Delineation of the Critical Parameters of Salt Catalysts in the N-Formylation of Amines with CO2

Article abstract of DOI:10.1002/chem.201901686

N-formylation of amines combining CO₂ as a C1 source with a hydrosilane reducing agent is a convenient route for the synthesis of N-formylated compounds. A large number of salts including ionic liquids (ILs) have been shown to efficiently catalyze the reaction and, yet, the key features of the catalyst remain unclear and the best salt catalysts for the reaction remain unknown. Here we demonstrate the detrimental effect of ion pairing on the catalytic activity and illustrate ways in which the strength of the interaction between the ions can be reduced to enhance interactions and, hence, reactivity with the substrates. In contrast to the current hypothesis, we also show that salt catalysts are more active as bases rather than nucleophiles and identify the pKa where the nucleophilic role of the catalyst switches to the more active basic role. The identification of these critical parameters allows the optimum salt catalyst and conditions for an N-formylation reaction to be predicted.

Full text of DOI:10.1002/chem.201901686

A Journal of
Accepted Article
Title: Delineation of the Critical Parameters of Salt Catalysts in the N-
Formylation of Amines with CO2
Authors: Martin Hulla, Daniel Ortiz, Sergey Katsyuba, Dmitry Vasyliev,
and Paul J. Dyson
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To be cited as: Chem. Eur. J. 10.1002/chem.201901686
Link to VoR: http://dx.doi.org/10.1002/chem.201901686
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10.1002/chem.201901686
Chemistry - A European Journal
Delineation of the Critical Parameters of Salt Catalysts in the N-
Formylation of Amines with CO2
Martin Hullaa, Daniel Ortiza, Sergey Katsyubab, Dmitry Vasylieva and Paul J. Dysona*
Abstract: N-formylation of amines combining CO2 as a C1 source
with a hydrosilane reducing agent is a convenient route for the
synthesis of N-formylated compounds. A large number of salts
including ionic liquids (ILs) have been shown to efficiently catalyze
the reaction and, yet, the key features of the catalyst remain unclear
and the best salt catalysts for the reaction remain unknown. Here we
demonstrate the detrimental effect of ion pairing on the catalytic
activity and illustrate ways in which the strength of the interaction
between the ions can be reduced to enhance interactions and,
hence, reactivity with the substrates. In contrast to the current
hypothesis, we also show that salt catalysts are more active as
bases rather than nucleophiles and identify the pKa where the
nucleophilic role of the catalyst switches to the more active basic
role. The identification of these critical parameters allows the
optimum salt catalyst and conditions for an N-formylation reaction to
be predicted.
ILs and other simple salts were shown to be efficient catalysts
for the N-formylation of amines employing CO2 as a C1 source
in combination with hydrosilane reducing agents (Scheme 1).10 It
was proposed that the nucleophilicity of the anion activates the
9,11,17
hydrosilane reducing agent enabling the reduction of CO2
or, more recently, ILs were shown to act as a base during
carbamate assisted activation (vide infra).18 In both cases, the
activity of the salt predominantly depends on the nature of the
anion with a well-defined trend in the halide series being I- < Br-
< Cl- << F-.11 Tetrabutylammonium fluoride ([TBA]F)9,11 and
Cs2CO319 were identified as particularly efficient catalysts for the
N-formylation reaction with comparable activity to the best metal
catalysts based on Fe,20 Rh,21 W22 and Cu.23,24 In addition,
cooperative catalytic behavior was observed between Zn
complexes and ILs.25 Although, the activity of
a salt is
predominantly dependent on the anion, the cation also plays a
significant role. Various functionalities can be introduced onto
the cation to help activate the amine, CO2 or the hydrosilane.
However, apart from the effect of the cation on the solubility of
the salt, in the case of alkali metal carbonates,19 the role of the
cation has not been systematically investigated. Consequently,
we decided to study a series of chloride salts (Figure 1) and
investigate the underlying mechanistic reasons behind the
observed differences in reactivity and then systematically modify
the anion in order to obtain a complete picture of the behavior of
salt catalysts.
Introduction
Carbon dioxide is a cheap, non-toxic and abundant waste
product of the petrochemical industries making it an attractive
C1 building block for chemical synthesis.1 However, its inherent
high stability limits its uncatalyzed reactions to high energy
substrates. For all other applications efficient catalysts are
needed to allow it to be effectively utilized as a reagent. Ionic
liquids (ILs) and other simple salts are promising catalysts for a
number of CO2 related applications including the synthesis of
cyclic carbonates,2–4 quinazolinediones,5,6 oxazolidinones,7,8 N-
methylamines,9 N-formylamines10,11 and other compounds.12–14
Synthetic modification of the cation and/or anion allows a near-
infinite number of salts to be prepared,15,16 while simultaneously
allowing their performance to be tuned for a desired application.
However, the design of more efficient salt catalysts is frequently
hampered by limited mechanistic understanding and incomplete
structure activity relationships, in part due to
benchmark reaction conditions.
a lack of
Figure 1: Structures of the cations employed in this study (all as chloride
salts).
Scheme 1: N-Formylation of Amines with CO2 and hydrosilane reducing
agents.
Results and discussion
Under standardized reaction conditions (10 mol% catalyst, 1 bar
CO2, 25 °C, 6 h, solvent-free) with N-methylaniline as the
substrate, 1-butyl-3-methylimidazolium chloride ([BMIm]Cl), the
prototype IL catalyst reported for this reaction,10 afforded the N-
methylformanilide product in 3% yield (Table 1, entry 2). Slightly
higher yields of 7, 11 and 15%, were obtained with 1-butyl-1-
[a]
[b]
M. Hulla, Dr. D. Ortiz, D. Vasyliev, Prof. Dr. P.J Dyson
Institute of Chemistry and Chemical Engineering
École Polytechnique Fédérale de Lausanne (EPFL),
CH-1015 Lausanne, Switzerland
E- mail: pjd@epfl.ch
Dr. Sergey KatsyubaTitle(s), Initial(s), Surname(s) of Author(s)
Arbuzov Institute of Organic and Physical Chemistry
FRC Kazan Scientific Center of RAS
methylpyrrolidinium
dimethylimidazolium
chloride
chloride
([BMP]Cl),
1-butyl-2,3-
and
([BdMIm]Cl)
Arbuzov st. 8, 420088, Kazan, Russia
tetrabutylammonium chloride ([TBA]Cl), respectively (Table 1
entries 3-5). The highest conversion was obtained with
tetraphenylphosphonium chloride ([Ph4P]Cl), which yielded the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201901686
Chemistry - A European Journal
product in 16% (Table 1, entry 6). In contrast, no product was
observed when the hydroxyl-functionalized imidazolium IL 1-
hydroxyethyl-3-methylimidazolium chloride ([HOEMIm]Cl) was
employed as the catalyst (Table 1, entry 1).
solvent tested, almost no differences can be seen among the
chloride salts tested with N-methylformanilide yields being
around 55% (Table S1).
Interestingly, higher yields are obtained for salts with benign
(alkyl-functionalized) cations rather than [HOEMIm]Cl and
[BMIm]Cl, which can interact with both the substrate and CO2 by
H-bonding or form N-heterocyclic carbenes (NHCs) following in
situ C(2)-H deprotonation.26,27 Hydrogen bonds play a key role in
Table 1: N-formylation of N-methylaniline with
catalysts.
a
series of chloride salt
a
number of salt catalyzed CO2 reactions such as the
cycloaddition of CO2 to epoxides,28,29 which like the N-
formylation reaction, is also predominantly driven by the anion.30
In addition, NHCs were shown to be excellent catalysts for the
N-formylation of amines with CO2 and hydrosilanes.31 However,
neither H-bonding interactions nor NHCs seem to facilitate the
reaction. We postulated that the cation only affects the reaction
indirectly by ion pairing, thereby decreasing the reactivity of the
anion.11 H-bond donor groups can interact with halide ions,
thereby increasing the ion pairing energy, resulting in the poor
yields obtained with [HOEMIm]Cl and [BMIm]Cl. Consequently,
we determined the relative strengths of the ion pair binding for
the series of chloride salts by electrospray ionization mass
spectrometry (ESI-MS).32,33 During the ESI-MS measurements,
the salts aggregate into clusters, the magnitude of which
depends on the cation-anion binding energies and sample
concentration. Under the conditions employed, clusters of
varying sizes from simple singly charged {[C]2[A]}1+ to quadruply
charged {[C]92[A]88}4+ aggregates were observed, depending on
the salt under study (Figure 2). The extensive clustering
observed indicates that ion pairing, under the reaction conditions
employed, is significant with a strong potential to affect the
reaction rate.
Entry
1
Catalyst
[HOEMIm]Cl
[BMIm]Cl
[BMP]Cl
[BdMIm]Cl
[TBA]Cl
Solvent
-
Yield (%)
0
2
-
3
3
-
7
4
-
11
15
16
0
5
-
6
[Ph4P]Cl
-
-
7
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
8
[HOEMIm]Cl
[BMIm]Cl
[BMP]Cl
[BdMIm]Cl
[TBA]Cl
7
9
14
16
20
22
20
13
60
61
71
71
70
72
10
11
12
13
14
15
16
17
18
19
20
2.5x108
a)
[Ph4P]Cl
-
139.1228
b)
2.0x108
1.5x108
1.0x108
5.0x107
0.0
8.0x105
6.0x105
4.0x105
2.0x105
0.0
[HOEMIm]Cl
[BMIm]Cl
[BMP]Cl
[BdMIm]Cl
[TBA]Cl
500
1000
1500
2000
m/z
2500
3000
3500
4000
313.2152
[Ph4P]Cl
200
400
600
800
1000
Reaction conditions: catalyst (10 mol%), N-methylaniline (1 mmol),
phenylsilane (2 mmol), solvent (1 ml), CO2 (1 bar), 25°C, 6 h, average GC
yield from three runs with decane as internal standard.
m/z
Figure 2: ESI-MS of [BMIm]Cl recorded in DMF, 1 µM. a) Low mass 50-1000
m/z: 139.1 and 313.2 m/z peaks correspond to [BMIm]+ and {[BMIm]2Cl}+,
Although the differences are small, a trend in the reactivity is
apparent, i.e. [HOEMIm]Cl < [BMIm]Cl < [BMP]Cl < [BdMIm]Cl <
[TBA]Cl ~ [Ph4P]Cl. With the addition of a polar aprotic solvent,
such as acetonitrile, DMF or DMSO, a moderate to large
increase in the reaction yields is observed and the differences
between the activities of the salts diminish (Table 1, entries 8-13
and 15-20). In MeCN the order of the reactivity remains largely
unchanged with [HOEMIm]Cl and [BMIm]Cl being the least
active catalysts and [TBA]Cl together with [Ph4P]Cl the most
active. In the case of DMF, the trend is almost completely lost
and only two groups of salts can be identified, such that
[HOEMIm]Cl ~ [BMIm]Cl < [BMP]Cl ~ [BdMIm]Cl ~ [TBA]Cl ~
[Ph4P]Cl (Table 1, entries 15-20). In DMSO, the highest polarity
(1-4)+
respectively. b) High mass 450-4000 m/z showing {[BMIm]3-92Cl2-88
}
peaks.
The extent of clustering is largely dependent on the ionic
bond strength and, therefore, clusters were generated from pairs
of different cations (i.e. from two salt catalysts with chloride as
the anion), which were then fragmented to assess the relative
bond strength of each ion pair.33,34 ESI-MS/MS fragmentation
studies were performed on cluster ions of formula {[C1][A][C2]}+
with the most weakly bound cation dissociating from the cluster,
and the remaining neutral ion pair not being observed. By
generating mixed ion-clusters of all possible combinations of the
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10.1002/chem.201901686
Chemistry - A European Journal
salts, followed by fragmentation studies, a relative cation-anion
binding scale was generated. The relative binding strength of the
ion pairs is [HOEMIm]Cl > [BMIm]Cl > [BMP]Cl > [BdMIm]Cl >
[TBA]Cl > [Ph4P]Cl, which is in complete agreement with the
prediction, where more tightly bound ion pairs result in lower
catalytic activity of the salt. Furthermore, the binding strength of
the [Ph4P]+ cation is, comparatively, so small that a mixed
cluster of this cation was only generated with the other weakest
interacting [TBA]+ cation. In all other cases, where a second salt
was present, no {[Ph4P]xCly}x-y clusters or [Ph4P]+ mixed clusters
were detected.
To quantify the trend and differences observed for the salts,
binding energies (BEs) and binding free energies (BGs) of
isolated ion pairs were estimated using DFT calculations (SI).
The calculated BEs and BGs (Table 2) confirm the order of
binding strength estimated by ESI-MS/MS. In addition, polar
aprotic solvents such as DMF and DMSO can efficiently
separate the ion pairs by charge screening, resulting in the loss
of the reaction trend observed under solvent-free reactions.
Combined, the ESI-MS/MS studies and DFT calculations
support the proposed hypothesis that salts with lower BE exhibit
higher catalytic activities. The influence of ion pairing on catalytic
activity, however, can be reduced by the reaction solvent.
as it limits the effect of ion pairing (Table S1) and due to the
availability of extensive pKa tables in this solvent.
Surprisingly, in the N-formylation of N-methylaniline, all
catalysts with pKa ≥ 7.5 afforded N-methylformanilide in around
50% yield (the maximum expected based on the experimental
conditions), whereas all salts with pka ≤ 4.0 were almost inactive
(Table 3). A linear increase in activity is observed for catalysts of
intermediate basicity with pKa values between 4.0 and 7.5
(Figure 3a). The only exception are para-substituted benzoate
and phenolate anions (Table 3, entries 5, 9 and 11), where the
yields are slightly lower than predicted from the linear trend,
presumably due to steric factors. Hence, it would appear that the
reaction is indeed base catalyzed by salts with pKa > 4.0, with a
maximum activity reached at pKa values ≥ 7.5. The minor
variations observed for anions with pKa values ≥ 7.5 can be
attributed to the difference in BEs and ion pairing (vide supra)
and to varying degree of catalyst inhibition by the reversible
binding of the anion to the hydrosilane.18
Table 3: N-formylation of N-methylaniline with
butylammonium salts with anions of varying basicity.
a
series of tetra-n-
Table 2: DFT calculated binding energies and binding free energies of the
salts studied (kcal.mol-1).
Entry
1
Catalyst
pKa*
0.9
Yield (%)
Entry
IL
Binding energy
103.2
96.2
Binding free energy
[TBA]Br
0
1
2
3
4
5
6
[HOEMIm]Cl
[BMIm]Cl
[BMP]Cl
[BdMIm]Cl
[TBA]Cl
[Ph4P]Cl
104.7
99.3
98.1
97.5
91.0
83.2
2
[TBA]Cl
1.9
1
3
[TBA][CF3CO2]
3.5
1
95.2
4
[TBA][sacharinate]
[TBA][2,4-dinitrophenolate]
[TBA][thiobenzoate]
[TBA][2-carboxybenzoate]
[TBA][dichloroacetate]
[TBA][2-hydroxybenzoate]
[TBA][SAc]
4.0
1
94.0
5
5.1
3
89.2
6
5.2
25
32
36
26
38
26
53
49
50
52
46
53
51
81.8
7
6.2
8
6.4
Different anions can result in large changes in the catalytic
activity as demonstrated with the halide series, where I- < Br- <
9
6.6
-
Cl- << F-.11 In contrast, tetrafluoroborate (BF4 ) and
-
hexafluorophosphate (PF6 ) salts are catalytically inactive.10
10
11
12
13
14
15
16
17
18
6.7
Based on these observations and the fact that [TBA]F can
activate hydrosilanes in the reduction of carbonyls,35–39 the
activity of salt catalysts was attributed to the nucleophilicity of
the anion and its ability to activate the hydrosilane reducing
agent prior to CO2 insertion.10,11 A number of salts including
[TBA]F,11 Cs2CO3,19 glycine betaine,40 zwitterionic P-ylide-CO2
adducts41 and various carboxylates42 were proposed to act this
way. However, more recent experimental evidence with tetra-n-
butylammonium acetate ([TBA][OAc]) suggests that the reaction
is base catalyzed.18
Hence, we decided to test a series of TBA+ salts with anions
of varying basicity in order to examine the effect of the base
strength on the N-formylation reaction (Table 3). To facilitate
comparison, reaction conditions were employed that give
intermediate N-methylaniline conversions with the most active
[TBA]F and [TBA][OAc] catalysts (5 mol% catalyst, DMSO, 1 bar
CO2, 25 °C, 1 h). The polar aprotic solvent DMSO was chosen
[TBA][2,4-dihydroxybenzoate]
[TBA][NO2]
7.1
7.5
[TBA][4-nitrobenzoate]
[TBA][benzoate]
[TBA][benzotriazolate]
[TBA][OAc]
9.1
11.1
11.9
12.6
13.4
15.0
[TBA][phthalimide]
[TBA]F.3H2O
Reaction conditions: catalyst (5 mol%), N-methylaniline (1 mmol), phenylsilane
(2 mmol), DMSO (1 ml), CO2 (1 bar), 25°C, 1 h, average GC yield from three
runs with decane as internal standard. *pKa of conjugate acid (BH+).43–46
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10.1002/chem.201901686
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Figure 3: Dependency of reaction yield on the pKa of the catalyst in DMSO in the N-formylation of a) N-methylaniline, b) 3,5-dimethylaniline and c) benzylamine.
These trends are consistent with the ability of the amine to
form a carbamate salt, which depends on the basicity of the
amine and inversely on the extent of its substitution.49 As a
result, 3,5-dimethylaniline requires weaker bases for carbamate
salt stabilization, whereas the N-substituted N-methylaniline
requires stronger bases to achieve a comparable reactivity. In
addition, the absence of
a clear pKa-activity trend for
benzylamine confirms the formation of a carbamate salt as the
rate determining step for amines that do not spontaneously form
Figure 4: The two highest energy transition states along the N-formylation
pathway
stable carbamate salts. Reaction of the amine with
a
formoxysilane intermediate was proposed as a second base
stabilized transition state along the reaction pathway (Figure 4,
TS2),47 which can explain the small increase in benzylamine
conversion if the rate-determining step is shifted to the latter
transition state. Overall, these trends confirm the reaction as
base catalyzed and indicate the optimal base strength for each
substrate.
While the base catalyzed reaction mechanism can explain
the linear increase in the reaction rate observed for N-
methylaniline and 3,5-dimethylaniline, as well as the absence of
such an increase for benzylamine, it does not explain the
catalytic activity of [TBA]Cl in the N-formylation of N-
methylaniline. Although, under the modified reaction conditions
(5 mol% catatalyst, 1 h), N-methylaniline conversion with
[TBA]Cl remains around 1%, [TBA]Cl is an active catalyst, which
resulted in the reaction yield increase from 13 to 70% under the
original reaction conditions (10 mol% catalyst, 6 h) in DMF
(Table 1, entries 14 and 19). Since chloride is a conjugate base
of a strong acid it is unlikely to act as a base. However, it can act
Based on DFT calculations with NHCs,47 it was proposed that a
base catalyst stabilizes the formation of a carbamate salt, which
in turn activates the hydrosilane for CO2 insertion (i.e. acting as
a nucleophile) (Figure 4, TS1). Recently, a similar observation
was made with [TBA][OAc], where a synergistic effect on the
rate of CO2 reduction between the [TBA][OAc] catalyst and N-
methylaniline was observed.18 From the activity-pKa trend
recorded here, it would appear that for N-methylaniline, a
catalyst with pKa values > 4.0 is required for the carbamate salt
stabilization, with maximum stabilization reached for all TBA+
salts with pKa values ≥ 7.5 in DMSO irrespective of the structure
of the anion. In addition, the stability of the carbamate salts are
further enhanced by polar solvents,48 which can also partly
explain the differences among the solvent free reactions and
reactions carried out in MeCN, DMF and DMSO. However, since
carbamate salt formation is predominantly dependent on the
amine used the observed trend with N-methylaniline does not
directly apply to other amines. In addition, the reaction
mechanism was shown to be, at least in part, substrate
dependent reflecting the tendency of some amines to
spontaneously form carbamate salts.18 We therefore decided to
evaluate two additional amines, 3,5-dimethylaniline (Table S2),
which interacts strongly with CO2, and benzylamine (Table S3),
which spontaneously forms a stable carbamate salt with CO2
even in the absence of a base catalyst. With 3,5-dimethylaniline
a similar trend to N-methylaniline is observed (Figure 3b). The
only difference being the apparent onset of the base catalyzed
reaction mechanism, as an upward trend is observed in the pKa
range from 0.9 to 8 instead of the range from 4.0 to 7.5, where
the activity plateaus. With benzylamine no clear upward trend is
observed (Figure 3c). However, a small step change in
conversion takes place between catalyst pKa values of 1.9 and
3.5, indicating that a base catalyst plays a role even for N-
formylation of amines that spontaneously form stable carbamate
salts.
as
a nucleophile following the original reaction pathway
proposed and directly activate the hydrosilane for CO2
insertion.10,11 In addition, the base catalyzed pathway is, in
principle, also dependent on nucleophilic activation of the
hydrosilane, but the role is fulfilled by the carbamate formed
rather than directly by the catalyst.47 As a result, the role of the
catalyst may be different, but the overall path remains mostly
unchanged, thus allowing a large number of bases and
nucleophiles to act as catalysts for the reaction. Nevertheless,
the base catalyzed mechanism remains energetically favored for
catalysts that can stabilize the carbamate salt.
Overall, including an earlier report on IL catalysts,10 three
groups of salts can be identified (Figure 5). First are salts with
-
-
non-nucleophilic/non-basic anions such as BF4 and PF6 which
are inactive. The second group is mildly active and is composed
-
of salts with nucleophilic anions such as Br-, Cl- and CF3CO2 .
These promote the nucleophilic pathway towards N-
formylamines for amines of low basicity. The third group
comprises very active catalysts and is composed of salts with
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10.1002/chem.201901686
Chemistry - A European Journal
basic anions such as F- or OAc-. The transition from the
nucleophilic pathway to the basic pathway is substrate
dependent and for N-methylaniline appears around a catalyst
pKa of 4, and no further benefit is observed by increasing the
pKa above 7.5. In comparison, all tested catalysts appear to
promote the basic pathway for 3,5-dimethylaniline, marked by a
gradual increase in catalytic activity with increasing basicity of
the anion, and only a small step increase is observed for
benzylamine, where carbamate salt formation is not the rate-
determining step.
We thank the Claude and Giuliana Foundation, the Swiss
Competence Center for Energy research (SCCER) and the
EPFL for funding.
Keywords: Sustainabe chemistry, N-Formylation, Carbon
dioxide, Hydrosilanes, Catalysis, Base catalysis, Ion-pairing
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Figure 5: Examples of salt anions divided into three groups based on the
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Conclusions
By combining the ion pairing data with the anion data, structure
activity relationships can be derived between the salt catalyst
and its catalytic activity in the N-formylation reaction. First, the
ion binding energy and associated ion pairing should be
minimized either by the design of the salt, i.e. delocalized or
buried charge on the cation to minimize ionic interactions with
the anion51 and use groups that minimize non-covalent
interactions.52 Alternatively, the use of polar aprotic solvents
such as DMF which solvate and separate the ions can be used.
Since hydrogen bonds significantly increase the ion binding
energy, hydrogen bond donor groups on the cation should be
avoided. Second, both nucleophilic and basic anions can be
used as catalysts, but considerably higher activity is observed
with basic anions with pKa > 4 and maximum above 7.5 for N-
methylaniline. Similar maxima appear above pKa values of 8 for
3,5-dimethylaniline and 3.5 for benzylamine. Further increasing
the pKa of the anion above these pKa values provides little
catalytic benefit, but allows for a wide window of modifications in
order to reach the desired physical properties of the salt catalyst.
The influence of the pKa also supports the role of salt catalysts
as bases in the reaction, the role of carbamate salts in the rate-
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FULL PAPER
Unbound and basic: Almost all salts
promote the N-formylation of amines
with CO2. However, not all do it well.
Herein, we present the physical
parameters of salt catalysts critical for
high activity. Namely their basicity,
which is linearly proportionate to the
catalytic activity of the salt and the
extent of ion pairing, which also
impacts significantly on the activity.
Martin Hullaa, Daniel Ortiza, Sergey
Katsyubab, Dmitry Vasylieva and Paul J.
Dysona*
Page No. – Page No.
Delineation of the Critical Parameters
of Salt Catalysts in the N-Formylation
of Amines with CO2
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