acceptorless alcohol dehydrogenation: a mechanistic
TRANSCRIPT
REVIEW
Acceptorless Alcohol Dehydrogenation: A MechanisticPerspective
Pragati Pandey1 • Indranil Dutta1 • Jitendra K. Bera1
Received: 1 August 2016 /Accepted: 18 August 2016
� The National Academy of Sciences, India 2016
Abstract Alcohols are unreactive and require strong
inorganic oxidants to convert to synthetically useful car-
bonyl compounds. Acceptorless dehydrogenation of alco-
hol is a green and atom-economic alternative, which
provides aldehyde (or ketone) without the use of sacrificial
acceptor molecules and the side product is molecular
hydrogen. This review provides a brief overview of the
initial work followed by recent advances in the field of
acceptorless alcohol dehydrogenation. Catalysts that
employ metal–ligand cooperation for alcohol activation
and dehydrogenation are covered in details. Different
mechanisms are examined and clear advantages associated
with a bifunctional pathway are outlined. Mechanistic
understanding at the molecular level helps to develop new
generation dehydrogenation catalysts. Recent works from
our group on this area along with literature reports are
discussed.
Keywords Acceptorless alcohol dehydrogenation �Bifunctional catalysis � Metal–ligand cooperation �Dehydrogenation mechanism �Bifunctional double hydrogen transfer
Abbreviations
A Angstrom
AAD Acceptorless alcohol dehydrogenation
AD Alcohol dehydrogenation
ADHC Acceptorless dehydrogenative coupling
Bn Benzyl
bMepi 1,3-Bis(6-methyl-2-pyridylimino)isoindolate
KOtBu Potassium tert-butoxide
BDHT Bifunctional double hydrogen transfer
bpyO a,a0-BipyridonateCp Cyclopentadienyl
Cp* Pentamethylcyclopentadienyl
Cy Cyclohexyl
DABCO 1,4-Diazabicyclo[2.2.2]octane
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
dppf 1,10-Bis(diphenylphosphino)ferroceneDFT Density functional theory
eu Energy unit
Et Ethyl
GC–MS Gas chromatography–mass spectrometry
HMB Hexamethyl benzene
IMes 1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-
ylidene
IiPr 1,3-Diisopropyl imidazol-2-ylideneiPr Isopropyl
MLC Metal ligand cooperation
Me MethylnBu n-Butyl
NHC N-Heterocyclic carbine
NTs N-Tosyl
Nu Nucleophile
OAc Acetate
OTf Trifluoromethanesulphonate
Ph Phenyl
phenO 2,9-Dihydroxy-1,10-phenanthrolinetBu Tertiarybutyl
TOF Turn-over-frequency
TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxyl
Tp0 Tris(3,5-dimethylpyrazolyl)borate
& Jitendra K. Bera
1 Department of Chemistry, Center for Environmental Sciences
and Engineering, Indian Institute of Technology Kanpur,
Kanpur 208016, India
123
Proc. Natl. Acad. Sci., India, Sect. A Phys. Sci.
DOI 10.1007/s40010-016-0296-7
1 Introduction
X–H (X=C, N or O) bonds are abundant in organic mole-
cules. Removal of two hydrogens from adjacent atoms
provides an access to unsaturated molecules (Scheme 1)
[1]. For example, dehydrogenation of alkanes affords
alkenes which are powerful precursors for a diverse array
of useful products [2–8].
A positive aspect of this reaction is the possibility of
removal of hydrogens as molecular hydrogen. The desat-
uration mechanism in natural system proceeds via an initial
hydrogen atom abstraction by a metal-oxo species [9–11].
This is followed by another fast hydrogen atom transfer to
produce an olefin and the reduced form of the catalyst
(Scheme 2). The catalyst is then regenerated by a terminal
oxidant. It should be noted here that enzymatic desatura-
tion does not produce molecular hydrogen. However,
synthetic organometallic catalysts can dehydrogenate sat-
urated organic molecule where hydrogens are liberated as
molecular hydrogen. This short review describes recent
advances in the acceptorless dehydrogenation of alcohol.
Particular emphasis is placed on the mechanism of the
desaturation process. This is not a comprehensive review of
the literature. Rather, it highlights key developments in the
field from a mechanistic perspective.
Alcohols are common precursors in chemical reactions
although they are unreactive because of the hydroxy unit
(OH), which is a poor leaving group and is difficult to
displace [12]. Activation of alcohols is usually achieved by
turning the hydroxy into a better leaving group. Conven-
tional methods are either by protonating the hydroxy group
or by converting it into a sulfonate or a halide [13].
However, these activation methods have several short-
comings. In conventional organic transformations, the
oxidation/dehydrogenation of alcohols involve the utiliza-
tion of stoichiometric or excess amounts of inorganic
oxidants such as chromium(IV) reagents, peroxides or
pressurized oxygen which are hazardous [14–16].
Employment of various co-catalysts, additives and com-
bined catalytic systems of metal complexes and terminal
oxidants (such as TEMPO) yields undesirable stoichio-
metric waste (Scheme 3) [17, 18].
From an environmental viewpoint, there is a need to
develop synthetic protocols that have high atom-economy,
employ cheap and safe reagents and produce no hazardous
waste. Towards this goal, dehydrogenation methodology
without the use of conventional oxidants are developed
paving the way for the advancement of acceptorless alco-
hol dehydrogenation (AAD) (Scheme 4).
2 Acceptorless Alcohol Dehydrogenation (AAD)
AAD is essentially a reaction that removes one hydrogen
molecule from ubiquitous yet considerably less reactive
alcohols to form carbonyls—a more potent synthon. Lib-
eration of hydrogen without the use of stoichiometric
oxidant/acceptor makes the AAD a green and environ-
mentally benign synthetic methodology [19–26]. Extrusion
of hydrogen atoms from neighboring atoms of an organic
molecule in the form of molecular hydrogen is, in most
cases, a thermodynamically uphill process. To drive the
equilibrium towards the product generation, the molecular
hydrogen should be effectively removed from the reaction
mixture. Alternatively, the unsaturated intermediates gen-
erated during the reaction can also be hydrogenated with
in situ generated hydrogen, a process known as ‘borrowing
hydrogen’ method (Scheme 5) [27–29].
3 A Brief Overview
There have been considerable activities during past three
decades or so on various homogeneous catalysts for alcohol
dehydrogenation (AD), i.e. the conversion of alcohols to
aldehydes/ketones through the direct formation of molec-
ular hydrogen [30]. One of the earliest finding from
Scheme 1 Dehydrogenation of alkane
Scheme 2 Enzymatic desaturation of alkane
Scheme 3 Conventional routes for oxidation of substrate with
concomitant formation of stoichiometric waste
Scheme 4 Acceptorless dehydrogenation
P. Pandey et al.
123
Dobson and Robinson group involved [Ru(OCOCF3)2(-
CO)(PPh3)2] (1) in the dehydrogenation of a series of pri-
mary and secondary alcohols [31]. This reaction required
an excess of a fluorinated carboxylic acid and was termed
as ‘acid-promoted’ reaction (Scheme 6). Jung and Garrou
introduced a class of parallel catalysts based on bidentate
diphosphine ligands and reported their mechanistic aspects
for dehydrogenation of primary alcohols [32].
Later Hulshof et al. found out that the dehydrogenation
of alcohols is often complicated due to decarbonylation
(reason of catalyst poisoning) and aldol condensations
under the reaction conditions [33]. Hulshof carried out their
studies with ruthenium complexes 2a–d containing fluori-
nated acid derivatives as ligands for the dehydrogenation of
alcohols (Scheme 7) [34].
Morton et al. [35, 36] introduced base promoted dehy-
drogenation catalyzed by various ruthenium and rhodium
complexes. It was the very first-time when alcohols of
lower molecular weight viz. ethanol, propanol and iso-
propanol were dehydrogenated with reasonable efficiency.
The activity for catalysts [RuH2(N2)(PPh3)3] and [RuH2(-
PPh3)4] could be significantly improved when the reactions
were carried out under visible light. Rhodium based cata-
lysts [RhCl(PPh3)3], [RhH(PiPr3)3], [RhCl((P(OPh)3)3]
were also employed for alcohol dehydrogenation and
resulted in moderate conversions [37, 38]. Wilkinson’s
catalyst was found inactive towards hydrogen generation
from isopropanol, however, addition of triethylamine
improved its activity [39, 40]. Under basic conditions, a
variety of ruthenium–arene and carbene complexes,
including [RuCl(PPh3)2Cp], [RuCl(PPh3)2(indenyl)],
[RuCl2(benzene)]2, [RuCl2(p–cymene)]2, [PhCH =
Ru(PCy3)2Cl2] and [Ru(IMes)–(PPh3)2CO(H)2], were suc-
cessfully tested for dehydrogenation of 1-phenylethanol
[41]. Beller and coworkers screened multiple ruthenium
precursors for dehydrogenation of isopropanol and found
[RuCl3.xH2O] and [RuCl2(p–cymene)]2 gave best TOF
when the reaction was carried out in the presence of two
equivalents of PCy3 [42]. In a subsequent study for iso-
propanol dehydrogenation, series of nitrogen donor ligands
were tested using the [RuCl2(p–cymene)]2 as precursor
[43]. Following this work, Albrecht, Madsen and Szym-
czak groups reported several catalysts based on various
phosphine, mesoionic triazolylidene, N-heterocyclic car-
bene and N,N,N–bMepi (bMepi = 1,3-bis(6-methyl-2-
pyridylimino)isoindolate) ligands which effectively per-
formed AAD reactions (Scheme 8) [44–54].
4 Classical Mechanism
Transition metal catalysts aid in the AAD reaction. Careful
mechanistic investigations reveal that classical AAD pro-
ceeds via an initial oxidative addition followed by b–Helimination of the metal-alkoxide leading to a metal-di-
hydride intermediate and the carbonyl product (Scheme 9)
[55–60]. The metal catalyst is then regenerated by the
liberation of a dihydrogen molecule via reductive elimi-
nation. The intermediacy of a metal-dihydride species is
confirmed by deutrated studies. When reactions are per-
formed with deuterated alcohol, a high level of H/D
scrambling in the final product supports a ‘dihydride
mechanism’ [61, 62]. This classical mechanism is associ-
ated with a number of disadvantages and limitations. Under
basic media, product aldehyde undergoes aldol-type rear-
rangement rendering the product separation very difficult.
Moreover, for certain metals like ruthenium, the metal
alkoxide is so stable that further b–hydride elimination is
hindered [63]. Also, redox adjustment of metal during the
catalytic cycle makes this an energetically unfavorable
process and usually requires elevated temperature to occur.
Hence, from synthetic and selectivity viewpoints, an
alternative approach was necessary which is devoid of such
shortcomings. This has been achieved by introduction of
bifunctional catalysts whose working principle is different
from a classical catalyst. The design principle of a
bifunctional catalyst and its mechanistic implications are
discussed in the following sections.
Scheme 5 Borrowing hydrogen methodology
Scheme 6 Acid-promoted dehydrogenation of alcohol
Acceptorless Alcohol Dehydrogenation: A Mechanistic Perspective
123
Scheme 7 Dimeric ruthenium catalysts containing acid derivatives for hydrogen generation
Ru ClN
N N
PhRu ClN
NN
N
OTf
Ru ClNN
N
O
O
MesRu Cl
NN N N
Ph
PF6
Ru ClNN
N
OSitBuMe2
Cl
Mes
Ru ClNN
NCl
Mes
Ru
Cl
NNN
N O
N
+Ph
NN
NIr
NIr Cp*
Cl
Cl
Cp*
NOTf
Ru ClN
NX
R1
R2R1 = ipr, CH2Ph, cyR2 = ipr, CH2Ph, cyX = Cl, PPh3n = 0, 1
n+
NN
NN
NRu
PPh3
PPh3
H
3 4 5 6
7 8 9
10 1211
Scheme 8 List of transition metal complexes used for AAD reaction
Scheme 9 Classical
mechanism of alcohol
dehydrogenation
P. Pandey et al.
123
5 Cooperative Catalysis
Traditional concept of a catalyst is based on the fact that
during catalysis, the metal center is the active site whereas
ligands are only present to provide steric and electronic
modulation. However, a new concept has emerged where
synergic participation of two or more chemical function-
alities carries out a difficult chemical process [64–68]. Both
metal–metal and metal–ligand cooperation (MLC) strate-
gies have been implemented in synthetic catalysts. Coop-
erative participation of two metals in close proximity has
been demonstrated to activate small molecule, controls
stereo-electronic features of a chemical process and facil-
itates product elimination (Scheme 10) [69–72]. Synthetic
catalysts are also designed where a cooperating ligand at
the vicinity of active metal site actively participates in
bond-activation process and undergoes reversible chemical
transformation during the catalytic cycle to make the pro-
cess more efficient, selective and atom-economic
(Scheme 11) [73–77]. The MLC has emerged as one of the
powerful concept to develop organometallic catalysts
[78–82].
This MLC paradigm offers several distinct advantages
for bond activation chemistry—(a) the combination of a
Lewis acid (metal ion) and Lewis base (ligand) pair is
particularly effective for polarizing neutral molecule
(e.g., H2); (b) the oxidative addition/reductive elimina-
tion steps are not required which, in principle, allow 3d
metals for small molecule activation chemistry; [83–85]
(c) a bifunctional mechanism affords thermodynamic
favorability for the activation of substrates. This strategy
has been used in Bera’s group for small molecule acti-
vation [86, 87].
6 Design Strategies of Bifunctional Catalysts
The design strategy of a bifunctional catalyst involves a
metal unit and a conjugated proton-responsive arm posi-
tioned at an appropriate place on the ligand architecture.
The synergistic interplay between the Lewis acid metal and
the Lewis base ligand facilitates substrate recognition,
activation, and transformation [88–94]. Efficiency and
selectivity of the catalysis can be tuned via electronic
diversity and structural flexibility of the cooperating
ligands. Proton responsive groups such as NH and OH
functional units are ideal targets because of their easy
accessibility, chemical stability and synthetic feasibility.
These groups serve several purposes viz. coordinating
groups, hydrogen bonding donors, hydrogen bonding
acceptors, and/or proton sources. The position of these
proton responsive groups is also vital in the catalyst design.
Depending upon the positioning of these groups with
respect to the metal, they can be classified as a, b and cprotic functionalized MLC. AAD reactions that occur
through a, b and c protic complexes are discussed below.
6.1 a–Protic Bifunctional Catalyst
There is a range of catalytic systems that employ a–proticamine/amido complexes and AAD and related reactions.
The cooperating group of the ligand in this category (i.e. aposition) binds to the metal directly. The most celebrated
example is the hydrogenation catalysts by Noyori and co-
workers [95–99]. Noyori system 13 is an example of abifunctionality which displays a chelate-stabilized inter-
convertible amido/amine couple (Scheme 12).
Another interesting example in this category is Grutz-
macher’s catalyst 14 that exploits the interaction between
Lewis acidic Rh and Lewis basic amide nitrogen
(Scheme 13) [100–103]. Although it requires cyclohex-
anone or methylmethacrylate as hydrogen acceptor, its
catalytic efficiency has been discussed for efficient dehy-
drogenative coupling of primary alcohols with amine,
water or methanol. Low catalyst loading, good chemose-
lectivities and high functional-group tolerance were found
in the reaction signifying its utility in the synthetic process.
Scheme 10 Bond activation via metal–metal cooperation
Scheme 11 Bond activation via metal–ligand cooperation
Scheme 12 Noyori’s a-protic amine/amido hydrogenation catalyst
Acceptorless Alcohol Dehydrogenation: A Mechanistic Perspective
123
Recently, Baratta et al. [104] have reported Ru and Os
based a–protic amine/amido system. These were employed
to catalyze AD of secondary alcohols to ketones
(Scheme 14). Ru complex 15 showed greater catalytic
efficiency than the corresponding Os complex 16 for AD.
Beller and co-workers introduced a–protic NH func-
tionalized Ru–PNP pincer complexes for dehydrogenation
of ethanol [105]. Complex 17 and 18 with NH functionality
show superior catalytic activity than complex 19 which is
devoid of NH proton at a position (Scheme 15). The active
form of the Ru–amido catalyst is achieved by treating the
complex 17 with NaOEt followed by elimination of
molecular hydrogen (Scheme 16).
Beller et al. has also reported 3d metal-based Fe com-
plexes 20 and 21 (Scheme 17) with aliphatic PNP ligand
which were found to be catalytically active in AAD under
base-free conditions [106]. It was interesting to note that
catalyst 20 was found to dehydrogenate methanol in the
presence of KOH (Scheme 18). Later on complex 20 and
21 were further investigated and expanded by Jones and
Schneider for AAD reactions (Scheme 19) [107].
Compared to metal–amide/amine complexes, the use of
metal–alkoxide/alcohol complexes for MLC is less com-
mon. This is attributed to the reduced basicity of coordi-
nated alkoxides and higher lability of coordinated alcohol
in late transition metal complexes. Gelman developed a
dibenzobarrelene-based PCsp3P pincer ligand and synthe-
sized an iridium complex 22 [108–110]. This contains a
polar alcohol/alkoxide based CH2–OH hemilabile sidearm
at a position to the metal center. This catalyst showed very
high catalytic efficiency in the AD of primary and sec-
ondary alcohols (Scheme 20).
Scheme 13 Grutzmacher’s catalyst for alcohol dehydrogenation in
presence of acceptor
M
H2N
Ph2P
Cl
Cl
NH2
PPh2
Fe
OH
R'R
O
R R'0.4 mol %15-16
KOtBu, 130 °C
15: M = Ru16: M = Os
H2
Scheme 14 AD of alcohols catalyzed by ruthenium and osmium
based a-protic amine/amido system
Scheme 15 Crucial role of NH functionality in the dehydrogenation
of ethanol
Scheme 16 Ruthenium-catalyzed dehydrogenation of ethanol to
ethyl acetate
Scheme 17 Iron based aliphatic PNP pincer complexes for AAD
Scheme 18 Iron-catalyzed methanol dehydrogenation
P. Pandey et al.
123
Recently Jones and coworkers have reported a nickel(II)
complex 23, supported by tris(3,5-dimethylpyrazolyl)bo-
rate ligand and 2-hydroxyquinoline ancillary ligand effec-
tively catalyzing AD of a variety of alcohols to afford
ketones, esters and lactones (Scheme 21) [111]. The pres-
ence of -OH group at the ortho position of quinoline is
crucial for AAD reaction as in the presence of 8-hydrox-
yquinoline, reaction doesn’t occur. Bera group has also
synthesized metal–metal singly bonded diruthenium com-
plexes, featuring a hydroxy appendage for AD reactions.
Detailed reactivity and mechanistic studies are discussed
later.
6.2 b–Protic Bifunctional Catalyst
b–Protic systems are also known where the NH/OH moi-
eties are not directly bonded to the metal center. Shvo’s
catalyst 25 is a landmark example of bifunctional catalyst
where the cooperative sites are built in the cyclopentadi-
enyl ring and positioned b to the metal [112–115].
Although the original catalyst is a dinuclear complex 24,
the active species contains a single Ru metal center
(Scheme 22) [116]. Shvo’s catalyst dehydrogenates sec-
ondary alcohols to the corresponding ketones. A concerted
migration of hydride and proton to the metal and ligand
center respectively is involved in this process. The bond
activation by MLC in Shvo’s system engages intercon-
version between Ru complexes with the g5–bound
Scheme 19 Proposed mechanisms for iron-catalyzed AAD
Scheme 20 a Elimination of H2 from complex 22. b AAD mech-
anism by complex 22
Scheme 21 Proposed mechanism for the nickel-catalyzed AAD
Acceptorless Alcohol Dehydrogenation: A Mechanistic Perspective
123
hydroxycyclopentadienyl and the g4–bound cyclopenta-
dienone moieties (Scheme 23).
6.3 c–Protic Bifunctional Catalyst: Aromatization/
Dearomatization
So far we have discussed systems where proton responsive
groups are disposed at a or b position relative to the metal
center and MLC operates via protonation/deprotonation.
Milstein group introduced systems with long distance c–protic functionality [21, 72, 117]. In the course of MLC,
ligand aromatic skeleton is disrupted and restored (arom-
atization/dearomatization) during the bond breaking/for-
mation process creating a platform for catalysis. A large
number of tridentate pincer ligands have been designed
which follow this strategy. The substituted lutidines or
2-picolines having one or two CH2 moiety in the ortho
position(s) of the central pyridine constitute the main
skeleton. This on deprotonation, by treatment with strong
base, undergoes dearomatization at the heteroaromatic unit
with generation of an exocyclic double bond and thus
resulting in active centers for MLC (Scheme 24). During
this process the pyridine ring loses its aromaticity and
N-atom act as amide donor. Alcohol is added to it restoring
the aromaticity. A metal-dihydride is generated via b-hy-dride elimination of the metal-alkoxide and aldehyde is
produced. The PNP- and PNN-type ruthenium pincer cat-
alysts (26 and 27) were found highly active for dehydro-
genative synthesis of imines, amides, esters and acetals
from alcohols [118–123].
However, in all these reactions, catalytic amount of base
is necessary for catalyst activation. Recently Milstein
group has synthesized electron-rich PNP and PNN type
ruthenium(II) hydrido borohydride pincer complexes (28,
29) which can catalyze alcohol dehydrogenation reactions
in the absence of a base [124]. The superior activity of
PNN complex compared to PNP complex is attributed to
the fact that PNN complex contains a heamilabile group
which provides a vacant site during catalysis (Scheme 25).
Using a similar protocol, several Cp*Ir based complexes
(30–32) have been synthesized by Yamaguchi, Fujita, and
Tanino using 2-hydroxypyridine, a,a0-bipyridonate (bpyO),and 2,9-dihydroxy-1,10-phenanthroline (phenO) as ligands,
respectively (Scheme 26) [125–129]. These catalysts are
proven to be an efficient platform for the AAD of alcohols
utilizing the concept of lactam–lactim tautomerism
(Scheme 27). It has been observed that catalyst 31
Cp*Ir(bpyO)(H2O) with ligand bpyO is more reactive than
30 with 2-hydroxypyridine as ligand or catalyst 32
Cp*Ir(phenO)(H2O) with phenO ligand [130]. The differ-
ence in reactivity can be rationalized as complex 31 is the
active form of the catalyst whereas in 30, hydroxypyridine
unit must be deprotonated to generate active species. The
decreased catalytic activity of 32 is attributed to the
reduced proton affinity of oxygen atom of phenO ligand
and to the lower ‘aromatization effect’ in highly conjugated
phenO ligand. Further, Yamaguchi and coworkers have
also developed the Rh and Ru complexes 33
Cp*Rh(bpyO)(H2O) and 34 (HMB)Ru(bpyO)(H2O) with
bypO ligand (Scheme 26) [131]. These catalysts have also
shown promising results for AAD reactions.
7 Mechanism of Bifunctional Catalysts
The AAD mechanism by a classical catalyst proceeds
through the intermediacy of a metal-dihydride intermediate
generated via alcohol oxidative addition followed by b–Helimination, and the catalyst is regenerated by reductive
elimination. But bifunctional catalyst involves transfer of a
a-C–H of alcohol to the metal center and proton of –OH
group to a ligand heteroatom thus generating a metal–
monohydride [61, 112]. Depending upon the nature of the
catalysts, there are two possible pathways that lead to the
formation of metal–monohydride intermediate during
catalysis—(a) stepwise inner-sphere mechanism via b–Helimination; (b) concerted transfer of proton and hydride
Scheme 22 Dimeric Shvo’s
complex and its active form in
solution
Scheme 23 Proposed mechanistic pathway for hydrogen transfer
involving alcohols using Shvo’s complex
P. Pandey et al.
123
via outer-sphere bifunctional double hydrogen transfer
(BDHT) (Scheme 28) [53, 127, 132, 133].
Ligand assisted inner-sphere mechanism involves direct
binding of substrate to the metal center. Such binding
necessarily requires a vacant site at the metal center, and
hence this is thermodynamically less favorable. However,
once metal–alkoxide bond formation takes place, it is
energetically feasible and driven towards product forma-
tion. However, metal–alkoxide bond being very stable, the
catalyst regeneration is sometimes kinetically not permitted
and it often leads to the catalyst deactivation after few
catalytic cycles. Extensive kinetic, deuterated and DFT
studies have been undertaken to decipher the mechanism
involved [49, 53, 134–136]. These studies revealed that the
rate limiting step is invariably the b–H elimination step.
Moreover, temperature dependence studies using Arrhenius
and Eyring plots give estimates of the activation energy of
the processes, which in turn predict if the reaction is
thermodynamically favored or forbidden. In literature, a
range of DS� values (?12 to -30 eu) are estimated for a b–H elimination turnover-limiting step from metal–alkoxide
species [137, 138]. Also as discussed, the metal–alkoxide
intermediate is a stable species and its direct isolation and
characterization is often the most convenient way to
understand the mechanism.
Contrary to that, in outer-sphere mechanism, substrate
does not bind directly to the metal center. Rather, syner-
gistic interaction of the catalyst (metal and ligand) with
alcohol leads to the product formation. Migration of proton
and hydride to the ligand and the metal center, respec-
tively, is a concerted process and proceeds via a six-
member transition state. This is followed by elimination of
molecular hydrogen and the catalyst regeneration. Such
type of proton–hydride shuttle between ligand and metal
center signifies the necessity of proton responsive ligand
arm such as NH/OH group in bifunctional catalysts.
Although the idea of BDHT is simple and uncomplicated,
designing experiments to conclusively establish this
Scheme 24 Aromatization–dearomatization during alcohol activation
Scheme 25 Dehydrogenation of secondary alcohol by 28, 29 in
absence of base
Scheme 26 A series of Cp*Ir,
Rh, and Ru complexes
developed by Yamaguchi and
co-workers for the AAD
reaction
Acceptorless Alcohol Dehydrogenation: A Mechanistic Perspective
123
mechanism is a challenging task. Kinetic studies unravel
the rate and the order of the reaction and Hammett plots are
also helpful in understanding the reaction mechanism.
Temperature dependence studies also give valuable infor-
mation regarding the activation parameters. Contrary to an
inner-sphere mechanism, relatively large negative entropy
of activation DS� values (*-30 eu) are indicative of a
BDHT mechanism [139]. This not only supports an asso-
ciative process but also suggests a higher degree of orga-
nization in the transition state, indicating that the catalyst
and the substrate are involved in association prior to
migration of proton and hydride. Analyzing deuterium
content in the final products while using deuterated sub-
strate give a comprehensive picture of the mechanism. DFT
calculations have also become an important tool particu-
larly for proposing the possible intermediates and the
energetics involved during the course of the reaction [140].
8 Metal–Metal Bonded Platform
All bifunctional catalytic systems mentioned above utilize
a single metal ion. The utility of metal–metal cooperation
in organometallic catalysis has been demonstrated on sin-
gly-bonded [Ru–Ru] systems [141]. In general, b-hydrideelimination of a metal–alkoxide intermediate occurs on a
single metal centre and proceeds via a four-membered
agostic species [142]. A bimetallic construct provides a
scope for cooperative b-hydride elimination that involves
both metals and may turn out to be energetically more
favourable (Scheme 29) [143].
Towards this objective, a crescent shaped 1,8-naph-
thyridine-diimine ligand is synthesized. Treatment of this
ligand with Ru2(OAc)4Cl resulted in the formation of a
metal–metal bonded compound 35. The catalytic efficacy
of 35 was examined for AAD reactions for a range of
Scheme 27 Proposed mechanism of AAD employing lactam–lactim tautomerism
Scheme 28 Generalized
mechanistic pathway for
a inner-sphere and b outer-
sphere mechanism
P. Pandey et al.
123
alcohols. Catalyst 35 (1 mol%) afforded 89 % conversion
of benzyl alcohol to benzaldehyde at 70 �C in toluene for
6 h. Optimization studies showed that KOH was the best
among a variety of bases. This was further extended for
acceptorless dehydrogenative coupling (ADHC) reactions.
A mixture of benzyl alcohol, triphenylphosphonium
methoxycarbonylmethylide (Wittig reagent, 1.5 equiva-
lents), 1 mol% 35 and 10 mol% KOH afforded E-methyl
cinnamate predominantly as confirmed by NMR analysis
(Scheme 30).
Carrying out AD reaction of benzyl alcohol under
identical reaction conditions with catalyst Ru2(OAc)4Cl,
having accessible axial site, yielded only 30 % of product.
This suggests that mere presence of a vacant axial site
around metal is not the sole requirement for product for-
mation. Rather, suitably designed ligand framework renders
trans ligands labile providing equatorial sites accessible for
catalysis. Accordingly, a mechanism has been proposed
where proceeds on the equatorial platform (Scheme 31).
Initially, the acetate group trans to the naphthyridine unit is
replaced by the alkoxide moiety. This is followed by a
bimetallic b-hydride elimination resulting in a Ru-hydride
intermediate along with the formation of aldehyde. The
aldehyde is then extruded and an alcohol molecule binds to
the metal. The catalyst is regenerated via a dehydrogenation
pathway involving an intramolecular proton transfer from
alcohol to the metal–bound hydride. Exhaustive kinetic
studies favored the proposed bimetallic mechanism. To find
out the order of the reaction with respect to catalyst 35,
initial rate was monitored. The linear relationship between
initial rate and the catalyst concentration ascertained that
the reaction is first-order with respect to 35 (Fig. 1a).
Scheme 29 Agostic interaction during b-hydride elimination on
a monometallic and b bimetallic platform
Scheme 30 Acceptorless dehydrogenative coupling using Wittig
reagent
Scheme 31 Proposed
mechanistic pathway for AAD
reaction
Acceptorless Alcohol Dehydrogenation: A Mechanistic Perspective
123
Using integrated rate law for the reaction of the type
A ? B with the constraint [A] = 1 and [B] = 0 at t = 0,
the ln[A] vs time plot shows a first-order kinetics (Fig. 1b).
These experimental findings taken together suggested that
one molecule of the catalyst 35 and alcohol are involved in
the rate-determining step. As one molecule of the catalyst
35 consists of two ruthenium centers, it is logical to pre-
sume that the reaction occurs on the bimetallic assembly.
Deuterium lebling study using a,a-[D2]-benzyl alcohol
showed deuterated benzaldehyde as the major product
(92:8 D/H, observed by GC–MS analysis) indicating the
involvement of a cooperative mechanism (Scheme 32).
A comparative study of the two reactions, (a) PhCH2OH
in toluene and (b) PhCD2OH in toluene–d8 showed kC–H/
kC–D = 2.71 ± 0.04 (Fig. 2). This demonstrated that the
C–H bond-breaking is one of the slower steps in the
reaction. When PhCH2OD was used as a substrate instead
of PhCH2OH, the rate of reaction is 4.94 ± 0.02 times
slower (Fig. 2). High kO–H/kO–D value is indicative of the
fact that elimination of molecular hydrogen during the final
stage of the catalytic cycle is likely to be the rate limiting
step. This proposition was further supported by the DFT
calculations which revealed that the dehydrogenation step
is most exothermic in nature (14.64 kcal/mol) (Fig. 3).
Scrutiny of a number of literature reports revealed that
AAD of primary alcohols by bifunctional catalysts invari-
ably yields esters as major products. Ester formation
process is rationalized by invoking Tischenko type reaction
or by hemiacetalyzation followed by dehydrogenation
[144–147]. The observed aldehyde selectivity in this
reaction was explained on the basis that aldehyde must
binds to the metal centre for effective hemiacetalyzation.
But the ligand architecture ensures that the aldehyde is
rapidly extruded from the [Ru = Ru] core nullifying any
possibility of hemiacetalyzation.
Another interesting aspect of this reaction is that the b-hydride elimination step proceeds via a five-membered
transition state involving two metal centers. The energy
requirement is lesser compared to a system where b-hy-dride elimination happens on a single metal center
involving a four-membered transition state. As a result, this
is a unique example where dehydrogenation is more
energy-demanding than b-hydride elimination indicating
metal–metal cooperation is operative here.
9 Dual Metal–Metal and Metal–LigandCooperation: Selective Synthesis of Imine
A bifunctional catalyst is developed on a metal–metal
bonded platform which displays both metal–metal and
metal–ligand cooperativity. The design strategy involved
the introduction of a protonic arm (–OH) on [Ru2(CO)4]2?
platform utilizing a naphthyridine functionalized N-hete-
rocyclic carbene (NHC) ligand [148]. This hydroxy unit,
positioned at site trans to the metal–metal bond, plays a
crucial role in exhibiting metal–ligand cooperation.
(Scheme 33).
A range of catalysts (36–39) were synthesized via aldol-
type C–C bond formation reactions using a variety of
electron-deficient aromatic aldehydes [149]. The diruthe-
nium core is bridged by the ligand where NHC unit binds
Fig. 1 a Dependence of initial rate on 35 and b Decay of benzyl alcohol vs time. Reprinted with permission from ref 143. Copyright 2016
American Chemical Society
OH
DD O
D/H
1 mol% 45
10 mol% KOHToluene, 70 °C
D/H = 92:8
Scheme 32 Deuterium scrambling using a,a-[D2]-benzyl alcohol for
AAD reaction
P. Pandey et al.
123
one axial site and the other site is occupied by the hydroxy
arm (Scheme 34). Catalyst 36 (1 mol%) afforded 98 %
conversion of benzyl alcohol to benzaldehyde under reflux
in toluene for 24 h. This has further been extended for
ADHC reactions. When 1.2 mmol of benzylamine was
added in presence of 4 A molecular sieves, N-benzylidine
benzylamine formed selectively (Scheme 35).
This reaction was found to be effective with a variety of
bases (DBU, DABCO, KOH, KOtBu, NaH). However,
further studies were carried with DABCO. With different
combinations of alcohols and amines, a set of total 25
reactions was carried out. The yields varied in the range
71–96 %. In order to understand the role of the hydroxy
appendage in 36, a comparative study with a similar
complex but devoid of the hydroxy side arm was also
undertaken. Catalyst 40 afforded dehydrogenation product
benzaldehyde in significantly lower yield (55 %)
(Scheme 36).
Similarly, corresponding imine conversion was found to
be much less. These observations clearly illustrate the
crucial role of the hydroxy appendage for the catalyst
activity. Accordingly, a mechanism is proposed using the
concept of bifunctionality. DFT calculations have been
carried out and the computed energetics support the
proposition. The active catalyst 41 is the deprotonated form
of 36, obtained on treatment with base. Employment of 41
as catalyst leads to product formation under base-free
condition. At first, alcohol is activated in a bifunctional
fashion by 41 to give [Ru–Ru]–alkoxide(axial) and the
hydroxy arm is opened up (Scheme 37). b-hydride elimi-
nation of the [Ru–Ru]-alkoxide affords aldehyde and a
[Ru–Ru]–H intermediate is generated, which is identified
by 1H NMR spectrum having a characteristic signal at
d = -7.37 ppm). Elimination of molecular hydrogen
generates the active catalyst.
The extruded aldehyde reacts with amine to give imine
as the final product. To gain further insight, kinetic Ham-
mett studies for key b-hydride elimination step was carried
out. A plot of ln(c0/c) of substituted benzyl alcohols against
the same values for benzyl alcohol resulted in a linear plot
confirming first order dependence of alcohol. The slopes of
the straight lines were plotted against all possible r values
(r?, r-, r.) of a particular substituent and a linear rela-
tionship is only obtained only with r? (Fig. 4).
This supports our proposition that a positive charge is
generated at the benzylic position of alcohol during b-hy-dride elimination. The possibility of a bifunctional mech-
anism over the classical mechanism, which necessarily
involves oxidative addition of alcohol to a low-valent
metal, has also been scrutinized by deuterated studies. As
discussed earlier, a classical mechanism of alcohol acti-
vation is associated with significant hydrogen scrambling
in the product imine. Madsen et al. employed catalyst
[RuCl2(IiPr)(p-cymene)] which lacks the metal–ligand
cooperation for AAD reactions. They observed 42 %
hydrogen incorporation in the final product when a,a–[D2]–
benzyl alcohol was used as substrate [49]. However, using
catalyst 36, a reaction of a,a–[D2]–benzyl alcohol with
Fig. 2 Reaction rates for PhCH2OH, PhCD2OH and PhCH2OD
versus time (min). Reprinted with permission from ref 143. Copyright
2016 American Chemical Society
Fig. 3 Computed reaction profile for AAD by catalyst 35. Energies
are shown in kcal/mol relative to A. Reprinted with permission from
ref 143. Copyright 2016 American Chemical Society
Scheme 33 Metal–ligand cooperation at axial site of a diruthenium
platform
Acceptorless Alcohol Dehydrogenation: A Mechanistic Perspective
123
benzylamine resulted the formation of deuterated N-ben-
zylidene benzylamine as major product (93:7 D/H
observed by GC–MS analysis), supporting the proposed
bifunctional mechanism (Scheme 38).
Although the reaction occurs at axial site of the [Ru–Ru]
bond, bridging acetate plays an important role during the
catalysis. For the b-elimination to occur, an accessible site
at the metal centre is required. During the reaction, the
bridging acetate changes its coordination motif from l2 tog1 providing a vacant site.
The most important aspect of this reaction is the selec-
tive formation of imine. Reaction of amine and aldehyde
invariably gives imine when it is carried out without the aid
of a catalyst [150]. However, in a metal-catalyzed reaction,
Scheme 34 Syntheses of
diruthenium-NHC complexes
containing hemilabile protonic
arm at the axial site
Scheme 35 Selective imine formation via ADHC of alcohols with
amines catalyzed by 36
Scheme 36 Catalyst 40 devoid
of the hydroxy unit
Scheme 37 Proposed
mechanistic pathway for imine
formation
Fig. 4 Hammett study for the imination of alcohol. Reprinted with
permission from ref 148. Copyright 2014 by John Wiley & Sons, Inc
P. Pandey et al.
123
there are two possibilities—(a) the amine attacks the metal-
coordinated aldehyde leading to a hemiaminal, which
subsequently undergoes dehydrogenation to generate
amide; (b) imine is formed by means of simple dehydra-
tion. The amine or N-alkylated products are also expected
as hydrogen is generated in the reaction. The ability of the
intermediate aldehyde to bind to the metal essentially
dictates the final product. For amide formation, aldehyde
must coordinate to the metal centre. However, the ligand
architecture in catalyst 36 makes it difficult for the alde-
hyde to bind the metal. Furthermore, the strong trans effect
of the axial NHC unit does not allow strong alcohol
binding. As a consequence, aldehyde is extruded from the
metal coordination sphere, which subsequently reacts with
amine to give imine. Use of molecular sieves to arrest
water molecules favors the reaction. Thus, this catalyst
exhibits both metal–ligand and metal–metal cooperations
for selective imine formation via dehydrogenative
coupling.
10 Future Outlook
Dehydrogenation is an important reaction that affords
unsaturated compounds and produce molecular hydrogen.
Alcohols are readily dehydrogenated to give carbonyl
compounds catalyzed by a variety of metal catalyst without
the use stoichiometric amount of oxidants or acceptor
molecules. The added advantage is the liberated hydrogen.
This raises the prospect of using these catalysts for rever-
sible dehydrogenation of organic liquid fuel for energy
storage and generation. Dehydrogenative coupling reac-
tions provide a vast array of C–C coupled products such as
imines, amines, amides and esters. Bifunctional catalysts
are particularly attractive since they activate alcohol
without redox change on the metal. Furthermore, metal–
ligand cooperation facilitates substrate activation and paves
a low-energy dehydrogenation pathway. Efforts are on to
develop bifunctional catalysts on diverse molecular plat-
forms involving different activation modes. Bimetallic
platform is shown to be effective for AAD reaction. Both
metal–metal and metal–ligand cooperations are exploited
to obtain selective dehydrogenative coupled products. A
clear understanding of AAD reactions would lead to cata-
lysts suited for more challenging amine and alkane
dehydrogenation reactions to obtain nitrile and alkenes
respectively.
Acknowledgments This work is financially supported by the
Department of Science and Technology (DST), India, and the Council
of Scientific and Industrial Research (CSIR), India. J.K.B. thanks
Department of Atomic Energy for DAE outstanding investigator
award. P.P and I.D. thank CSIR, India for fellowships.
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