Efficient Transfer Hydrogenation of Ketones using Methanol as Liquid Organic Hydrogen Carrier

Article abstract of DOI:10.1002/cctc.202000228

Herein, we demonstrate an efficient protocol for transfer hydrogenation of ketones using methanol as practical and useful liquid organic hydrogen carrier (LOHC) under Ir(III) catalysis. Various ketones, including electron-rich/electron-poor aromatic ketones, heteroaromatic and aliphatic ketones, have been efficiently reduced into their corresponding alcohols. Chemoselective reduction of ketones was established in the presence of various other reducible functional groups under mild conditions.

Full text of DOI:10.1002/cctc.202000228

Accepted Article
Title: Efficient Transfer Hydrogenation of Ketones using Methanol as
Liquid Organic Hydrogen Carrier
Authors: Nidhi Garg, Soumen Paira, and Basker Sundararaju
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10.1002/cctc.202000228
ChemCatChem
COMMUNICATION
Efficient Transfer Hydrogenation of Ketones using Methanol as
Liquid Organic Hydrogen Carrier
Nidhi Garg,[a] Soumen Paira,[a] and Basker Sundararaju*[a]
Dedication ((optional))
[a]
N. Garg, S. Paira and Prof. B. Sundararaju
Department of Chemistry
Indian Institution of Technology Kanpur, Kanpur
Uttar Pradesh, India - 208016.
E-mail: basker@iitk.ac.in
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
Abstract: Herein, we demonstrate an efficient protocol for transfer
hydrogenation of ketones using methanol as practical and useful
liquid organic hydrogen carriers (LOHC) under Ir(III) catalysis.
Various ketones including electron-rich/electron-poor aromatic
ketones, heteroaromatic ketones and aliphatic ketones have been
efficiently reduced into their corresponding alcohols. Chemoselective
reduction of ketones was established in the presence of various
other reducible functional groups under mild conditions.
the requirement of safe and high-pressure reactor setup is often
necessary. Transition metal catalysts have been widely
employed for transfer hydrogenation of carbonyl derivatives
such as ketones/aldehydes into alcohols or alkyne
semihydrogenation etc. using iPrOH, HCO2H as OHS in place of
gaseous molecular hydrogen.[14] However, the use of methanol
as LOHC is sporadically used in the literature for the reduction of
ketones. This is partly because dehydrogenation of methanol
mediated by transition metal liberates formaldehyde
(energetically uphill process) and metal-hydride thus
subsequently releases the hydrogen. The in situ-formed
formaldehyde reacts with base in the presence of water to form
formate that subsequently produces hydrogen and CO2,
mediated by the metal as shown in Scheme 1.
Methanol is considered as one of the attractive liquid organic
hydrogen carriers (LOHC) and it is produced abundantly from
natural gas, coal and biomass.[1] It has the potential to be a
promising future energy carrier owing to its low-cost and high
hydrogen content (12.5% wt), and useful as C1 feedstock in the
methanol economy.[2],[3] However, hydrogen production from
methanol is an uphill process (63.7 kJ/mol).[4] Hence, the
methanol-water reformation process requires high temperature
(>200 C) and produces high concentration of CO (a poison in
proton exchange fuel membrane fuel cells).[5],[6] Some notable
examples based on homogeneous ruthenium catalysts were
reported earlier for the production of hydrogen without any CO
liberation.[7] However, they largely suffer from low activity and
restricted reactivity as they generate one molecule of H2 per
MeOH. Very recently, Beller,[8] Grützmacher[9] and Milstein[10]
reported ruthenium-catalyzed efficient generation of hydrogen
from methanol-water mixtures at a temperature below 100°C,
although the requirement of base is unavoidable. Fujita and co-
workers reported an efficient Cp*Ir(III)/bipyridonate catalyst for
hydrogen generation from methanol-water solution without
producing any toxic CO gas under mild and weakly basic
conditions.[11] In spite of such clean and safe methodology that
generates hydrogen from methanol, transfer hydrogenation of
carbonyl derivatives using methanol has been seldom reported
in comparison to other organic hydrogen surrogates (OHS).[12]
Reduction of carbonyl derivatives into their respective alcohols is
an important transformation, widely practiced in academia and
Scheme 1. TM-catalyzed Methanol Dehydrogenation.
The dehydrogenation of methanol catalyzed by transition metals
produces 3H2 molecule per MeOH in comparison to other OHS.
For example, the hydrogen liberated from alcohol (as H+ + H-)
directly transfer to the unsaturated C=X (where X= C, O, N)
bond mediated by transition metals. Despite the fact that the
MeOH is cheap and abundant LOHC, only a few reports are
documented for the reduction of C-C multiple bonds such as α,β-
unsaturated carbonyls,[15] alkene and alkyne[16] using Iridium
and nickel complexes. Smith and Maitlis reported transfer
hydrogenation of ketones into alcohols with moderate yields
using Ru(II) at very high temperature and MeOH as LOHC.[18]
Xiao and co-workers reported selective reduction of aldehyde
into alcohols using rhodacycle at 90°C.[18] Crabtree reported the
use of the bis-carbene-Ir complexes for transfer hydrogenation
of ketones into alcohols with moderate yields, however, it
requires stoichiometric amount of base and elevated
temperature under microwave conditions.[19] Hence, efficient
industry.
The use of stoichiometric amount of traditional
reducing agents such as LiAlH4 or NaBH4 is still practiced for the
reduction of carbonyl derivatives such as ketones, although
chemoselective reduction is a cause for concern.[13] On the
other hand, selective reduction of carbonyl derivatives in
particular ketone using cheap yet hazardous molecular
hydrogen catalyzed by transition metals is also explored, though
1
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10.1002/cctc.202000228
ChemCatChem
COMMUNICATION
catalytic systems are required for the reduction of ketones into
We began our investigations by screening various reaction
parameters for an efficient transfer hydrogenation of ketone with
methanol using acetophenone as a model substrate in the
presence of 2 mol% of [Cp*MX2]2 and 5 mol% of 2,2’-Bipyridine-
6,6’-diol in combination with a small amount of base at 60°C for
24 h as shown in Table 1. Among the group 9 metals screened,
Cp*Ir(III) provided the transfer hydrogenated product whereas
Cp*Rh(III) gave 29% of 2a and Cp*Co(III) did not furnish any
reduction product of 1a (entries 1-4, Table 1). Unfortunately, the
the corresponding alcohols under base (stoichiometric) free and
11g]
mild conditions. Inspired by the work of Fujita[11a-f,
and
Crabtree,[19] and in continuation of our studies in Cp*Co(III)
chemistry,[20] we sought to compare the reactivity of group 9
metals (Co, Rh and Ir) for transfer hydrogenation of ketones
using MeOH as LOHC.
Table 1. Reaction Optimizationa
in
situ-formed
dicationic
cobalt
complex
did not give any product formation suggesting that the 3d
congener of group 9 metal are perhaps not efficient for transfer
hydrogenation with methanol under the standard conditions. In
order to realize quantitative product formation, we further
evaluated the amount of base by keeping Ir(III)/L1 catalytic
system. Increase in base loading did not provide any significant
change in the product formation whereas no base addition
impedes the reaction completely (entries 5-7). Change of ligand
from L1 to other similar N,N-donor ligands (L2-L4) did not
provide any product formation signifies that the presence of –OH
group is critical (entries 8-10). Change in concentration or use of
methanol/water mixture did not improve secondary alcohol (2a)
formation (entries 11-12). Among the bases we screened, KOH
was found to be the best provided in combination with L1 and
Cp*Ir(III) for efficient transfer hydrogenation of ketone (1a) using
methanol as LOHS.
Optimal results were achieved and to check the general
applicability of the catalytic system, we investigated a wide
variety of ketones as depicted in Scheme 2. Electron-donating/
electron-withdrawing substituents such as Me, OMe, F, Cl, Br
etc. appears to have an insignificant effect on the yields and
they successfully afforded the corresponding alcohols in
moderate-to-excellent yields. Moieties like halides on the aryl
ring remain unaffected without dehalogenation and the position
of the substitution was found to be insignificant to the catalytic
system (2b-2i). The catalytic system proved to be an effective
one with naphthyl-substituted ketones as well and smoothly
gave the desired products in excellent yield (2j, 2k). Delightfully,
the developed catalytic system is highly compatible with the
increasing steric bulk over substrate. As can be seen, ketones
Entr
y
[M] (mol %)
Ligand
(mol %)
Base
(mol %)
Solvent
Yield[b]
1
2
3
4
5
[Cp*RhCl2]2 (2)
[Cp*IrCl2]2 (2)
[Cp*CoI2]2 (2)
Cp*Co(CO)I2 (2)
[Cp*IrCl2]2 (2)
L1(5)
L1(5)
L1(5)
L1(5)
L1(5)
KOH (10)
KOH (10)
KOH (10)
KOH (10)
KOH (50)
MeOH
MeOH
MeOH
MeOH
MeOH
29
89 (88)
n.d.
n.d.
85
KOH
(100)
6
[Cp*IrCl2]2 (2)
L1(5)
MeOH
76
7
8
[Cp*IrCl2]2 (2)
[Cp*IrCl2]2 (2)
[Cp*IrCl2]2 (2)
[Cp*IrCl2]2 (2)
L1(5)
L2 (5)
L3 (5)
L4 (5)
-
MeOH
MeOH
MeOH
MeOH
n.d.
26
like
propiophenone,
valerophenone,
isobutyrophenone,
pivalophenone, benzophenone are converted with high activity
leading to the desired products in good-to-excellent yields (2l-
2v). Structurally diverse ketones such as 1-tetralone, 1-indanone
and 5-dibenzosuberenone (2w-2y) are also viable substrates
and are cleanly reduced with moderate-to-good yields. To our
delight, hetero-aryl ketones were well tolerated under the
catalytic system and the system did not get deactivate (2z, 2aa-
2ac). Of practical significance, aliphatic alcohols work equally
well (2ad-2ak). Thus, the catalytic system enables the transfer
hydrogenation of a wide range of ketones using methanol as
LOHC under mild reaction conditions.
KOH (50)
KOH (50)
KOH (50)
KOH (50)
9
n.d.
n.d.
10
MeOH:
H2O
11
12
13
14
15
[Cp*IrCl2]2 (2)
[Cp*IrCl2]2 (2)
[Cp*IrCl2]2 (2)
[Cp*IrCl2]2 (2)
[Cp*IrCl2]2 (2)
L1(5)
L1(5)
L1(5)
L1(5)
L1(5)
89[c]
66[d]
48[c]
52[c]
31[c]
KOH (50)
MeOH:
H2O
NaOH
(50)
MeOH:
H2O
CsOH
(50)
MeOH:
H2O
LiOH(50)
MeOH:
H2O
After identifying the potentially active catalytic system, its
application in organic synthesis was explored, this desires a high
degree of chemoselectivity. To showcase this aspect, we
investigated the optimum conditions for functionalized ketones
and they are chemoselectively reduced in presence of various
other reducible moieties such as alkene, alkyne, cyano, nitro,
ester, ether etc. that remained untouched (2al-2aq).
[a]
All reagents were added under argon atmosphere unless otherwise stated
using 1a/[Ir]/L/KOH in 0.2/0.004/0.01/0.02 mmol in a closed Schlenk tube in
CH3OH (0.2 M) at 60 °C for 24 h. Yield calculated by Gas Chromatography
using n-dodecane as internal standard; number in parenthesis are isolated
yield. [c] 1M concentration of MeOH:H2O (7:3) was used. [d] 1M concentration of
MeOH:H2O (1:1) was used.
[b]
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[a]
Scheme 2. Scope of ketones. Reaction conditions: 1/[Ir]/L1/KOH in 0.4/0.008/0.02/0.04 mmol using methanol (2.0 mL) as solvent at 60 °C for 24 h.
[b]
[c]
1/[Ir]/L1/KOH in 0.4/0.016/0.04/0.08 mmol. Reaction performed with 0.2 mmol scale with respect to 1u. 1am/[Ir]/L1/KOH in 0.2/0.008/0.02/0.04 mmol using
methanol (1.0 mL) as solvent at 60 °C for 24 h. All the numbers given here are isolated yields after column chromatography.
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Based on these findings, to demonstrate the utility of the
developed system, the methodology was further extended to
late-stage functionalization of steroid-based molecules which are
versatile motifs in the natural products. Though challenging, the
catalytic system impressively demonstrated the reduction of
natural products such as stanolone, 16-dehydropregnenolone
acetate, pentoxifylline and carvone (2ar-2au). These results
strongly suggest that the developed methodology offers great
opportunities for the medicinal application which is undoubtedly
is of central importance.
required). The catalytic system we have developed
demonstrated high chemoselectivity, does not require any
additional organic solvent or special equipments etc. Further
improvements in the catalytic reaction as well as catalytic
reduction of other functional groups are currently underway in
our laboratory.
Acknowledgements
To gain more insight into the dehydrogenation pathways of
methanol, transfer hydrogenation of acetophenone was
repeated in deuterated methanol (CD3OD) which resulted in the
corresponding 56% deuterium incorporated alcohol as shown by
1H NMR implying that methanol acts as LOHC (Scheme 3a).
Next, we carried out the reaction with HCO2Na as hydrogen
donor in the absence of methanol provided the expected product
in 75% yield (Scheme 3b). However, no reaction was observed
when paraformaldehyde was used as a hydrogen source under
the neat conditions. These control experiments suggest that the
in situ-formed aldehyde perhaps convert immediately into
formate in the presence of base that subsequently acts as
hydrogen donor for the reduction of ketones (Scheme 3c). Under
the given conditions, lowering the catalyst concentration to 0.005
mmol results to 55% yield, leading to the turnover number (TON)
of 110 (Scheme 5d).
Financial Support provided by CEFIPRA (IF-5805-1) to carry out
this work is gratefully acknowledged. NG and SP thanks to CSIR
for their fellowship. PK Kelkar Young Faculty Award to BS is
gratefully acknowledged.
Keywords: Dehydrogenation of Methanol • Iridium • Ketones •
Secondary Alcohols • Transfer Hydrogenation
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is the well-defined metal-ligand system that works well under
moderately basic conditions (only catalytic amount of base
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Entry for the Table of Contents
An efficient Ir(III)-catalyzed transfer hydrogenation of ketones into corresponding alcohol using methanol as liquid organic hydrogen
carrier is demonstrated.
Institute and/or researcher Twitter usernames: @basker25071980
6
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