Rational selection of co-catalysts for the deaminative hydrogenation of amides

Article abstract of DOI:10.1039/c9sc03812d

The catalytic hydrogenation of amides is an atom economical method to synthesize amines. Previously, it was serendipitously discovered that the combination of a secondary amide co-catalyst with (^iPrPNP)Fe(H)(CO) (^iPrPNP = N[CH₂CH₂(PⁱPr₂)]₂^-), results in a highly active base metal system for deaminative amide hydrogenation. Here, we use DFT to develop an improved co-catalyst for amide hydrogenation. Initially, we computationally evaluated the ability of a series of co-catalysts to accelerate the turnover-limiting proton transfer during C-N bond cleavage and poison the (^iPrPNP)Fe(H)(CO) catalyst through a side reaction. TBD (triazabicyclodecene) was identified as the leading co-catalyst. It was experimentally confirmed that when TBD is combined with (^iPrPNP)Fe(H)(CO) a remarkably active system for amide hydrogenation is generated. TBD also enhances the activity of other catalysts for amide hydrogenation and our results provide guidelines for the rational design of future co-catalysts.

Full text of DOI:10.1039/c9sc03812d

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DOI: 10.1039/C9SC03812D
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Rational Selection of Co-Catalysts for the Deaminative
Hydrogenation of Amides
Lluís Artús Suàrez,a,‡ Upul Jayarathne,b,‡ David Balcells,a Wesley H. Bernskoetter,*,b Nilay Hazari,c
Received 00th January 20xx,
Accepted 00th January 20xx
Martín Jaraiz,d,e Ainara Nova*,a,f
DOI: 10.1039/x0xx00000x
The catalytic hydrogenation of amides is an atom economical method to synthesize amines. Previously, it was
serendipitously discovered that the combination of a secondary amide co-catalyst with (iPrPNP)Fe(H)(CO) (iPrPNP =
-
N[CH2CH2(PiPr2)]2 ), results in a highly active base metal system for deaminative amide hydrogenation. Here, we use DFT to
develop an improved co-catalyst for amide hydrogenation. Initially, we computationally evaluated the ability of a series of
co-catalysts to accelerate the turnover-limiting proton transfer during C–N bond cleavage and poison the (iPrPNP)Fe(H)(CO)
catalyst through a side reaction. TBD (triazabicyclodecene) was identified as the leading co-catalyst. It was experimentally
confirmed that when TBD is combined with (iPrPNP)Fe(H)(CO) a remarkably active system for amide hydrogenation is
generated. TBD also enhances the activity of other catalysts for amide hydrogenation and our results provide guidelines for
the rational design of future co-catalysts.
undergoes C–N bond cleavage to yield an amine and an aldehyde
(step 2). Subsequent hydrogenation of the aldehyde affords the
corresponding alcohol (step 3).13,14
Introduction
The selective hydrogenation of carbonyl complexes is one of the
most important and widely used catalytic reactions in organic
synthesis.1–3 However, the reduction of electron rich carboxylic acid
derivatives, such as amides, is still difficult.4,5 The ubiquity of the
amide functional group in biological systems, pharmaceuticals, and
industrial chemicals6 has spurred considerable effort to create
efficient catalytic systems for amide hydrogenation. Nevertheless,
amides are still typically reduced using waste generating
stoichiometric reagents, such as LiAlH4, and to date only a small
number of homogenous catalysts can directly hydrogenate amides
to amines.5,7–12 These catalysts, which include both precious and
base metal systems, provide proof-of-principle that this atom
economic transformation is possible, but can still be improved.1
Current mechanistic models for transition metal catalyzed amide
reduction, in particular deaminative hydrogenation to produce an
amine and an alcohol, propose a sequential reduction of the amide
to an intermediate hemiaminal (step 1, Scheme 1), which then
Step 1
carbonyl hydrogenation
Step 2
: C-N bond
protonolysis
Step 3
: Formaldehyde
carbonyl hydrogenation
: Amide
O
HO
H
R'
O
H2
R'
H2
C
H
H
R'
+
R
N
R
N
N
HO
R
R
H
R'
H
O
C
O
R'
R'
H
H
H
H
N
M
N
M
Scheme 1 Proposed reaction steps for the deaminative hydrogenation of amides to
amines and methanol catalyzed by Noyori type catalysts represented as N(H)–M(H).
Most well-defined catalysts for deaminative hydrogenation rely on a
Noyori-type,14,15 bifunctional pathway whereby a metal-hydride and
adjacent ligand based proton are delivered to the carbonyl C=O
moiety (Scheme 1). Intriguingly, recent mechanistic studies indicate
that while the Noyori-type catalyst structure is essential for
facilitating the dihydrogen addition steps of the process (1 and 3, in
Scheme 1), the proton transfer between the O- and N-ends of the
hemiaminal (step 2), which triggers the cleavage of the C–N bond,
does not involve necessarily the metal catalyst.13 In addition, step 2
is the turnover-limiting step, indicating that novel methods to
facilitate hemiaminal cleavage are required to improve catalytic
amide hydrogenation.
a. Hylleraas Centre for Quantum Molecular Sciences, Department of Chemistry,
University of Oslo, P.O. Box 1033, Blindern, N-0315 Oslo, Norway.
b. Department of Chemistry, University of Missouri, Columbia, Missouri, 65211, USA.
c. Department of Chemistry, Yale University, P.O. Box 208107, New Haven,
Connecticut, 06520, USA.
Our laboratories have previously investigated amide hydrogenation
catalyzed by the iron(II) complex, (iPrPNP)Fe(H)(CO) (iPrPNP =
d. Department of Electronics, ETSIT, University of Valladolid, Paseo Belén 15, 47011
Valladolid, Spain.
-
N[CH2CH2(PiPr2)]2 ) (FeN) using both computational and experimental
e. IU CINQUIMA, University of Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain.
f. Department of Chemistry, UiT-The Arctic University of Norway, N-9037 Tromsø,
Norway
methods (Scheme 2).5,13 In deaminative amide hydrogenation using
FeN, a key serendipitous finding was that the reaction is promoted by
a co-catalytic amount of a secondary amide (formamide in Scheme
2). This effect was particularly pronounced in the hydrogenation of
tertiary alkylic amides, such as DMF, which are important because
they are key intermediates in the homogeneous hydrogenation of
‡ These authors contributed equally to this study.
Electronic Supplementary Information (ESI) available: Experimental details
(including procedure for co-catalyst screening and synthesis of
(
PhPNHP)RuH(CO)(HCONPh)) and computational details (including information on
the microkinetic models with DMF and 4-formylmorpholine, results obtained with
diphenylformanilide, and optimized coordinates) are provided via a link at the end
of the document. See DOI: 10.1039/x0xx00000x
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CO2 to methanol mediated by amines.16,17 The interplay of the two single site hydrogen bond donors (entries 4-7, 10)Voierw Awrtiitchle Obnolitnhe
amides equivalents (i.e. one reactant and one co-catalyst) adds hydrogen bond donor and acceptor sites whiDchOcI:o1u0l.d10a3c9t/Cas9SpCu0s3h8-p12uDll
complexity to the mechanism. Computational studies indicate that proton shuttles (entries 1-3, 8 and 11). Various aryl and alkyl
the secondary amide lowers the barrier to the proton transfer that substituents (i.e. H, Me, iPr, tBu, Ph) were introduced into the pool of
occurs in hemiaminal C–N bond cleavage (∆G‡HT, in Scheme 2) co-catalysts, to sample a wide range of stereoelectronic effects. In
because the NH moiety acts as a proton-shuttle.13 However, the use molecules with C=O or C=N functional groups, only electron-rich
of a secondary amide as a co-catalyst has two major pitfalls: 1) systems were chosen to minimize the hydrogenation of the co-
secondary amides can form stable adducts with FeN (Gadd, in catalyst. Although there are co-catalysts that are hydrogenated
Scheme 2) via 1,2-addition across the iron-amide bond, which lowers when used as reactants (e. g. formanilide and acetamide),5 when
the concentration of the active species in catalysis; and 2) the amide they are used in catalytic concentrations their consumption is slower
co-catalyst can be consumed during the reaction, which undermines than that of the reactants, enabling their co-catalytic effect.13 The
its contribution as a co-catalyst and introduces a product separation ability of each potential co-catalyst to assist with the hemiaminal
problem.5 Here, we use
a
rational approach involving DFT proton transfer5,18,19 involved in the C–N bond cleavage (step 2 in
calculations to design co-catalysts tailored for the deaminative Scheme 1) was quantified by computing the transition state(s)
hydrogenation of tertiary amides. Our best co-catalyst, associated with this process (∆G‡HT; Scheme 2 and Fig. 1), which can
triazabicyclodecene (TBD), acts as push-pull proton shuttle for C–N be either concerted (with TBD, methanol and morpholine) or step-
bond cleavage, and leads to significant improvement in iron wise (all other co-catalysts). In the latter, the N-protonation of the
catalyzed deaminative amide hydrogenation. Importantly, the hemiaminal is followed by its O-deprotonation, which is rate-limiting
improvement from TBD also occurs for a number of other transition for all co-catalysts except urea. The thermodynamic preference of
metal catalysts for deaminative amide hydrogenation, suggesting the co-catalyst to trap the iron complexwas quantified by computing
that the addition of co-catalysts of this type is a general strategy for the free energy for the formation of the off-cycle adducts from FeN
improving amide reduction.
(∆Gadd; Scheme 2 and Fig. 1). In this framework, all co-catalysts were
screened with the aim of finding an optimal balance between a low
H
H
∆G‡ and a thermoneutral or endergonic value of ∆Gadd. Catalyst
PiPr2
HT
hydrogenation (∆Ghyd; Scheme 2) competes with adduct formation
and, thus, there is an interplay between the free energies of both
reactions. In the case of FeN, ∆Ghyd (which will depend on the nature
of the catalyst) was calculated to be -10.2 kcal mol-1 under the
experimental conditions.13 The value of ∆Gadd - ∆Ghyd (∆GP, in Table
1) is therefore a measure of how adduct formation may limit the
reaction by catalyst poisoning (i.e. a more positive value is indicative
of less deactivation). For example, the production of methanol may
be expected to inhibit catalysis by adduct formation with FeN (entry
7; ∆Gadd = -6.9 kcal/mol). However, catalyst hydrogenation is even
more favorable (∆Ghyd = -10.2 kcal mol-1) making the FeHNH the likely
preferred species (∆GP = 3.3 kcal mol-1).
N
Fe CO
PiPr2
O
H
catalyst
hydrogenation
FeHNH
N
substrate
Ghyd
OH
PiPr2
H2
N
N
Fe CO
PiPr2
H
FeN
hemiaminal
H
C
Ph
Ph
O
N
H
N
H
O
O
catalyst poisoning
co-catalyst
GHT
H
N
Gadd
CH3
CH3
The DFT calculations using DMF as a model substrate yielded optimal
results for TBD (triazabicyclodecene) as a co-catalyst (Table 1, entry
1). The basic and rigid character of the guanidine scaffold provides a
Ph
C
O
N
H
H
H
proton shuttle-
assisted transfer
O
Ph
N
H
O
C
H
low proton transfer barrier (∆G‡ = 21.3 kcal mol-1), facilitating the
N
HT
H
PiPr2
Fe CO
PiPr2
C–N bond cleavage of the hemiaminal intermediate. Additionally,
TBD yielded a ∆Gadd close to zero (-1.5 kcal mol-1) and the second
largest ∆Gadd - ∆Ghyd (8.7 kcal mol-1), suggesting that the formation of
the adduct does not compete with the hydrogenation of the amide.
zwitterion
+
isomer
H2
N
FeN FeHNH
NH(CH3)2
H
product
adduct
CH2O
CH3OH
1,2,3-triphenylguanidiene (entry 8) yielded a similar ∆G‡ barrier,
HT
product
but with a more negative ∆Gadd value (-9.3 kcal mol-1), likely due to
its lower basicity compared to TBD. Acetanilide (entry 2) also
afforded promising results, in this case showing that replacement of
H by Me in the originally reported formanilide co-catalyst (entry 3)
changes ∆Gadd - ∆Ghyd from negative to positive, meaning lower
competition of the adduct formation towards amide hydrogenation.
Among single site hydrogen bond donors, phenols (entries 4-6)
exhibited some promise as a proton shuttle, although sterically large
substituents were required to alleviate formation of iron adducts
(AdductO, Fig. 1). Interestingly, morpholine and urea yield the largest
energy barrier of all of the co-catalysts (34.6 and 35.3 kcal mol-1,
respectively). This result suggests that a purely basic co-catalyst,
Scheme 2 Reaction mechanism for the deaminative hydrogenation of amides by Noyori-
type catalysts. Isomer = Fe N-bound form of the adduct. Color code: Hemiaminal
formation (blue), C–N cleavage by proton transfer (red), formaldehyde hydrogenation
(green) and adduct formation (black).
Results and discussion
Computational Co-catalyst design.
On the basis of the mechanism shown in Scheme 2, DFT calculations
were performed on a series of potential organic co-catalysts for the
hydrogenation of DMF using FeN (Table 1; see ESI for computational
details). The co-catalysts assessed included molecules with either
2 | J. Name., 2012, 00, 1-3
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although beneficial to prevent adduct formation, does not assist with experimentally (1.4 M of DMF, 0.02 M of TBD, 1 mM of FeN and fixed
View Article Online
5
DOI: 10.1039/C9SC03812D
the hemiaminal proton transfer. Overall, the computational results concentration of 0.162 M of H2, at 100 °C), the microkinetic model
indicate that the best co-catalysts are those which provide spatially yielded a high conversion of 27% over a short reaction time of 2
separated hydrogen bond donor and acceptor sites which can act as hours. This conversion is substantially higher than the conversion
push-pull proton shuttles, together with a basic character and/or with formanilide as co-catalyst (12%). The same trend was observed
steric bulky groups to prevent the formation of adducts.
by using 4-formylmorpholine as the substrate (see ESI),23
a
benchmark tertiary amide used in our prior studies on FeN-catalyzed
catalyzed deaminative hydrogenation. In this case, the conversions
with TBD and formanilide were 56% and 46%, respectively.
Table 1. Evaluation of Co-Catalysts for the Hydrogenation of Tertiary Amides with FeN.
O
R
H
FeN
R
[
], [Co-cat]
N
R
H
N
R
+
MeOH
30 atm H2, THF
2h, 100 o
Concerted proton transfer TSs
Step-wise proton transfer (highest in energy TSs)
C
R2
NH2
R1
N
R
H
Ph
O
O
X
N
H
O
X
N
N
H
N
R1
H
H
N
H
O
a
b
c
H
Entry
Co-catalyst
∆G‡
∆Gadd
∆GP
TONd
Conv.d
H
N
H
N
H
O
HT
H
N
CH3
CH3
O
N
CH3
CH3
O
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
TSNN-C
TSX-C
TSO-SW
TSN-SW
TSNH-SW
N
1
2
21.3
25.3
-1.5
-8.3
8.7
1.9
830
780
59%
55%
Methanol (X=O)
Morpholine (X=N)
Amide (X=O)
Guanidine (X=N)
N
N
TBD
Phenols
Urea
H
H
Adducts with the lowest energy
Ph
N
CH3
Ph
NH2
R2
N
N
R3
O
O
N
O
H
PiPr2
N
H
H
H
N
H
X
PiPr2
PiPr2
H
PiPr2
N
Fe CO
PiPr2
H
N
H
N
Fe CO
PiPr2
H
N
Fe CO
3
4
22.6
24.3
-12.2
-11.5
-2.0
-1.3
630
--
45%
--
Ph
N
Fe CO
PiPr2
PiPr2
O
H
H
CH3
AdductNN
AdductX
Methanol (X=O)
AdductNX
Amide (X=O)
AdductON
TBD
Urea
Morpholine (X=N)
Guanidine (X=N)
H3C
CH3
OH
Fig. 1 TSs and adducts obtained from DFT calculations to compute the assisted proton
transfer barrier (∆G‡HT) and adduct formation free energy (∆Gadd) for the co-catalysts
shown in Table 1.
CH3
5
21.8
-11.4
-1.2
--
--
iPr
iPr
OH
CH3
Experimental co-catalyst and catalyst testing.
6
7
25.5
29.6
4.4
14.6
3.3
560
510
40%
37%
The computational predictions of co-catalyst efficacy were examined
experimentally using 4-formylmorpholine (Table 1). Each potential
co-catalyst was tested in catalytic trials with a 1.75 mol% loading,
along with 0.07 mol% FeN under previously optimized conditions.5
Due to the high activity of the catalyst, the variable amount of time
required to manipulate the pressure vessel between trials, and the
need to equilibrate the vessel at the reaction temperature, it was not
possible to acquire reliable initial rate measurements (conversions <
10%). Instead, reaction times were limited to 2 hours to minimize
conversion and provide kinetically relevant comparisons. The
reaction progress was monitored by amide conversion because of
chromatographic issues in quantifying the morpholine product.
However, no signals other than starting materials, morpholine and
methanol were observed by GC-FID. As predicted by DFT, TBD proved
tBu
tBu
OH
CH3OH
-6.9
Ph
N
H
Ph
8
22.3
-9.3
1.4
440
31%
N
N
H
Ph
9
No additive
--
--
--
320
320
22%
22%
HN
10
34.6
8.0
18.2
O
O
11
35.3
-8.8
1.4
90
6%
H2N
NH2
∆G‡ (in kcal mol-1) corresponds to the calculated energy of the proton-
a
HT
transfer transition state with the highest energy for DMF assisted by the co-
catalysts (Scheme 2, Fig. 1). b ∆Gadd (in kcal mol-1) corresponds to the calculated
energy for the formation of the adduct (isomer with the lowest energy) formed
by [FeN] with the co-catalysts (Scheme 2, Fig. 1). c∆GP = ∆Gadd - ∆Ghyd (-10.2 kcal
mol-1 for all co-catalysts). d Experimental reaction conditions: 30 atm H2, 5 μmol
of [FeN] (0.07 mol %), (1.75 mol %) of each additive and 7 mmol of 4-
formylmorpholine in 5 mL of THF at 100 °C for 2h. TON and Conv. were
determined by GC-FID analysis of the products and remaining starting material.
Each entry is the average of two or more trials.
a
remarkable co-catalyst, affording a greater than two fold
enhancement in TON (compare entries 1 and 9) over the short
reaction time. Examination of the influence of TBD loading from 0 to
250 µmol (See ESI; Fig. S7) indicated a strong correlation between
TON and [TBD], saturating at approximately 200 µmol. The
computational results also successfully predicted the relative ability
of the other co-catalysts. For additives in which ∆GP is positive, the
best co-catalysts should be those which lower the ∆G‡HT involved in
the hemiaminal C–N bond cleavage, as illustrated in entries 1, 2, 6
and 7. In cases where iron deactivation is problematic due to a large
negative ∆Gadd, then the key barrier to amide hydrogenation is
approximated by the total energy difference between ∆Gadd - ∆Ghyd
The high co-catalytic activity predicted for TBD (entry 1) was further
analyzed by performing microkinetic modelling20–22 using the
complex reaction network we previously found for amide
hydrogenation (see ESI).13 Under the conditions typically used
and ∆G‡ which explains the superior performance of acetanilide
HT,
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over formanilide (entries 2 and 3). The only discernable variation non-metal mediated hemiaminal cleavage in our computed
View Article Online
DOI: 10.1039/C9SC03812D
from this trend is the unexpectedly poor performance of 1,2,3- mechanism, we hypothesized that the co-catalytic
triphenylguanidiene (entry 8), which may react in a different manner enhancements observed here with FeN should be generalizable
as indicated by an immediate color change upon treatment with FeN. to other systems. Indeed, highly active ruthenium catalysts
Table 3. Co-Catalytic Enhancement of Amide Hydrogenations using TBD.a
The use of urea in the reaction appeared to inhibit the reaction
(lower conversion than without additive), which is likely due to other
FeN
O
0.07 mol% [
x mol% TBD
]
irreversible reactions with the iron species or difficulties in drying the
very hydroscopic parent amide. Still, our rational co-catalyst design
has led to the identification of a remarkably active catalytic system
for selective amide hydrogenation.
R'
H
R'
N
R'
N
+
R'OH
60 atm H2, THF
16h, 120 o
R''
R''
C
Entry
Substrate
[TBD]
TONc
Table 2. Comparison of Co-Catalysts for Amide Hydrogenation with Pincer Supported
Group 8 Catalysts.a
Me
N
0
1.75
0
50
300
1150
5180
140
230
120
120
170d
O
H
H
1
2
3
Me
Ph
Ph
0.07 mol% [M]
H
O
1.75 mol% [Co-cat]
N
H
N
+
MeOH
30 atm H2, THF
2h, 100 °C
Ph
N
O
O
0.45
0
O
Catalyst
Co-catalyst
None
TONb
320
830
630
310
1200
0c
Convb
H
N
Me
1.75
0
O
23%
59%
45%
22%
86%
0c
H
N
PiPr2
Ph
4
1.75
1.75d
Ph
N
Fe
CO
O
PiPr2
TBD
H
FeN
a
Reaction conditions: 60 atm H2, 5 μmol of [Fe] (0.07 mol %), x μmol of TBD,
HCONHPh
None
and 7 mmol of 4-formylmorpholine in 5 mL of THF at 120 0C for 16h. b 30 atm
H2 at 100 °C for 2h. c TON were determined by GC-FID and NMR analysis of the
products and remaining starting material. Each entry is the average of three or
more trials. dTBD was substituted by N-phenylacetamide (Table 1; entry 2).
HBH3
H
PPh2
recently reported by Beller and Sanford24–26 also exhibit
substantial enhancement in activity upon co-catalytic addition
of TBD or formanilide (Table 2). The (PhPNHP)Ru(H)(CO)(BH4)
(RuBH4NH) precatalyst (PhPNHP = HN[CH2CH2(PPh2)]2) exhibited a
near 4-fold increase in TON for 4-formylmorpholine
hydrogenation over a short 2 hour reaction time in the presence
of TBD, making it one of the most active systems for
hydrogenation of this benchmark substrate. In this case,
formanilide inhibits the reaction by forming a stable ruthenium
adduct (Fig. S6). In contrast, with the (PNN)Ru(H)(CO)(BH4)
(RuPNN) (PNN = 3-(di-tert-butylphosphino)-N-[(1-methyl-1H-
imidazol-2-l)methyl]propylamine) precatalyst, the relative
difference in performance between TBD and formanilide is not
as large, likely because the steric bulk of the tert-butyl
substituents on the phosphine donors lowers the stability of a
formanilide adduct.
The co-catalytic effect of TBD with FeN across different classes
of amides was also investigated experimentally (Table 3).
Examples of dialkyl and diaryl formamides (entries 1 and 2)
exhibited significant enhancement in TON in the presence of
TBD compared to the reaction without co-catalyst. N-
phenylacetamide (entry 3), a substrate that previously proved
challenging for FeN, was also hydrogenated with greater
productivity in the presence of TBD. However, no enhancement
was observed upon TBD treatment of the corresponding
N
Ru
CO
TBD
PPh2
H
NH
RuBH4
HCONHPh
none
PtBu2
440
1170
1040
31%
84%
74%
HBH3
HN
Ru
N
CO
H
TBD
N
HCONHPh
RuPNN
a Reaction conditions: 30 atm H2, 5 μmol of [Fe or Ru] (0.07 mol %), 125 μmol
of co-catalyst, and 7 mmol of 4-formylmorpholine in 5 mL of THF at 100 0C for
2h. For [Ru] co-catalysts 10 μmol of NEt3 was added to activate the catalyst. b
Determine by GC-FID analysis of the products and remaining starting material.
Each entry is the average of two or more trials. c Formanilide reacts irreversibly
with this Ru catalyst to form an adduct, see ESI for details.
The few homogenous transition metal catalysts reported for
deaminative hydrogenation are all proposed to follow similar
pathways (Scheme 1), with Noyori-type bifunctional
mechanisms being prominent.14,15 Given the importance of
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benzamide (entry 4). This may be due to steric limitation at the
carbonyl moiety created by the larger phenyl substituent. In
this case, substituting TBD for a smaller co-catalyst provided a
modest increase in TON. These results suggest the co-catalytic
effect of TBD and related shuttles may be effective with more
diverse amides. Admittedly, the enhancement observed with
1
2
3
4
5
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diphenylformanilide was initially unexpected because
a
mechanism involving the iron-catalyst instead of formanilide,
was previously proposed for the hemiaminal C–N bond cleavage
using aryl amide substrates.13 However, the calculated G‡
HT
using the diphenylformanilide hemianimal intermediate and
TBD is lower (G‡ = 21.8 kcal mol-1) than the barrier for the iron-
assisted mechanism (G‡ = 28.6 kcal mol-1, see Fig. 2). This
result is in agreement with the enhanced reactivity observed for
the hydrogenation of diphenylformanilide using TBD as co-
7
catalyst (see Fig. 2).
8
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H
N
H
O
Ph
Ph
N
H
N
N
H
O
H
N
PiPr2
10
11
N
Fe CO
PiPr2
H
Ph
Ph
H H
28.6 kcal mol-1
21.8 kcal mol-1
Fig. 2 Gibbs energies associated with the C–N bond cleavage TSs for diphenylformamide
assisted by FeN and the TBD co-catalyst.
12
13
Conclusions
In conclusion, this work establishes the basis for co-catalyst
optimization in amide deaminative hydrogenation reactions using
Noyori-type catalysts. Key factors in the co-catalyst design include a
push-pull motif of hydrogen bonding sites to assist the C–N bond
cleavage of the hemiaminal and controlled acidity and steric
hindrance to prevent catalyst poisoning. Notably, these design
principles yielded co-catalysts enhancing the activity of systems
based on different transition metals. The generality of the co-catalyst
effect and its mechanistic understanding provide new opportunities
for the catalytic hydrogenation of challenging electron-rich carbonyl
compounds.
14
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The microkinetic model was performed using COPASI 4.22
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Microkinetic models show that 4-formylmorpholine reacts
in a similar manner than DMF (see ESI).
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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Ll.A., D.B. and A.N. thank the support from the Research Council
of Norway (FRINATEK Grant No. 250044 and Center of
Excellence Grand No. 262695), the Norwegian Metacenter for
Computational Science (NOTUR, nn4654k) and NordForsk,
(Grand No. 85378). U.J., W.B. and N.H. acknowledge support
from the U.S. Department of Energy, Office of Science, Basic
Energy Sciences, Catalysis Science Program (DE-SC0018222).
26
N. M. Rezayee, C. A. Huff and M. S. Sanford, J. Am. Chem.
Soc., 2015, 137, 1028–1031.
Notes and references
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Finding the balance: A combination of theory and expDeOrIi:m10e.1n03t9w/Ca9SsC03812D
used to rationally design co-catalysts for the deaminative
hydrogenation of amides. The optimal co-catalysts mediate the
proton transfers required in the key C–N bond cleavage step, while
preventing the formation of stable adducts with the metal catalyst.
Computational screening of a series of amides, guanidines and
alcohols identified TBD as the most promising co-catalyst, which
was confirmed experimentally with multiple pincer supported transition metal catalysts.