amount of hexane.
Furthermore, the retrieved complex can be subjected to a new
catalytic reaction which gave 82% yield of the imine with a 4.5%
catalyst loading.
When the optimized reaction in Table 2, entry 16 was per-
formed with PhCD2OH instead of PhCH2OH, the product was
exclusively PhCD]NCy with no hydrogen incorporation into
the benzylic position. This may imply that the dehydrogenation
takes place by a monohydride pathway and no metal-dihydride
species is formed.
To investigate whether the hydride abstraction takes place in
the rate-limiting step, the primary kinetic isotope effect (KIE)
was measured. The initial rate was determined with both
PhCD2OH and PhCH2OH in the reaction with cyclohexylamine
which gave a KIE of 2.00. This somewhat modest value shows
that breakage of the C–H bond is one of several slow steps in the
transformation.
To gain more experimental information about the reaction
pathway, the studies were also supplemented by a Hammett
study where the change in charge at the benzylic position
between the starting material and the transition state can be
determined. We have previously used Hammett studies with
para-substituted benzyl alcohols to analyze the rate-limiting
step in dehydrogenations catalyzed by ruthenium and iridium
complexes.20 Thus, ve para-substituted benzyl alcohols (X ¼
OCH3, CH3, F, Cl and NO2) were allowed to compete with the
parent benzyl alcohol in the imination with cyclohexylamine.
The reactions were monitored by GC, which allowed for deter-
mining the consumption of each alcohol. Assuming a rst order
reaction in the alcohol, their relative reactivities (kX/kH) can be
determined as the slope of the line when ln(c0/c) for one para-
substituted benzyl alcohol is plotted against the same values for
benzyl alcohol. These plots gave straight lines for all ve para-
substituted benzyl alcohols and made it possible to use the
8
73
85
61
71
9
10c
11
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Table 4 Imination of amines with benzyl alcohola
Scheme 1 Pyrrole synthesis from but-2-ene-1,4-diol and amines.
Entry
1
Amine
Imine
Yieldb (%)
90
with a hydride transfer from the alcohol. Attempts to use
different sets of s values22 gave a poor correlation and radical
intermediates are therefore not involved in the catalytic cycle.
This was also conrmed by conducting the imination in the
presence of one equiv. of the radical trapping agents cyclohexa-
1,4-diene and 2,4-diphenyl-4-methylpent-1-ene which in both
cases had no inuence on the imine yield.
2
3
4
5
69
88
66
83
To further understand the mechanism, we used density
functional theory (DFT) calculations to estimate the Gibbs free
energies of possible intermediates and transition states. The
starting point was the Mn(salen)OBn complex 9, where Cl has
been replaced by a benzylic alkoxide (Fig. 4). This trans-
formation involves the elimination of HCl, which is possible
under the basic conditions. In fact, an experiment in the
absence of a base (complex 2 and benzyl alcohol) gave no
conversion at all while the absence of the amine (complex 2,
benzyl alcohol and Ca3N2) resulted in 20% of benzyl benzoate.
The initial idea was that complex 9 undergoes b-hydride
elimination. However, the activation energy for this process was
found to be prohibitively high (at 37.9 kcal molꢁ1 relative to 9)
which is partly due to the lack of an available coordination site.
Instead, we found an alternative reaction where the hydride is
transferred from the benzylic carbon to the imine carbon of the
salen ligand. The activation energy was merely 17.6 kcal molꢁ1
and the product complex 11 is at 6.6 kcal molꢁ1. A similar
pathway has been identied in the activation of (PNNP)Fe(II)
eneamido complexes with isopropanol.23 The product benzal-
dehyde is then replaced by benzyl alcohol, from which a proton
is transferred to the amide nitrogen of the reduced salen ligand.
The resulting complex where one imine of the salen is
6
7
73
19
8
9
74
63
10
62
a
Conditions: BnOH (1 mmol), amine (1 mmol), 2 (0.05 mmol), Ca3N2
(0.167 mmol), toluene (4 mL), reux, 48 h. b Isolated yield.
Hammett equation lg(kX/kH) ¼ sr to construct a Hammett plot
(Fig. 3). A good correlation was obtained with the standard s
values21 giving a straight line with a r value of ꢁ1.24. This
negative slope shows that substrates with electron-donating
groups react faster and that a partial positive charge is built
up at the benzylic carbon in the rate-limiting step consistent
Fig. 3 Hammett plot for the imination with para-substituted benzyl
alcohols.
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Fig.
4 Activation of Mn(III)(salen)OBn to form the active amido
complex.
Fig. 5 Proposed catalytic cycle and relative Gibbs free energies.
hydrogenated is at ꢁ5.2 kcal molꢁ1 relative to 9. The lowest
activation energy found from the hydrogenated intermediate
was for another hydride transfer to the second imine of the
salen, with a transition state at 14.5 kcal molꢁ1 (maximum DGact
¼ 19.7 kcal molꢁ1, see ESI† for more details).
dehydrogenation although the latter in a low yield (Table 1).
When the imination with 5% of the salan complex 8 was
repeated with KOtBu as the base, a 56% yield was obtained of N-
benzylidene cyclohexylamine. This result can be explained by
elimination of HCl from 8 to afford the catalytically active
species 12.25 Similar eliminations of hydrogen halides under
basic conditions have been described with (PNP)Mn(I), (PNP)
Ru(II) and (PNNP)Fe(II) complexes to form the corresponding
amido compounds.4b,26 Notably, a post analysis by LCMS of the
imination with salan complex 8 showed the formation of salen
complex 2 as the main manganese species together with minor
amounts of some unidentied complexes. None of the starting
complex 8 could be detected aer the imination. These obser-
vations show that a salan complex can be converted into the
corresponding salen complex under the reaction conditions
and explains why salen complex 2 is almost fully recovered aer
the reaction. So far, however, we have not been able to identify
Aer complete dissociation of benzaldehyde a key species 12
is formed, where one imine is hydrogenated to the amine and
the other is reduced to an amide ligand. This species resembles
intermediates from alcohol dehydrogenations with (PNP)Ru(II),
(PNP)Mn(I), (PNNP)Fe(II) and (PNP)Ir(III) catalysts24 which have
an amide ligand that can act as a Brønsted base and a metal that
can serve as a hydride acceptor. They have all been proposed to
react via an outer-sphere hydrogen transfer mechanism.24 The
main difference is the metal and the oxidation state, which in
the current case is manganese(III). The same outer-sphere
hydrogen transfer was identied here and the activation
energy is 26.7 kcal molꢁ1 relative to 12 and 27.2 kcal molꢁ1
relative to 15, which corresponds to a TOF of 83 hꢁ1 at the
reaction conditions (Fig. 5). The calculated KIE of this reaction
is 2.9, which is in reasonable agreement with the experimental
value of 2.0. Finally, we calculated the relative rates of the para-
substituted benzyl alcohols used in the experimental study. The
relative rates were calculated from the prereactive complex 15
and a good agreement was found with the experimental results
giving a very similar r value (Fig. 6). Aer the formation of the
manganese(III) hydride intermediate 17, benzaldehyde is
assumed to react irreversibly with the amine. From complex 17
the formation of hydrogen gas requires an activation energy of
22.6 kcal molꢁ1, in a step that regenerates the active catalyst.
The proposed mechanism indicates that the Schiff base
functionality of the salen ligand is crucial for the reactivity. This
was also conrmed by isolating the salen complex aer the
imination reaction with PhCD2OH and cyclohexylamine. The
isolated complex showed the incorporation of one deuterium
atom on each of the Schiff base carbons as would be expected
from the proposed mechanism. The involvement of the Schiff
base was also observed in the optimization where both the salen
complex
2
and the salan complex
8
catalyzed the Fig. 6 Hammett plot calculated by DFT.
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a pathway by which hydrogen is eliminated from a salan
complex to afford the salen compound.
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Conclusions
¨
In summary, we have described a new catalyst for the accept-
orless dehydrogenation of alcohols. The manganese(III) salen
complex 2 mediates the formation of imines from alcohols and
amines with the liberation of hydrogen gas. The reaction can be
performed with different alcohols and amines and can be
extended to the synthesis of pyrroles. Complex 2 can be recov-
ered from the reaction and used again without signicantly
affecting the catalytic activity. The mechanism is believed to
involve a bifunctional pathway where both the metal and the
ligand participates in the dehydrogenation reaction. We envi-
sion the discoveries will spur much interest in the development
of new transformations with hydrogen gas and manganese(III)
catalysts.
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Conflicts of interest
There are no conicts to declare.
6 For additional examples, see: (a) D. Wei, A. Bruneau-Voisine,
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Acknowledgements
The project was supported by the Technical University of Den-
mark through PhD fellowships to SVS and CS. We thank
Mathias Børsting for his assistance in performing the Hammett
study and determining the KIE.
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