Dynamic Covalent Chemistry of Aldehyde Enamines: BiIII- and ScIII-Catalysis of Amine–Enamine Exchange

Article abstract of DOI:10.1002/chem.201702363

The dynamic exchange of enamines from secondary amines and enolizable aldehydes has been demonstrated in organic solvents. The enamine exchange with amines was efficiently catalyzed by Bi(OTf)₃ and Sc(OTf)₃ (2 mol %) and the equilibria (60 mm) could be attained within hours at room temperature. The formed dynamic covalent systems displayed high stabilities in basic environment with <2 % by-product formation within one week after complete equilibration. This study expands the scope of dynamic C?N bonds from imine chemistry to enamines, enabling further dynamic methodologies in exploration of this important class of structures in systems chemistry.

Full text of DOI:10.1002/chem.201702363

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Title: Dynamic Covalent Chemistry of Aldehyde Enamines: Bi(III)- and
Sc(III)-Catalysis of Amine-Enamine Exchange
Authors: Yang Zhang, Sheng Xie, Mingdi Yan, and Olof Ramström
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Dynamic Covalent Chemistry of Aldehyde Enamines: Bi(III)- and
Sc(III)-Catalysis of Amine-Enamine Exchange
Yang Zhang,[a] Sheng Xie,[a] Mingdi Yan,*[a][b] and Olof Ramström*[a]
Abstract: The dynamic exchange of enamines from secondary
amines and enolizable aldehydes has been demonstrated in
organic solvents. The enamine exchange with amines was
efficiently catalyzed by Bi(OTf)3 and Sc(OTf)3 (2 mol%) and the
equilibria (60 mM) could be attained within hours at room
temperature. The formed dynamic covalent systems displayed high
stabilities in basic environment with < 2% by-product formation
within one week after complete equilibration. This study expands
the scope of dynamic C-N bonds from imine chemistry to enamines,
enabling further dynamic methodologies in exploration of this
important class of structures in systems chemistry.
species.[46–48] This fact is most likely associated with the
enhanced nucleophilic reactivity of enamines, which can lead to
aldol-type reactions and thus quench the dynamic systems in
the process. However, in recent studies with enamine-azide
cycloadditions,[49] isolated or in situ-generated aldehyde
enamines were found to be relatively stable. Moreover, a recent
study also reported high stability of enamines in the presence of
1,8-diazabicycloundec-7-ene (DBU).[50] These results inspired
us to explore enamines as constituents for constitutional
dynamic chemistry. Since imines are generally labile under
basic conditions, this furthermore renders enamine exchange
unique from other C-N-based dynamic covalent systems.
Introduction
The emergence of constitutional dynamic chemistry, relying on
reversible reactions/interactions to change the constitution of
systems, has led to the establishment of
a range of
applications.[1–3],[4–14] For example, the design and discovery of
ligands, receptors, reactions, and catalysts have been
established,[15–30] a range of materials have been produced,[31–
35] and a basic understanding of complex networks and systems
has been established.[36–41] To meet with the operational
requirements of generating and applying complex systems, new
types of exchange reactions that enable novel constitutional
diversity are in high demand. In this context, constitutional
dynamic systems based on enamine exchange could be of
interest. For example, the integration of enamine bonds as
constitutional linkages enables the capability of cis/trans
isomerization, in principle controllable by noninvasive light.[42] In
addition, enamines are widely recognized as valuable activated
species in many important organic transformations,[43] thus
Figure
1 Exchange reactions of aldehyde enamines: (a) formation and
hydrolysis; (b) amine-enamine exchange; (c) aldehyde-enamine exchange.
The understanding of enamine chemistry has expanded
substantially in recent years due to the growing interest in
organocatalysis mediated by secondary amines.[43,51] The
relative tendencies of carbonyl compounds and amines to
condense into enamines has, for example, been evaluated
(Figure 1a).[52] In general, the condensation products from
aldehydes and amines display considerably higher degrees of
enamines at equilibrium compared to the corresponding ketone
species.[52] The condensation reactions between aldehydes and
amines can furthermore be selectively accomplished at ambient
temperature in the absence of added catalysts.[53] The high
chemoselectivity is in this context indicative of potential
compatibility with dynamic systems composed of diverse
opening
chemistry.[22,44]
In contrast to extensively explored imine exchange,[45]
a
pathway to catalyst discovery via dynamic
enamine exchange has not been evaluated in dynamic covalent
chemistry, other than for 3-iminoesters and ketones in
equilibrium with the corresponding α,β-unsaturated carbonyl
chemical
components.
For
aldehyde
enamines,
transenaminations (Figure 1b-c) have also been reported,
albeit very preliminarily.[54] These studies have been limited to
pyrrolidine derivatives, mainly involving Macmillan- and
Jørgensen-Hayashi catalysts. For constitutional dynamic
chemistry, the performance of the dynamic exchange, the
reactant scope, and the robustness of the systems are of
primary concern, especially regarding the modular structures
required. These challenges have been targeted in the present
study, where we report on efficient enamine exchange
processes with respect to reaction type, solvents, catalysts and
component structural effects (Figure 1).
[a]
[b]
Dr. Y. Zhang, Dr. S. Xie, Prof. Dr. M. Yan, Prof. Dr. O. Ramström
Department of Chemistry
KTH - Royal Institute of Technology
Teknikringen 36, S-10044 Stockholm, Sweden
E-mail: mingdi@kth.se, ramstrom@kth.se
Prof. Dr. M. Yan, Prof. Dr. O. Ramstrom
Department of Chemistry,
University of Massachusetts Lowell
1 University Ave., Lowell, MA 01854, USA
E-mail: mingdi_yan@uml.edu, olof_ramstrom@uml.edu
Supporting information for this article is given via a link at the end of
the document.
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Results and Discussion
catalyzed imine exchange under identical conditions, thus
supporting the use of catalyzed transenamination for generation
of constitutional dynamic systems.[40] Other Lewis-acidic metal
salts, including Zn(OTf)2, Cu(OTf)2 and AgOTf, also displayed
catalytic effects, but to lower extents (Table 2, entries 5-7). In
contrast to the Lewis acids, the use of trifluoroacetic acid only
resulted in 4 times rate enhancement (Table 2, entry 2). In
general, the equilibrium ratios remained unchanged upon
addition of catalysts, with selectivities very close to the
uncatalyzed reaction (selectivity ~ 1.7). Addition of Cu(OTf)2,
however, was found to shift the equilibrium to some extent
(selectivity = 1.4). The reason for this effect was in part
associated with a higher degree of by-product formation (~ 4%
after 10 h).
The equilibrium constants (Keq) for typical secondary amines
and aldehydes in different solvents were first evaluated (Table
1). This was accomplished by following the reactions by 1H
NMR, in accordance to a reported protocol (see supporting
information for details).[52] The amines were thus added to
aldehyde solutions in dry CDCl3, C6D6 or DMSO-d6, and the
equilibrations followed. A slight excess of the respective amine
was used in order to avoid formation of hemiaminal-type
intermediates,[55] and iminium hydroxides were only detected in
trace amount in all tests.[52] All condensations proceeded
smoothly without catalysts, where the equilibria in chloroform
and DMSO were attained within 1 h. In benzene, on the other
hand, equilibration was sluggish and the equilibrium time
exceeded 10 h. Highly favored enamine equilibria (Keq > 100)
were observed for phenylacetaldehyde with all secondary
amines, likely due to enhanced enamine stabilization through
conjugation. 3-phenylpropanal, resulting in unconjugated
enamines, showed fast equilibration and yielded significant
amounts of enamines (Keq up to 1.4 in CDCl3). Considering the
amine structure, acyclic diethylamine generally showed lower
enamine formation than cyclic amines, likely owing to the
weaker nucleophilicity and enhanced steric hindrance. In
addition, the observed equilibrium constants showed a high
dependence on the solvent, where chloroform favored the
enamine to a lower extent, while DMSO resulted in the highest
degree of enamine formation.
Table 2 Catalyzed transenamination.a
O
H
N
H
N
kf
N
N
+
+
kb
O
a
b
1
2
Entry
Catalystb
-
Selectivityc
Kobs
2.9
2.9
2.9
2.8
3.2
2.1
2.8
kf (M-1 h-1)d
0.024 ± 0.0005
0.17 ± 0.01
7.4 ± 0.3
Acceleratione
1
2
3
4
5
6
7
1.7
1
CF3COOH
Bi(OTf)3
Sc(OTf)3
Zn(OTf)2
Cu(OTf)2
AgOTf
1.7
7
1.7
310
310
200
180
40
1.7
7.5 ± 0.3
Table 1 Equilibrium constants (Keq) for enamine formation.a
1.8
4.7 ± 0.2
1.4
4.3 ± 0.3
Solvent
1.7
0.97 ± 0.08
CDCl3
C6D6
> 3000
802
1300
> 300
> 3200
1.1
990
0
a
Enamine 1 (62.8 mM), piperidine (62.8 mM), in CDCl3, 22 °C, monitored by
1H NMR. 2 mol% (added as 0.1 M CD3CN solution). Ratio of enamine 2 /
b
c
d
enamine 1 at equilibrium.
Calculated by nonlinear regression analysis
towards standard reaction model (cf. Supporting Information). e Relative ratio:
kf/kuncat
DMSO-d6
CDCl3
> 3200
1.4
.
0.14
The effect of the catalyst loading was then studied on the model
transenamination reaction (Figure 2, and Table S1). The rates
increased linearly with increased catalyst loading (< 8%)
(Figure S3), indicating a process first order in catalyst. The
fraction of enamine 2 at equilibrium was gradually influenced at
higher catalyst loadings. For Bi(OTf)3, loadings at 4-20 mol%
resulted in fractions of enamine 2 of 60-48%, as compared to
the case with < 2 mol% catalyst, which resulted in 63%. The
shift was even more significant when Sc(OTf)3 was used, where
4-20 mol% catalyst yielded fractions of 58-40%. Similar
observations have also been recorded for Sc(III)-catalyzed
imine exchange.[56] Coordination of the amines to the metal
cations may explain these equilibrium fraction shifts, and the
weaker coordination between the softer bismuth(III) and the
amine nitrogen correlates with a lower degree of equilibrium
shift compared with the Sc(III) species. With a catalyst loading
of < 2 mol%, the final equilibrium remained the same as in the
uncatalyzed system.
C6D6
13
11
0.68
68
DMSO-d6
1200
960
a
Reactions were conducted at 25 °C in CDCl3, C6D6 and DMSO-d6,
monitored by 1H NMR. See Figure S1 for details.
The effects of Brønsted- and Lewis acids on the amine-
enamine exchange were subsequently evaluated. The
exchange between isolated (E)-4-styrylmorpholine (1) and
piperidine (a) was thus studied in CDCl3, leading to equilibrium
formation with (E)-1-styrylpiperidine (2) and morpholine (b,
Table 2). A catalyst loading of 2 mol% was used throughout,
and the process was monitored by 1H NMR (cf. Supporting
Information). The resulting reactions with bismuth triflate
Bi(OTf)3 (Table 2, entry 3) and scandium triflate Sc(OTf)3
(Table 2, entry 4) displayed the highest rates (7.4 - 7.5 M-1 h-1)
in attaining enamine equilibria, and > 300 times rate
enhancement compared to the uncatalyzed transenamination
reaction (Table 2, entry 1). It can be noticed that this rate is
generally > 2 orders of magnitude higher than Sc(OTf)3-
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A
methyl-1-phenylmethanamine
(d),
(S)-(-)-N,α-
0.6
dimethylbenzylamine (e), dibenzylamine (f) and pyrrolidine (g)
(Figure 3)). The selectivity under both catalyzed and
uncatalyzed conditions followed the order: enamine 7 > 2 > 4 >
1 > 6 > 3 ~ 5, which correlated well with the stability trend of the
enamine formation, where amines with higher nucleophilicities
led to more stabilized enamines. Interestingly, the best
selectivity among acyclic amines was recorded for N-methyl-1-
phenylmethanamine (d), presumably owing to lower steric
hindrance, thus leading to a more stable enamine compared
with other amines (e, f).
0.4
0.2
0.0
20%
4%
2%
0.5%
0%
0
200
400
600
800
time (min)
B
0.6
0.4
0.2
0.0
20%
4%
2%
0.5%
0%
0
200
400
600
800
time (min)
Figure
2
Equilibration process between enamines 1 and 2 (initial
concentration of 1: 62.8 mM), at different loadings of Sc(OTf)3 (a), and
Bi(OTf)3 (b). Determined by 1H NMR following the enamine signals at 23 °C
in CDCl3.
The performance of the catalysis was also evaluated in four
typical solvents (Table 3). The rates of the forward reaction in
the uncatalyzed process (kf,uncat
influenced by the solvent, with
)
were relatively strongly
a solvent order for the
transenamination rate of MeCN > DMSO ~ CDCl3 > Benzene,
which correlated well with the solvent effect of the condensation
process. The catalytic effects of Sc(III) and Bi(III) varied with
the different solvents, and the rate acceleration was most
pronounced in benzene. Furthermore, the use of coordinating
solvents, such as DMSO, decreased the catalytic effects
substantially. Similar effects were also observed in Sc(OTf)3-
catalyzed imine exchange.[40] The fastest equilibrium formation
of the model reaction was observed in CD3CN using Bi(OTf)3,
where a forward rate of 16.0 M-1 h-1 was achieved.
Table 3 Catalyzed transenamination between compounds 1 and 2 in different
solvents.a
Figure 3 Exchange reactions between enamines (1 or 8) and secondary
amines.
Entry
Solvent
kf (M-1h-1)c
ScIII b
BiIII b
Accd
310
Accd
310
Control
0.024 ±
0.0005
1
2
3
4
CDCl3
C6D6
7.4 ± 0.3
7.5 ± 0.3
The selectivity values recorded for the Bi(III)- and Sc(III)-
catalyzed reactions were for most systems analogous to the
corresponding uncatalyzed reactions (Table 4). A slight shift
0.015 ±
0.001
4.0 ± 0.2
270
2.9
54
4.1 ± 0.2
280
3.6
49
towards the pyrrolidine-based enamine
7 was however
observed with Sc(III) (Table 4, entry 6). Furthermore, all acyclic
and cyclic amines displayed relatively close selectivity values in
the exchange reactions with enamine 1. This isoenergetic effect
is advantageous for dynamic covalent reactions that are aimed
for more complex constitutional systems.
The rates (kf) of the Bi(III)-catalyzed and uncatalyzed
enamine exchange reactions both followed the same order
(Table 4, entries 3 > 5 > 4 > 6 > 1 > 2). The highest rate (Table
4, entry 3) was observed for N-methyl-1-phenylmethanamine
(d), being more than one order of magnitude faster than all the
other amines. However, the relative rate enhancements of the
catalyzed reactions compared to the uncatalyzed counterparts
DMSO-
d6
0.090 ±
0.003
0.11 ±
0.009
0.031 ±
0.001
CD3CN
16.0 ± 1.1
15.0 ± 1.0
0.30 ± 0.2
a Enamine 1 (62.8 mM), piperidine (62.8 mM), 22 oC, monitored by 1H NMR; b
2 mol% (added as 0.1 M in CD3CN); Calculated by nonlinear regression
analysis towards standard reaction model (cf. Supporting Information);
Acceleration; relative ratio: kf/kuncat
c
d
.
The influence of the amine structure on the kinetic (kf) and
thermodynamic (selectivity) parameters of the exchange
process was studied with enamine 1 and diethylamine (c), N-
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(kf/kf,uncat) followed a different order of amine substrates (for
Bi(III): Table 4, entries 3 > 6 > 1 > 4 > 2 > 5). Sc(III) behaved
similar to Bi(III), mainly differing for amines 6 and 7 (Table 4,
entries 5 and 6), where the rates were almost a factor two lower.
The relative results for the non-conjugated enamine exchange
(Table 4, entry 7) were very similar to those for the
corresponding conjugated enamine (Table 4, entry 1).
Table 4 Selectivities and exchange rates between enamines 1 and 8 and secondary amines.a
Entry
Enamines
Selectivity
ScIII b
1.7
kf (M-1h-1)c
ScIII
BiIII b
1.7
0.4
1.5
0.4
0.3
4.0
1.8
Control
1.7
BiIII
Control
kf(Bi) : kf(Sc) : kf(control)
310 : 310 : 1
210 : 190 : 1
310 : 300 : 1
250 : 230 : 1
75 : 37 : 1
1
2
3
4
5
6
7
1/2
1/3
1/4
1/5
1/6
1/7
8/9
7.4 ± 0.3
3.1 ± 0.04
270 ± 40
13 ± 0.1
20 ± 1.2
12 ± 1.3
166 ± 11
7.5 ± 0.3
2.8 ± 0.06
260 ± 30
12 ± 0.2
9.8 ± 0.3
6.8 ± 1.0
178 ± 12
0.024 ± 0.0005
0.015 ± 0.0008
0.87 ± 0.02
0.5
0.4
1.5
1.5
0.4
0.4
0.052 ± 0.01
0.26 ± 0.01
0.3
0.3
5.4
4.0
0.038 ± 0.002
0.54 ± 0.003
320 : 180 : 1
310 : 330 : 1
1.8
1.7
a Enamine (62.8 mM), amine (62.8 mM), 22 °C, in CDCl3, monitored by 1H NMR. b 2 mol% (added as 0.1 M CD3CN solution); c Calculated by nonlinear regression
analysis towards standard reaction model (cf. Supporting Information); d Relative ratio: kf/kuncat
.
High constitutional stabilities were observed at equilibrium for
both the catalyzed- and uncatalyzed transenamination
Acknowledgments
reactions. As monitored by 1H NMR, < 3% variations in the
spectra were recorded for up to 7 days. In these tests, two
equivalents of amine were added together with one equivalent
of aldehyde, in congruence with the situation in the amine-
enamine exchange reactions. As expected, the major side
reaction recorded was the aldol condensation, identified in
independent experiments (cf. Supporting information).
The study was in part supported by the Royal Institute of
Technology and the Swedish Research Council. YZ and SX
thank the China Scholarship Council for special scholarship
awards.
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Conclusion
In summary, reversible exchange reactions of aldehyde
enamines (C=C-N) have been studied, showing comparable
capabilities of generating constitutional dynamic system as
other reversible C-N bonds, such as imines. Different amines
and aldehydes were evaluated, for which efficient exchange
reactions in general could be shown. Secondary amines and
aldehydes thus readily condensed to enamines at room
temperature in various organic solvents, and the equilibration
constants were shown to be influenced by the solvent
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accomplished within hours. Complementary to imine systems,
the current dynamic enamine systems showed improved
stability with less side reactions under basic conditions. The
results support the potential of using enamine-mediated
exchange processes to generate constitutional dynamic
systems for different applications in dynamic chemistry.
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10.1002/chem.201702363
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Yang Zhang, Sheng Xie, Mingdi Yan,*
and Olof Ramström*
Page No. – Page No.
Dynamic Covalent Chemistry of
Aldehyde Enamines: Bi(III)- and
Sc(III)-Catalysis of Amine-Enamine
Exchange
Dynamic Chemistry. The dynamic exchange of enamines from secondary amines
and enolizable aldehydes can be efficiently catalyzed by Bi(III) and Sc(III) at room
temperature. Dynamic enamine systems, stable under basic conditions, were
formed in organic solvents with up to > 300 times higher equilibration rates than the
corresponding uncatalyzed reactions.
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