Examination of the Dynamic Covalent Chemistry of [2 + 3]-Imine Cages

Article abstract of DOI:10.1021/acs.joc.0c01887

The synthesis of shape-persistent organic cage compounds by the formation of imine bonds opens the possibility to realize cages of different sizes, geometries, topologies, and functions. It is generally assumed that the imine bond is rather chemically labile allowing a self-correction mechanism until thermodynamic equilibrium is reached, which is often the case if a cage is formed. However, there are some contradictory experimental data to this assumption. To get a deeper insight into the imine bond dynamics of covalent organic cages, we studied the formation and exchange of both dialdehydes and triamines of two different [2 + 3] imine cages with the aid of a deuterated dialdehyde molecular building block.

Full text of DOI:10.1021/acs.joc.0c01887

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Article
Examination of the Dynamic Covalent Chemistry of [2+3]-Imine Cages
Tobias H. G. Schick, Frank Rominger, and Michael Mastalerz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01887 • Publication Date (Web): 15 Sep 2020
Downloaded from pubs.acs.org on September 16, 2020
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Examination of the Dynamic Covalent Chemistry of [2+3]-Imine Cages
Tobias H. G. Schick, Frank Rominger, and Michael Mastalerz*
1
1
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Organisch-Chemisches Institut Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld
2
70, 69120 Heidelberg (Germany).
E-mail: michael.mastalerz@oci.uni-heidelberg.de
Et
Et
Et
Et
Et
Et
Et
Et
N
N
N
N
N
N
tBu
N
N
tBu-d9
tBu-d9
conditions?
tBu
d9-tBu
N
N
tBu
N
N
Et
Et
Et
Et
tBu-d9
conditions?
N
N
N
N
O
O
N
N
N
N
N
tBu-d9
tBu-d9
N
N
tBu
conditions?
d9-tBu
tBu
N
N
N
N
tBu
N
Abstract
The synthesis of shape-persistent organic cage compounds by the formation of imine bonds
opens the possibility to realize cages of different sizes, geometries, topologies and functions. It
is generally assumed that the imine bond is rather chemically labile allowing a self-correction
mechanism until thermodynamic equilibrium is reached, which is often the case if cage is
formed. However, there are some contradictory experimental data to this assumption. To get a
deeper insight into the imine bond dynamics of covalent organic cages, we studied the
formation and exchange of both dialdehydes and triamines of two different [2+3] imine cages
with the aid of a deuterated dialdehyde molecular building block.
Introduction
The interest in shape-persistent organic cages has increased significantly since a few years.1
This is mainly attributed to the relatively easy access to even larger structures from rather simple
molecular building blocks through the formation of imine bonds.1d, 1g, 2 By this reaction a large
variety of cages with different sizes and geometries have meanwhile been reported.1a, 3, 4 Based
5
on the assumption that the bond formation and opening of the imine units is dynamic, it is
generally proposed that the imine cages are thermodynamically controlled products rather than
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6
kinetically controlled ones. It is worth mentioning that (almost) all theoretical calculations
predicting cage structures are based on this assumption.6, 7
Indeed, a number of experimental findings somehow support this hypothesis. Some pioneering
work was reported by Warmuth et al., investigating cage formations based on a resorcinarene
0
1
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tetraaldehyde with various diamines and triamines. In different solvents, the same molecular
building blocks gave cages of different geometries. Although this is still not fully understood,
it demonstrates the synthetic potential of dynamic covalent chemistry. Unfortunately, no clear
evidence for the dynamic nature of the imine bonds was given e.g. by switching between the
cages by switching or adding solvent in situ. Mukherjee and coworkers have investigated a four
component system (two bis-aldehydes plus two triamines) and observed a highly selective self-
9
sorting, giving two products exclusively. Based on experimental data on cage stabilities and
formation possible exchange of molecular building blocks was elaborated and later on more
1
0
detailed studied: A thermodynamic less stable cage was transferred to a more stable one by
adding either another triamine or dialdehyde. A similar observation was made by the Li group.11
Cram and Stoddart suggested an imine exchange of a carcerand by an acid catalyzed bar-
1
2
opening/bar closing mechanism by exchanging diamine units. Very recently, Kolodziejski et
al. presented a very detailed study of the self-sorting and exchange of aldehyde precursor units
13
of TREN-based cages. We and others studied chiral self-sorting, which also rely on a dynamic
interconversion of imine bonds.14,4i Most convincing experiments to demonstrate the dynamic
of the imine bond formation were done by the Li group by investigating the interconversion of
a pillared [2+3] cage into a tetrahedral [4+4] cage under different conditions. Depending on
1
5
temperature or concentration, a clear shift towards one of these two cages was observed. No
exchange of other building blocks were needed.
Despite the large number of examples supporting a thermodynamically controlled formation of
imine cages, there are also observations made, proposing that imine cages are rather kinetically
controlled products. For instance, the formation of a cubic [4+4] salicylimine cage was
monitored by time with MALDI-TOF mass spectrometry.1a, 4h At no time any oligomeric by-
products with m/z-values larger than the cage has been found, suggesting that the formation of
the cage is a kinetically controlled reaction. Here, the cage formation is driven by precipitation,
similar as for most salicylimine cages described previously.4e, 4g, 16 One clear example of a
kinetically controlled product is the formation of truncated tetrahedral [4+4] imine cages that
1
7
have been made in acetonitrile. As soon as trifluoroacetic acid is added, the cages decompose
to give an insoluble polymeric material, which turned out to be a crystalline covalent-organic
framework (COF).17 As has been mentioned above, computational screening of large
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combinatorial libraries of possible cages is relying on the assumption that these are
thermodynamically favored and exactly these truncated [4+4] cages were predicted not to
6
b
form. Besides the “lost hit” of the truncated tetrahedral [4+4] cages, there are a few more
examples, where such calculations were not able to explain the experimentally found preferred
product. In this respect, Cooper and coworkers observed the cage enlargement of a [4+6] to an
1
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0
6
c
[8+12] imine cage, despite the theoretical calculated preference for the smaller one. The same
group observed the formation of open-pot cages preferably to a social self-sorted mixture of
4+6] and [4+4] imine cages despite the calculated thermodynamic favor toward the mixture.7
[
Because of all these ‘contradictory’ findings we were interested in investigating the dynamics
of the imine bonds of organic cages more detailed, once these have formed. To exclude any
driving forces by electronic differences of the used amines or aldehydes or different solubility
of either reactants, intermediates or cages, we decided to look at scrambling of [2+3] imine
cages and their deuterated congeners under different conditions, which we describe herein.
Results and Discussion
Synthesis & Characterization of Authentic Material
According to previous protocols,18, 13, 19 the imine cages 4, 4-d27, 5 and 5-d27 were synthesized
by stirring the corresponding aldehydes 1 or 1-d9 with the triamines 2 or 3 in methanol for 2
days to give the cages in isolated yields between 53% and 99% yield respectively (Scheme 1).
1
13
All cages were fully characterized by H and C NMR spectroscopy, MS, IR and elemental
analysis (see Supporting Information). Furthermore, the cages are characterized by single-
crystal X-ray diffraction (Fig. 2)
R
NH2
Et
MeOH
MeOH
2d, r.t. NH2
2d, r.t.
NH2
O
O
Et
N
1
(R = tBu)
H N
2
1-d9
(R = tBu-d9)
H N
2
Et
NH2
3
2
Et
Et
Et
N
N
N
N
N
N
N
R
R
N
N
R
R
N
R
N
R
N
Et
Et
N
N
Et
4
(R = tBu), 70%
4-d27 (R = tBu-d9), 53%
5 (R = tBu), 99%
5-d27 (R = tBu-d9), >99%
Scheme 1. Synthesis of [2+3] imine cages 4 and 5 and their deuterated congeners.
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The incorporation of the deuterated tert-butyl groups (tBu-d9) into the cage 4-d27 was
unambiguously proven by missing the signal of the tert-butyl protons at δ = 1.37 ppm, which
was previously observed for cage 4 (see Fig. 1). Similar observation was made for the pair 5
and 5-d27 (here the tert-butyl protons resonate at 1.39 ppm). More important for our studies is
the clear differentiation by MALDI-TOF MS. The molecular isotopic peak for cage 4 ([M+H]+)
0
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appears at m/z = 961.684 and is shifted by 27 mass units to m/z = 988.853 for cage 4-d27
+
(
[M+H] ) For cage 5 and it deuterated congener 5-d27 the peaks are found at m/z = 755.549
+
+
(
[M+H] ) and 782.718 ([M+H] ), respectively.
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e
d
Et
Et
Et
N
N
Et
a
N
tBu
b
f
tBu
c
f
b
N
N
e
tBu
a)
b)
N
Et
Et
d
1
1
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a
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e
c
a
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e
d
e
c
8
.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
chemicalshift /ppm
e
d
N
N
N
f
c)
b
N
tBu
a
f
tBu
c
a
a
N
N
tBu
N
b
N
c
d
d
e e
d)a
b
c
d
d
e e
8
.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
chemicalshift /ppm
1
Figure 1. H NMR spectra (CD Cl , 600 MHz) of cage 4 and 4-d27 (top) and 5 and 5-d27
2
2
(
bottom) for comparison.
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Figure 2. X-Ray crystal structures of cages 4 (a) and 5 (b). Hydrogen (deuterium) atoms and
solvent have been omitted for clarity.
Solvent Effect on Cage Formation
As mentioned above, several conditions (different solvents, presence or absence of catalytic
amounts of acid) have been reported for the synthesis of cages. For [2+3] imine cages of the
1
8a,
general structure of 4, typically EtOH, MeOH, CH Cl , CHCl , or acetonitrile are reported.
2
2
3
18b, 18d, 18e, 19a, 19c
Since we found for [4+4] cages that these are formed exclusively in acetonitrile
without acid, a solvent screening (with and without acid) was done for the cage synthesis of 4
and 5 to study its influence (see Schemes 2 & 3 and Tables 1 & 2, for NMR analytics see
Supporting Information fFgures S46–S49). It is worth mentioning that although all reactions
were performed at least twice, we were not interested in determination of exact yields, rather
than estimating the amount of formed cage in solution and in the solid state of a formed
precipitate. If a precipitate was formed this was collected by filtration, dried, weighed and
1
analyzed by H NMR spectroscopy. The remaining mother liquor was dried, a defined amount
1
of 1,3,5-trimethoxybenzene added as internal standard and investigated by H NMR
spectroscopy to estimate the amount of formed cage by integration of a characteristic proton
signal (4:  = 7.18 ppm, 5:  = 7.59 ppm) and 1,3,5-trimethoxybenzene ( = 7.09 ppm).
Et
Et
N
N
Et
conditions
see Table 1
N
N
tBu
NH Et
tBu
2
NH2
3
+ 2
tBu
N
N
Et
H N
Et
tBu
Et
Et
O
O
Et
2
1
2
4
Scheme 2. Formation of cage 4 under various conditions.
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Table 1. Formation experiments of cage 4 in different solvents with and without addition of
TFA. Reaction time: 2 d; reaction temperature: room temperature.
amount 4 in
Total
Yield
precipitate
(4)
mother
Entry
solvent
TFA
amount 4[b]
liquor[a]
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
MeOH
EtOH
–
80%
40%
73%
–[c]
0%
80%
55%
73%
44%
88%
58%
73%
46%
73%
63%
80%
51%
88%
58%
86%
60%
–
15%
0%
MeCN
CH Cl
–
–
44%
15%
0%
2
2
CHCl3
–
73%
58%
64%
–[c]
THF
–
Dioxane
Toluene
MeOH
EtOH
–
9%
–
46%
0%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
73%
46%
80%
–[c]
1
1
1
0
1
2
17%
0%
MeCN
CH Cl
51%
8%
2
2
13
CHCl3
80%
58%
86%
–[c]
1
1
1
4
5
6
THF
0%
Dioxane
Toluene
0%
60%
1
[
a] calculated from H NMR spectrum with the addition of 1,3,5-trimethoxabenzene as
standard [b] sum of yield of precipitate and mother liquor [c] no precipitate formation
observed after reaction.
First we investigated the formation of cage 4 in different solvents without acid. With the
exception of DCM and toluene (Entries 4 and 8), in all other solvents the pure cage precipitated
in yields between 40% and 86%. The highest yield (86%) was observed in MeOH (Entry 1),
the lowest in EtOH (40%, entry 2). It is worth mentioning that in MeOH, MeCN and THF no
cage was found in the residual mother liquor, suggesting that it is little soluble herein and
precipitation is the driving force. As mentioned above, in DCM and toluene (Entries 4 and 8)
no precipitate was formed, but about 40% of cage formation was detected in solution. The same
reactions were performed under the addition of 2 mol% of TFA. In general, the observed trends
were comparable to the experiments without acid, with the only difference that in all solvents
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1
1
1
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1
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1
1
1
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2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
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3
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
with the exception of methanol) the yields increased, in solvents such as in 1,4-dioxane even
significantly from 57% to 86% (entries 7 and 15).
N
N
N
tBu
conditions
see Table 2
N
N
H N
NH2
tBu
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
3
+ 2
tBu
NH2
N
N
tBu
O
O
N
1
3
5
Scheme 3. Formation of cage 5 under various conditions.
Table 2. Formation experiments of cage 5 in different solvents with and without addition of
TFA. Reaction time: 2 d; reaction temperature: room temperature.
amount 5 in
Total
Yield
precipitate
(5)
mother
liquor[a]
94%
93%
8%
Entry
solvent
TFA
amount 5[b]
1
2
3
4
5
6
7
8
9
MeOH
EtOH
–
–[c]
94%
93%
67%
92%
72%
89%
76%
68%
99%
90%
80%
92%
76%
83%
73%
80%
–
–[c]
MeCN
CH Cl
–
59%
–[c]
–
92%
72%
21%
7%
2
2
CHCl3
–
–[c]
THF
–
68%
69%
–[c]
Dioxane
Toluene
MeOH
EtOH
–
–
68%
99%
90%
4%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
–[c]
1
1
1
1
0
1
2
3
–[c]
MeCN
CH Cl
76%
–[c]
92%
76%
0%
2
2
CHCl3
–[c]
14
THF
83%
73%
–[c]
1
1
5
6
Dioxane
Toluene
0%
80%
1
[
a] calculated from H NMR spectrum with the addition of 1,3,5-trimethoxabenzene as
standard [b] sum of amount cage 5 of precipitate and mother liquor [c] no precipitate
observed after reaction.
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9
The formation of TREN-cage 5 was investigated under same conditions as cage 4 (see Scheme
3 and Table 2, for NMR analytics see Supporting Information Figures S50–S53). In contrast to
cage 4, cage 5 was much more soluble and stayed in solution in most solvents, except in MeCN,
THF and dioxane (Entries 3,6 & 7). The yields were close to quantitative in the protic solvents
MeOH and EtOH (Entries 1 & 2) and NMR spectra are as clean as those of the precipitates
mentioned above. The remaining solutions of the reactions in MeCN, dioxane and THF con-
tained beside the cage 5 significant amounts of other species as can be seen by additional signals
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
in the related H NMR spectra, that cannot be assigned to any cage protons. In DCM, toluene
and CHCl (Entries 4,5 & 8) no precipitate was observed and cage 5 was formed in solution,
3
however, especially in toluene and DCM the formation was not nearly as clean as from EtOH.
Comparable to the experiments for cage 4, here the addition of a catalytic amount of TFA has
the same effect and cage 5 was formed in substantially higher yields; in MeOH even
quantitatively. It is worth mentioning that for those solvents the formation was less clean
(toluene, DCM and MeCN), only in DCM the appearance of byproducts vanished upon addition
of TFA.
Exchange Experiments
To investigate the dynamic nature of the imine bond, cage 4 and cage 4-d27 were mixed in
approx. equal amounts, treated under the same conditions as described above and the slurry or
solution was investigated by MALDI-TOF MS (Scheme 4 and Table 3, see also Figure 3). The
only difference to the conditions above is the elongation of reaction time to seven days to allow
the system to adjust thermodynamic equilibrium.
Et
Et
Et
Et
Et
Et
N
N
N
N
N
N
N
N
tBu
d9-tBu
tBu
d9-tBu
N
N
N
N
tBu
d9-tBu
Et
Et
Et
Et
4-d27
Et
Et
Et
4
conditions
Et
Et
Et
Et
Et
Et
N
N
N
N
N
N
N
tBu
tBu
d9-tBu
tBu
N
N
N
N
d9-tBu
d9-tBu
N
Et
Et
Et
Et
Et
4-d18
4-d9
Scheme 4. Scrambling of cage 4 and cage 4-d27 at various conditions (see Table 3).
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Scrambling experiments of cage 4 and 4-d27 in different solvents with and without
addition of TFA.
4-d0[a]
4-d9[a]
4-d18[a]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✔(✔)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✔(✔)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
4-d27[a]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
Entry
solvent
MeOH
EtOH
TFA
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✔(✔)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✔(✔)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
1
2
–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
3
MeCN
CH Cl
–
4[c]
–
2
2
5
6
7
8
9
CHCl3
–
THF
–
Dioxane
Toluene
MeOH
EtOH
–
–
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
1
1
1
1
1
1
1
0
1
MeCN
CH Cl
2[c]
2
2
3
4
5
6
CHCl3
THF
Dioxane
Toluene
[a] observed in MALDI MS, [b] after addition of water, [c] please note that the intensity of the
found signals for 4-d9 and 4-d18 is very low.
First we screened the exchange without the addition of acid. Only in DCM very small peaks of
4-d18 and 4-d9 were observed by MALDI-TOF MS (see Supporting Information, Figures S54–
S57). Although the solvents have not been dried, to ensure that water is present in reasonable
amounts to allow the possibility of imine bond hydrolysis, water was added and the mixtures
stirred for another 7 days. Basically, the results were the same. Even the addition of catalytic
amounts of acid did not foster exchange in other solvents than DCM, where small peaks of
scrambled cages are observed by MS, concluding that at least a reasonable solubility is
necessary to allow dynamic exchange.
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M-d0
m/z = 960
M-d9
m/z = 969
M-d18
m/z = 978
M-d27
m/z = 987
Toluene
M-d9
m/z = 969 m/z = 978
Toluene
M-d18
1,4-Dioxane
THF
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
,4-Dioxane
THF
CHCl3
CHCl3
CH Cl
CH Cl2
2
2
2
MeCN
MeCN
EtOH
MeOH
EtOH
9
65
975
980
985
970
m/z
MeOH
950
960
970
980
990
1000
m/z
Figure 3. MALDI mass spectra of scrambling reactions of cage 4 and cage 4-d27 according to
Scheme 4 and Table 3 without TFA and with water (Entries 1-8)
TREN-based cages 5 and 5-d27 were treated the same (Scheme 5 & Table 4, see Supporting
Information, Figures S58–S61). Although cage 5 is soluble in a larger number of solvents than
cage 4, under no conditions exchange was observed concluding that the aliphatic imine bond
of the TREN precursor is even more stable than the one of the benzylic imine in cage 4.
N
N
N
N
N
N
N
N
tBu
N
N
tBu-d9
tBu
d9-tBu
N
N
tBu
N
N
tBu-d9
N
N
5
5-d27
conditons
N
N
N
N
N
N
N
N
tBu
N
N
tBu-d9
tBu
tBu
N
N
tBu-d9
N
N
tBu-d9
N
N
5-d9
5-d18
Scheme 5. Scrambling of cage 5 and cage 5-d27 at various conditions (see Table 4).
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 4. Scrambling experiments of cage 5 and 5-d27 in different solvents with and without
addition of TFA.
5-d0[a]
5-d9[a]
5-d18[a]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
5-d27[a]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
Entry
solvent
MeOH
EtOH
TFA
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✔(✔)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
✘(✘)[b]
1
2
3
4
5
6
7
8
9
–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
MeCN
CH Cl
–
–
2
2
CHCl3
–
THF
–
Dioxane
Toluene
MeOH
EtOH
–
–
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
1
1
1
1
1
1
1
0
1
2
3
4
5
6
MeCN
CH Cl
2
2
CHCl3
THF
Dioxane
Toluene
[a] observed in MALDI MS [b] after addition of water
Next we were reacting the cage 4 with three equivalents of deuterated aldehyde 1-d9 in various
solvents, with and without acid (Scheme 6 and Table 5, for NMR analytics see Supporting
Information fFgures S63–66 and S68–71). Whereas without acid scrambling was observed only
in THF (Entry 6), with TFA scrambling was observed in all aprotic solvents. Most pronounced
in toluene and THF (Entries 14 & 16); here all scrambled products are observed by MALDI
MS (see Supporting Information fFgures S62, S68) whereas for MeCN, DCM and CHCl the
3
intensity of observed signals is decreasing with higher degree of deuteration. The 4-d0 signal
is still the most intense one in all spectra, whereas in toluene and THF the distribution is more
of a Gaussian form with the highest peaks for 4-d9 and 4-d18, suggesting that scrambling is
still kinetically hampered in DCM, MeCN and CHCl . Especially for DCM, where the cage is
3
soluble this clearly shows that it is not solubility exclusively, which is responsible for a
scrambling to occur or not.
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Et
Et
N
Et
N
N
tBu
N
tBu
N
N
tBu
Et
Et
Et
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
O
O
condition
tBu-d9
1-d9
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
N
N
N
N
N
N
N
N
N
N
N
N
tBu-d9
tBu-d9
tBu
tBu
+
d9-tBu
d9-tBu
+ d9-tBu
tBu
N
N
N
N
N
N
tBu-d9
Et
Et
Et
Et
Et
Et
Et
4-d9
4-d18
4-d27
Scheme 6. Scrambling experiments of cage 4 with dialdehyde 1-d9 under various conditions
(see Table 5).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 5. Scrambling experiments of cage 4 with aldehyde 1-d9 in different solvents with and
without addition of TFA.
4-d9[a]
4-d18[a]
4-d27a]
Entry
solvent
MeOH
EtOH
TFA
1
2
3
4
5
6
7
8
9
–
✘
✘
✘
✘
✘
✔
✘
✘
✘
✘
✘
✔
✘
✘
✘
✘
✘
✘
✔
✔
✘
✔
✘
✘
✘
✘
✘
✔
✘
✘
✘
✘
✘
✘
✔
✔
✘
✔
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
MeCN
CH Cl
–
–
2
2
CHCl3
–
THF
–
1,4-Dioxane
Toluene
MeOH
EtOH
–
✘
✘
✘
✘
(✔)
(✔)
✔
–
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
1
1
1
1
1
1
1
0
1
2
3
4
5
6
MeCN
CH Cl
2
2
CHCl3
THF
✔
1,4-Dioxane
Toluene
✘
✔
[a] observed by MALDI MS; (✔): very weak signal intensity
The TREN cage 5 behaved very differently to cage 4 (Scheme 7 and Table 6, for NMR analytics
see Supporting Information Figures S63–66 and S68–71. For MS MALDI see Supporting
Information FFigures S72 and S77). Here, without acid a weak scrambling occurred in
methanol and toluene with the non-deuterated signal for cage 5 still being the most prominent
one besides some very small peaks of all partially deuterated cages 5-d9, 5-d18 and 5-d27, little
higher than the background noise. With the addition of acid the situation changes. Now
scrambling was observed additionally in MeCN, which can be explained by facilitated
hydrolysis and condensation reactions due to a lowered energy barrier of transition states.
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N
N
N
N
N
tBu
tBu
N
N
tBu
N
5
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
condition
tBu-d9
1-d9
N
N
N
N
N
N
N
N
N
N
N
tBu
N
N
tBu
N
N
tBu-d9
tBu-d9
d9-tBu
+ d9-tBu
tBu
+
d9-tBu
N
N
N
N
tBu-d9
N
N
N
N
N
5-d9
5-d18
5-d27
Scheme 7. Scrambling experiments of cage 5 with dialdehyde 1-d9 under various conditions
see Table 6).
(
Table 6. Scrambling experiments of cage 5 with aldehyde 1-d9 in different solvents with and
without addition of TFA.
Entry
solvent
MeOH
EtOH
TFA
5-d9[a]
(✔)
✘
5-d18[a]
(✔)
✘
5-d27a]
(✔)
✘
1
2
3
4
5
6
7
8
9
–
–
MeCN
CH Cl
–
✘
✘
✘
–
✘
✘
✘
2
2
CHCl3
–
✘
✘
✘
THF
–
✘
✘
✘
1,4-Dioxane
Toluene
MeOH
EtOH
–
✘
✘
✘
–
(✔)
(✔)
✘
(✔)
(✔)
✔
(✔)
(✔)
✔
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
1
1
1
1
1
1
1
0
1
2
3
4
5
6
MeCN
CH Cl
(✔)
✘
(✔)
✘
✘
2
2
✘
CHCl3
✘
✘
✘
THF
✘
✘
✘
1,4-Dioxane
Toluene
✘
✘
✘
✔
✔
✔
[
a] observed by MALDI MS; (✔): very weak signal intensity
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Finally, we were investigating the addition of the opposite amines to the cages and the
1
precipitates as well as the mother liquor investigated by H NMR spectroscopy (see Supporting
Information, Tables S5–S7, Figures S82–S93). First we treated cage 4 under different
conditions with 3 equivalents of TREN 3 (Scheme 8 & Figure 4, see also Supporting
Information). It is worth mentioning that mass spectra showed both cages 4 and 5, which results
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are somewhat contradictory to H NMR spectra. However, we conclude that cage 5 with its
TREN unit and the containing tertiary amine is much more sensitive to be ionized than cage 4
and can be seen even in traces. Therefore, we discuss NMR results preferably. Without acid,
transformation to cage 5 was observed in DCM and MeOH, but here only in the liquid phases.
The solid phases were clean cage 4 in all experiments. This changed somewhat with the addition
of acid. Now the precipitate from acetonitrile contained TREN cage 5 too. The corresponding
solutions showed major peaks of TREN cage 5 in DCM, CHCl MeCN, toluene and in MeOH.
3
1
It is worth mentioning that in no of the measured mass spectra nor by H NMR spectroscopy
any formation of mixed cage 6 was observed, suggesting that it does not need two different
aldehydes and two different amines to observe self-sorting effects, such as observed in the
molecular marriage experiment by Mukherjee et al.1d, 9
The opposite reaction of TREN cage 5 with stoichiometric amount of triamine 2 showed
1
without acid no substantial formation of cage 4, neither by H NMR spectroscopy nor by MS,
suggesting that the TREN cage 5 is thermodynamically significantly more stable than cage 4.
1
An exception is methanol, here cage 4 was observed by MS and in the solid state by H NMR.
With the addition of acid the trend was basically the same, with the difference that cage 4 was
seen now aside cage 5 in the solid from MeCN and in the solid from MeOH it was cage 4
1
exclusively. By concentration dependent H NMR analysis of a reaction of amines 2 and 3 plus
aldehyde 1 in odd stoichiometric ratios in CD Cl at room temperature we calculated a reaction
2
2
constant of approx. K ≈ 11 in favor of TREN cage 5, which corresponds to a ΔG of approx.
eq
eq
-5 kJ/mol. In toluene-d8 where both cages are soluble, the reaction equilibrium constant is with
K ≈ 8 comparable.
eq
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Et
Et
Et
N
N
N
N
tBu
H N
NH2
2
N
+ 2
tBu
N
N
tBu
NH2
Et
Et
Et
3
1
1
1
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0
4
Et
Et
N Et
N
N
N
tBu
tBu
conditions
N
N
tBu
N
6
N
N
N
NH Et
2
N
tBu
NH2
+
2
tBu
Et
H N
Et
N
N
tBu
N
2
N
2
5
Scheme 8. Exchange of cages 4 to 5 and vice versa by the addition of amine 3 or 2 respectively.
For conditions see Supporting Information.
1
Figure 4 H NMR spectra (300 MHz, CD Cl ) of cage 5 (top) and 4 (middle) and of the isolated
precipitate (bottom) after reaction of cage 4 with 2 equiv. of amine 3 in CH Cl with catalytic
2
2
2
2
amounts of TFA.
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Discussion
To summarize, we had a closer and more detailed look on the imine cage formation and their
exchange of building blocks (aldehydes or amines) after once formed. For this initial study,
[2+3] imine cages based on the two most frequently used triamines were investigated. A large
solvent screening with or without the addition of TFA as catalyst revealed that the two cages
behave already differently. Whereas the cage 4 based on the benzylic amine 2 is precipitating
from almost every solvent (except DCM and toluene), this seems to be the driving force in
agreement with Le Chatelier’s principle of removing cage 4 from the system (here the solution)
and hamper its reaction. Indeed, TFA does not change the situation significantly, only yields
have risen a bit. It is worth mentioning that those systems (toluene and dichloromethane), where
cage 4 was not precipitating the amounts of formed cage were always much lower than in the
cases where it solidified; once more underlining the suggestion that the formation is mainly
kinetically driven by precipitation.
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TREN-based cage 5 mainly stays in solution in most solvents and is formed in high to
quantitative yields. Here, yields are higher when it does not precipitate, suggesting that it is
more thermodynamically stable in comparison to cage 4.
Both cages once formed do not scramble with their deuterated congeners in any solvent, neither
with or without the addition of acid nor the addition of water or both. Only for cage 4 very small
peaks in the MS, not substantially higher than the noise of the baseline for scrambled cages are
observed in dichloromethane. Even when deuterated isopthalaldehyde 1-d9 is added to the
reaction mixtures of cage 4 no scrambling is observed in all solvents, except in THF. Here,
peaks of scrambled cages can be observed in the MS, but with low intensity, again not much
higher than the noise. With TFA a clear scrambling was observed in toluene, where cage 4 is
soluble, and some scrambling in DCM, CHCl and THF occured. No scrambling was observed
3
in EtOH or MeOH – solvents most often used to synthesize these [2+3]-cages. Again cage 5 is
different. No scrambling was observed with aldehyde 1-d9, when no acid is present, but
scrambling is detected in toluene, MeCN and EtOH with acid. Cage 5 is thermodynamically
favored over cage 4 by ΔG = -5 kJ/mol. Nevertheless, cage 4 was not converted to cage 5
eq
upon the addition of TREN, when the reaction mixture was kept in the solid state – once more
emphasizing how important the solvent and solubility of cages and intermediates therein are, to
allow the system to reach thermodynamic equilibrium.
To demonstrate the role of kinetics in imine cage chemistry, we were able to convert
thermodynamically more stable cage 5 to cage 4 nearly quantitatively based on the knowledge
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generated herein. If a solution of cage 5 in methanol is treated with amine 2 (20 equiv.), cage 4
precipitates in pure form and 87% yields (Scheme 9).
Et
Et
N
N
N
N
N
Et
NH Et
2
N
N
tBu
N
N
tBu
NH2 MeOH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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0
tBu
+
20
tBu
Et
H N
Et
N
N
tBu
N
N
tBu
Et
Et
2
Et
N
5
2
4 (87%)
Scheme 9. Quantitative transformation of cage 5 to cage 4.
Conclusions
This study emphasizes how important the role of solvent for imine cage formation is and that
once the cage has formed, under most conditions it does not undergo a dynamic exchange with
an aldehyde of the same solubility and reactivity as the one already used for the cage forming
reaction. This does not necessarily mean that it is (but it can be!) the kinetic product, especially,
when it precipitates out of the reaction mixture as has been stated by De Rycke et al. already
before: “The literature emphasizes the thermodynamic stability of such assemblies [cages] but
in precipitation processes one might consider the reaction to be kinetically controlled.”18b This
may explain, why computational screening of thermodynamic data (such as heat or energy of
formation) of final compounds exclusively can lead to contradictory experimental observations,
such as has been reported in the case of the formation of a (thermodynamically unfavored) cage
7
6c
pot or a (thermodynamically unfavored) larger ‘doubled’ cage. Although by high throughput
screening of thermodynamic heat of formations of cages a large number of interesting new cage
structures were found to form, but purely relying on these calculation can lead to the missing
1
7,
of very interesting structures, such as the tetrahedral [4+4] imine cages from our group, which
have successfully been synthesized and studied further.18c, 20 As Jelfs and coworkers recently
7
pointed out, computations of kinetic pathways of cage formations are much more complicated
and time-consuming than those for calculating relative energies of formation, but may need to
be considered in cases, where theoretical and experimental data do not give the same picture.
Keywords: Imine • Organic Cage Compounds • Dynamic Covalent Chemistry (DCC) •
Scrambling • Isotope Labelling
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6
Experimental Section
General Remarks
Melting points (not corrected) were measured with a Büchi Melting Point B-545. IR-Spectra
were recorded on a Bruker Tensor 27 spectrometer on a ZnSe ATR crystal. NMR spectra were
taken on a Bruker Avance III 300 (300 MHz), Bruker Avance DRX 300 (300 MHz), Bruker
Avance III 400 (400 MHz), Bruker Avance III 500 (500 MHz) and Bruker Avance III 600
(600 MHz) spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) relative to
traces of the non-deuterated solvent in the corresponding deuterated solvent. Structural
assignments were made with additional information from gCOSY, gHSQC, and gHMBC
experiments. HRMS experiments were carried out on a Fourier Transform Ion Cyclotron
Resonance (FTICR) mass spectrometer solariX (Bruker Daltonik GmbH, Bremen, Germany)
equipped with a 7.0 T superconducting magnet and interfaced to an Apollo II Dual ESI/MALDI
source. MALDI-TOF MS experiments were carried out on a Bruker Daltonik Reflex III, on a
Bruker ApexQe or on a Bruker AutoFlex Speed TOF with DCTB (trans-2-[3-(4-tert-
butylphenyl)-2-methyl-2-propenylidene]malononitrile) as matrix. Elemental analysis was
performed by the Microanalytical Laboratory of the University of Heidelberg using an
Elementar Vario EL machine. Crystal structure analysis was accomplished on a STOE Stadivari
diffractometer with a copper source (Cu Kα = 1.54178 Å). All crystallographic information
files (2016234 (4-d27), 2016637 (4), 2016235 (5)) have been deposited in the Cambridge
Crystallographic Data Centre and can be downloaded free of charge via
www.ccdc.camac.uk/data_request/cif.
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Synthesis of (2,4,6-triethylbenzene-1,3,5-triyl)trimethanamine (2)
1,3,5-Tri(bromomethyl)-2,4,6-triethylbenzene 21
and
(2,4,6-triethylbenzene-1,3,5-triyl)-
trimethanamine (2)22 were obtained following literature known procedures. All obtained
analytical data were in accordance with literature.21, 22
Synthesis of 1-(tert-butyl)-3,5-dimethylbenzene
To an ice bath cooled solution of m-xylene (5.00 mL, 40.5 mmol) and tert-butylchloride (2.50
mL, 22.7 mmol) in dichloromethane (10 mL) aluminum chloride (250 mg, 187 mmol) was
added. After stirring the reaction mixture for 1h it was allowed to warm up to room temperature
and stirred for another 1.5 hours at room temperature. Under ice bath cooling water (150 mL)
was added and the aqueous phase was separated and extracted with dichloromethane (3 × 50
mL). The organic layers were combined and dried over magnesium sulfate. After filtration the
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solvent was removed under reduced pressure (10 mbar, 50°C) to give a pale-yellow oil (2.54 g,
15.7 mmol, 70%). n25 = 1.493, H NMR (300 MHz, CDCl ): 훿 (ppm) = 7.02 (s, 2H, Ar-2/6-
1
D
3
H), 6.84 (s, 1H, Ar-4-H), 2.33 (s, -CH ), 1.31 (s, 9H, -C(CH ) ). The analytical data are in
3
3 3
accordance withliterature.23, 24
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
Synthesis of 5-(tert-butyl)isophthalic acid
Potassium permanganate (33.0 g, 207 mmol), 1-(tert-butyl)-3,5-dimethylbenzene (5.60 g, 34.5
mmol) and sodium carbonate (9.65 g, 91.1 mmol) were suspended in a mixture of water/tert-
butanol [60 mL, 1:1 (v/v)] and stirred under reflux (oilbath) for 1h. After cooling the reaction
mixture to room temperature, the solid was separated by filtration, washed with water (200 mL)
and disposed. The mother liquor was diluted with a saturated solution of sodium thiosulfate
(400 mL) and he resulting solid separated by filtration. The mother liquor was washed with
methyl-tert-butylether (3 × 100 mL) and acidified with 5M hydrochloride acid (100 mL). After
cooling the aqueous phase with an ice bath, a colorless solid precipitated, which was isolated
1
by filtration. (4.73 g, 21.3 mmol, 62%) Mp > 300°C, H NMR (300 MHz, MeOD): 훿 (ppm) =
8
.44 (s, 1H, Ar-4-H), 8.30 (s, 2H, Ar-2/4-H), 1.39 (s, 9H, -C(CH ) ). The analytical data are in
3 3
accordance with literature.23
Synthesis of (5-(tert-butyl)-1,3-dihydroxymethylenebenzene
Under argon atmosphere and ice bath cooling a solution of 5-(tert-butyl)isophthalic acid (4.00
g, 18.0 mmol) in tetrahydrofuran (dry, 70 mL) was added to a suspension of lithium aluminium
hydride (4.10 g, 108 mmol) in tetrahydrofuran (dry, 100 mL). The ice bath cooling was removed
and the reaction mixture stirred for 12 h. Water (50 mL) was slowly added under ice bath
cooling and a saturated solution of sodium tartate (50 mL) was added. The reaction mixture
was extracted with ethyl acetate (3 × 200 mL), the organic layers were combined and dried over
magnesium sulfate. After filtration the solvent was evaporated under reduced pressure (8 mbar,
[1]
1
5
0°C) to give the diol as a colorless solid (4.00 g, 20.6 mmol, quant.). Mp > 76°C , H NMR
(300 MHz, CDCl ): 훿 (ppm) = 7.32 (s, 2H, Ar-2/4-H), 7.19 (s, 1H, Ar-4-H), 4.68 (s, 4H, -
3
2
5
CH OH), 1.33 (s, 9H, -C(CH ) ). The analytical data are in accordance with literature.
2
3 3
Synthesis of 5-(tert-butyl)isophthalaldehyde (1)
To 1,3-bis(hydroxymethyl)-5-tert-butylbenzene (4.00 g, 20.6 mmol) and manganese dioxide
18.0 g, 206 mmol) chloroform (90 mL) was added. The reaction mixture was stirred under
(
reflux (oilbath) for 12 h and then cooled to room temperature. After filtration over Celite the
solvent was removed under reduced pressure (10 mbar, 50°C) to give the dialdehyde as a
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6
[1] 1
colourless solid (2.33 g, 12.3 mmol, 60%). Mp > 64°C , H NMR (300 MHz, CDCl ): 훿 (ppm)
3
= 10.1 (s, 2H, CHO), 8.18 (s, 3H, Ar-H), 1.41 (s, 9H, -C(CH ) ). The analytical date are in
3
3
accordance with literature.25
Synthesis of 1-(tert-butyl)-3,5-dimethylbenzene-d9
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To a solution of m-xylene (2.50 mL, 18.6 mmol) and tert-butylchloride (1.19 mL, 9.90 mmol)
in dichloromethane (5 mL) aluminum chloride (115 mg, 86.0 mmol) was added under ice bath
cooling. After stirring the reaction mixture for 1h the cooling was removed and the reaction
mixture was stirred for another 1.5 h at room temperature. Water (30 mL) was added under ice
bath cooling, the aqueous phase was separated and extracted with dichloromethane (3 × 20
mL). The organic layers were combined and dried over magnesium sulfate. After filtration the
solvent was removed under reduced pressure (6 mbar, 50°C) to give a colorless oil (1.15 g, 7.10
mmol, 72%). n25 = 1.493, H NMR (400 MHz, CDCl ): 훿 (ppm) = 7.02 (s, 2H, Ar-2/6-H),
1
D
3
13
6
.84 (s, 1H, Ar-4-H), 2.35 (s, -CH ). C{1H} NMR (100 MHz, CDCl ) δ (ppm) = 151.6 (C1),
3 3
137.5 (C3, C5), 127.2 (C4), 123.3 (C2, C6), 34.8 (C(CD ) ) 30.46 (“octett”, J = 16 Hz,
3
3
CD
-1
C(CD ) ), 22.1 (CH ). FT-IR (ATR): 휈 (cm ) = 3023 (m), 2918 (m), 2864 (m), 2731 (m), 2215
3 3
3
(
s), 2160 (m), 2124 (m), 2073 (m), 2051 (m), 1767 (w), 1738 (w), 1603 (s), 1466 (m), 1376
m), 1205 (m), 1170 (m), 1126 (m), 1060 (s), 1033 (s), 891 (w), 850 (s), 814 (m), 750 (m), 698
(
(s), 632 (w). HRMS-EI (pos): m/z = 46.0697 (4), 66.1262 (13), 109.0982 (10), 121.0990 (15),
+
1
53.1546 (100), 171.1963 (30). [M] calcd. for C H D , 171.1968; found, 171.1963.
12
9
9
Elemental analysis calcd. for C H D O : C 84.12, H 10.60; found: C 84.02, H 10.71.
1
2
9
9
2
Synthesis of 5-(tert-butyl)isophthalic acid-d9
Potassium permanganate (6.47 g, 40.6 mmol), 1-(nonadeutero-tert-butyl)-3,5-
dimethylbenzene-d9 (1.15 g, 6.73 mmol) and sodium carbonate (1.88 g, 17.7 mmol) were
suspended in a mixture of water/tert-butanol [30 mL, 1:1 (v/v)] and stirred under reflux (oilbath)
for 1h. After cooling the reaction mixture to room temperature, the solid was separated by
filtration, washed with water (50 mL) and disposed. The mother liquor was diluted with a
saturated solution of sodium thiosulfate (100 mL) and the formed solid was separated by
filtration. The mother liquor was washed with methyl-tert-butylether (3 × 50 mL) and acidified
with 5M hydrochloride acid (50 mL). After cooling the aqueous phase with an ice bath a
colorless solid precipitated, which was collected by filtration (911 mg, 3.94 mmol, 59%). Mp
1
>
300°C. H NMR (300 MHz, MeOD): 훿 (ppm) = 8.47 (s, 1H, Ar-4-H), 8.29 (s, 2H, Ar-2/4-
1
3
H). C{1H} NMR (150 MHz, MeOD) δ (ppm) = 169.2 (COOH), 153.4 (C1, C3), 132.3 (C5),
31.9 (C4, C6), 129.3 (C2), 35.1 (C(CD ) ), 30.4 (“octett”, J = 19 Hz, C(CD ) ). FT-IR
1
3
3
CD
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-1
(
ATR): 휈 (cm ) = 2823 (w), 2552 (w), 2219 (w), 1684 (s), 1602 (m), 1451 (m), 1409 (m), 1331
(m), 1283 (s), 1242 (m), 1153 (m), 1115 (m), 1058 (m) 949 (m), 917 (m), 851 (m), 760 (m),
7
1
2
50 (m), 737 (m), 695 (m), 680 (m). HRMS-EI (pos): m/z = 94.0733 (5), 119.0798 (3),
+
81.0478 (34), 213.1030 (100), 231.1449 (5). [M] calcd. for C H D O , 231.1452; found,
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31.1449. Elemental Analysis. calcd. for C H D O :C 62.32, H 6.10, found: C 62.54, H 6.24.
1
2
5
9
4
Synthesis of (5-(tert-butyl)-1,3-dihydroxymethylenebenzene-d9
Under argon atmosphere and ice bath cooling a solution of 5-(nonadeutero-tert-
butyl)isophthalic acid (911 mg, 3.94 mmol) in tetrahydrofuran (dry, 20 mL) was added to a
suspension of lithium aluminium hydride (895 mg, 23.5 mmol) in tetrahydrofuran (dry, 20 mL).
The ice bath cooling was removed and the reaction mixture stirred for 12 h. Water (25 mL) was
slowly added under ice bath cooling and a saturated solution of sodium tartate (25 mL) was
added. The reaction mixture was extracted with ethyl acetate (3 × 100 mL), the organic layers
were combined and dried over magnesium sulfate. After filtration the solvent was evaporated
under reduced pressure (10 mbar, 50°C) to give the diol as a colorless solid (699 mg, 3.43
1
mmol, 87%). Mp > 75–76°C, H NMR (300 MHz, CDCl ): 훿 (ppm) = 7.31 (s, 2H, Ar-2/4-H),
3
1
3
7
.19 (s, 1H, Ar-4-H), 4.69 (s, 4H, -CH OH), 1.76 (s, 2H, -OH). C{1H} NMR (100 MHz,
2
CDCl ) δ (ppm) = 152.2 (C1, C3), 141.1 (C5), 123.6 (C4, C6), 123.0 (C2), 65.7 (CH OH), 34.3
3
2
-1
(C(CD ) ) 30.4 (“octett”, J = 16 Hz, C(CD ) ). FT-IR (ATR): 휈 (cm ) = 3286 (m), 2945 (m),
3
3
CD
3 3
2
1
1
922 (m), 2867 (m), 2215 (m), 2123 (m), 2071 (m), 2050 (m), 1603 (m), 1466 (m), 1443 (m),
421 (m), 1360 (m), 1321 (m), 1306 (m), 1264 (m), 1237 (m), 1202 (m), 1163 (m), 1050 (s),
016 (s), 973 (s), 893 (m), 879 (m), 853 (m), 815 (m), 750 (m), 715 (m), 700 (m), 659 (m).
-
HRMS-ESI (neg): m/z [M-H] calcd. for C H D O , 202.1799; found, 202.1802. Elemental
1
2
8
9
2
Analysis calcd. for C H D O : C 70.89, H 8.83, found: C 70.86, H 9.06.
1
2
8
9
2
Synthesis of 5-(tert-butyl)isophthalaldehyde-d9 (1-d9)
To 1,3-bis(hydroxymethyl)-5-(nonadeutero-tert-butyl)benzene (699 mg, 3.44 mmol) and
manganese dioxide (3.00 g, 3.44 mmol) chloroform (15 mL) was added. The reaction mixture
was stirred under reflux for 12 h and then cooled to room temperature. After filtration over
Celite the solvent was removed under reduced pressure (10 mbar, 50°C) to give the product a
1
colourless solid (459 mg, 2.30 mmol, 67%). Mp > 60–61°C, H NMR (300 MHz, CDCl ): 훿
3
1
3
(ppm) = 10.1 (s, 2H, CHO), 8.19 (s, 1H, Ar-H), 8.18 (s, 2H, Ar-H). C{1H} NMR (150 MHz,
CDCl ) δ (ppm) = 191.7 (CHO), 153.9 (C5), 137.1 (C1, C3), 131.8 (C4, C6), 129.2 (C2), 34.7
3
-1
(
C(CD ) ) 30.0 (o, J = 16 Hz, C(CD ) ). FT-IR (ATR): 휈 (cm ) = 3369 (w), 3253 (w), 3052
3
3
3 3
(w), 2933 (w), 2839 (w), 2737 (w), 2218 (m), 2126 (w), 2056 (w), 1943 (w), 1846 (w), 1701
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(
s), 1687 (s), 1596 (m), 1462 (m), 1397 (m), 1382 (m), 1294 (m), 1197 (m), 1146 (m), 1055
(m), 1010 (m), 967 (m), 891 (m), 823 (m), 736 (m), 686 (m), 652 (m). HRMS-EI (pos): m/z =
+
7
9.0512 (1), 94.0728 (4), 149.0570 (16), 181.1122 (100), 199.1543 (4) [M] calcd. for
C H D O , 199.1553; found, 199.1543. Elemental Analysis calcd. for C H D O : C 72.32,
1
2
5
9
2
12
5
9
2
0
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4
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6
7
8
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0
1
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6
7
8
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8
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H 7.09, found: C 72.46, H 7.14.
Synthesis of Imine Cage 4
To a solution of dialdehyde 1 (119 mg, 0.63 mmol) in methanol (25 mL) a solution of (2,4,6-
triethylbenzene-1,3,5-triyltrimethanamine 2 (100 mg, 0.40 mmol) in methanol (25 mL) was
added dropwise over 10 minutes. After stirring the reaction mixture for 2 days at room
temperature the precipitate was collected by filtration and washed with methanol (50 mL). The
solid was dried in vacuum (10 mbar, 50°C) to give 4 as a colorless solid (134 mg, 0.14 mmol,
1
7
0%). Mp > 300°C. H NMR (300 MHz, CD Cl ): 훿 (ppm) = 8.00 (s, 6H, H-C(Ar’)=N-), 7.98
2
2
(s, 6H, Ar’-4/6-H), 7.27 (s, 3H, Ar’-2-H), 4.98 (s, 12H, Ar-CH -N), 2.42 (q, J = 7.4 Hz, 12 H,
2
1
3
Ar-CH CH ), 1.37 (s, 27H, -C(CH ) ), 1.20 (t, J = 7.5 Hz, 18H, Ar-CH CH ). C{1H} NMR
2
3
3 3
2
3
(150 MHz, CD Cl ) δ (ppm) = 159.7 (HC(Ar)=N-), 152.5 (Ar’C-1/3), 144.5 (ArC-2/4/6), 137.2
2 2
(Ar’C-5), 132.4 (ArC-1/3/5), 127.5 (Ar’C-2), 126.6 (Ar’C-4/6), 56.0 (Ar-CH ), 35.4 (Ar’-
2
-1
C(CH )), 31.6 (Ar’-C(CH )), 23.8 (Ar-CH CH ), 16.2 (Ar-CH CH ). FT-IR (ATR): 휈 (cm ) =
3
3
2
3
2
3
2964 (s), 2902 (s), 2871 (s), 1643 (s), 1593 (m), 1479 (m), 1452 (m), 1365 (m), 1322 (m), 1264
(m), 1228 (m), 1158 (m), 1043 (m), 975 (m), 698 (m), 657 (m). HRMS-MALDI (DCTB): m/z
+
[M+H] calcd. for C H N , 961.6836; found, 961.6835. Elemental Analysis calcd. for
6
6
85
6
C H N ⋅MeOH: C 81.00, H 8.93, N: 8.46 found: C 81.38, H 8.73, N: 8.48.
6
6
84
6
Synthesis of Imine Cage 4-d27
To a solution of dialdehyde 1-d9 (50 mg, 251 µmol) in methanol (10 mL) a solution of (2,4,6-
triethylbenzene-1,3,5-triyltrimethanamine 2 (45 mg, 181 µmol) in methanol (10 mL) was
added dropwise over 10 minutes. After stirring the reaction mixture for 2 days at room
temperature the precipitate was collected by filtration and washed with methanol (20 mL). The
solid was dried in vacuum (10 mbar, 50°C) to give 4-d27 as a colorless solid (47 mg, 47.6 µmol,
1
5
4
3%). Mp > 300°C. H NMR (600 MHz, CD Cl ): 훿 (ppm) = 8.33 (br, 12H, HC(Ar)=N-, Ar’-
2
2
/6-H), 7.27 (s, 3H, Ar’-2-H), 4.98 (s, 12H, Ar-CH -N), 2.41 (q, J = 7.6 Hz, 12 H, Ar-CH CH ),
2
2
3
1
3
1.20 (t, J = 7.5 Hz, 18H, Ar-CH CH ). C{1H} NMR (150 MHz, CD Cl δ (ppm) = 159.6
2
3
2
2)
(
HC(Ar’)=N-), 152.5 (Ar’C-1/3), 144.4 (ArC-2/4/6), 137.2 (Ar’C-5), 132.4 (ArC-1/3/5), 127.5
Ar’C-2), 126.5 (Ar’C-4/6), 55.9 (Ar-CH ), 34.7 (Ar’-C(CD )), 30.3 (“octett”, J = 19 Hz,
(
2
3
CD
-1
Ar’-C(CD )), 23.7 (Ar-CH CH ), 16.2 (Ar-CH CH ). FT-IR (ATR): 휈 (cm ) = 2967 (m), 2874
3
2
3
2
3
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(
m), 2830 (m), 2214 (m), 1642 (s), 1592 (m), 1487 (m), 1452 (m), 1376 (m), 1312 (m), 1265
(m), 1235 (m), 1200 (m), 1158 (m), 1060 (m), 1044 (m), 975 (s), 868 (m), 786 (w), 750 (m),
+
6
9
8
93 (m), 656 (s), 610 (m). HRMS-MALDI (DCTB): m/z [M+H] calcd. for C H D N ,
66 58 27
6
88.8530; found, 988.8529. Elemental Analysis calcd. for C H D N ⋅MeOH: C 79.79, H
6
6
57 27
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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8
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0
.61, N: 8.42; found: C 79.65, H 8.55, N: 8.35.
Synthesis of Imine Cage 5
To a solution of dialdehyde 1 (50 mg, 0.26 mmol) in methanol (10 mL) a solution of tris(2-
aminoethyl)amine 3 (25 mg, 0.17 mmol) in methanol (10 mL) was added dropwise over 10
minutes. After stirring the reaction mixture for 2 days at room temperature, the solvent was
removed under reduced pressure (10 mbar, 50°C) to give 5 as a colorless solid (74 mg, 0.10
1
mmol, >99%). Mp = 200°C (dec.). H NMR (400 MHz, CDCl ): 훿 (ppm) = 8.25 (s, 6H, Ar-
3
4
/6-H), 7.59 (s, 6H, HC(Ar)=N-), 5.13 (s, 3H, Ar-2-H), 3.80 (br, 6H, CH -CH -N=CH), 3.28
2 2
(br, 6H, CH -CH -N=CH), 2.96 (br, 6H, CH -CH -N=CH), 2.71 (br, 6H, H -CH -N=CH), 1.40
2 2 2 2 2 2
1
3
(s, 27H, C(CH ) ). C{1H} NMR (150 MHz, CDCl δ (ppm) = 161.1 (HC=N-), 152.3 (ArC-
3
3
3)
1
/3), 136.8 (ArC-5), 130.3 (ArC-2), 124.6 (ArC-4/6), 60.3 (CH -CH -N=CH), 56.4 (CH -CH -
2 2 2 2
-1
N=CH), 35.3 (C(CH ) ), 31.6 (C(CH ) ). FT-IR (ATR): 휈 (cm ) = 3423 (w), 2961 (m), 2869
3
3
3 3
(m), 2835 (m), 1642 (s), 1592 (m), 1476 (m), 1434 (m), 1381 (m), 1364 (m), 1337 (m), 1298
(m), 1266 (m), 1227 (m), 1163 (m), 1067 (m), 1036 (m), 953 (m), 921 (s), 880 (m), 810 (m),
+
7
33 (m), 703 (m), 665 (m). MS-MALDI (DCTB): m/z [M+H] calcd. for C H N , 775.5489;
48 67
8
found, 755.549. Elemental Analysis calcd. for C H N ⋅0.5 H O: C 75.45, H 8.84, N: 14.66;
6
6
66
8
2
found: C 75.44, H 8.64, N: 14.67.
Synthesis of Imine Cage 5-d27
To a solution of dialdehyde 1-d9 (20 mg, 101 µmol) in methanol (4 mL) a solution of Tris(2-
aminoethyl)amine 3 (10 mg, 65.5 µmol) in methanol (4 mL) was added dropwise over 2
minutes. After stirring the reaction mixture for 2 days at room temperature, the solvent was
removed under reduced pressure (6 mbar, 50°C) and the colorless residue was suspended in
acetone (25 mL). The insoluble solid was disposed after filtration and 5-d27 was obtained as a
colorless solid (20 mg, 34.3µmol, >99%) after removal of the solvent under reduced pressure
1
(6 mbar, 50°C). Mp = 210°C (dec.). H NMR (600 MHz, CD Cl ): 훿 (ppm) = 8.23 (s, 6H, Ar’-
2
2
4/6-H), 7.57 (s, 6H, HC(Ar)=N-), 5.10 (s, 3H, Ar-2-H), 3.74 (br, 6H, CH -CH -N=CH), 3.27
2
2
br, 6H, CH -CH -N=CH), 2.95 (br, 6H, CH -CH -N=CH), 2.65 (br, 6H, CH -CH -N=CH).
2
2
2
2
2
2
1
3
C{1H} NMR (150 MHz, CDCl δ (ppm) = 161.1 (HC=N-), 152.4 (ArC-1/3), 137.3 (ArC-5),
3
)
1
30.5 (ArC-2), 124.8 (ArC-4/6), 60.6 (CH -CH -N=CH), 56.6 (CH -CH -N=CH), 34.8
2 2 2 2
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-1
(
C(CD ) ), 30.6 (“octett”, J = 18 Hz, C(CD ) ). FT-IR (ATR): 휈 (cm ) = 2945 (m), 2909
3
3
CD
3 3
(m), 2873 (m), 2833(m), 2214 (m), 2122 (m), 2073 (m), 2052 (m), 1642 (s), 1558 (m), 1433
(
m), 1379 (m), 1363 (s), 1337 (m), 1295 (m), 1266 (m), 1238 (m), 1204 (m), 1162 (m), 1063
(
s), 1034 (s), 929 (m), 902 (m), 878 (m), 795 (m), 749 (m), 717 (m), 697 (s), 664 (m). HRMS-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
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8
9
0
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2
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4
5
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7
8
9
0
+
MALDI (DCTB): m/z [M+H] calcd. for C H D N , 782.7183; found, 782.7183. Elemental
4
8
39 27
8
Analysis. calcd. for C H D N ⋅H O: C 72.07, H 8.57, N: 14.01 found: C 72.18, H 8.31, N:
4
8
39 27 68
2
1
3.91.
Cage formation experiment of compound 4 without TFA
After dissolving aldehyde 1 (9 mg, 47.4 µmol) in 2 mL of solvent (a: methanol, b: ethanol, c:
acetonitrile, d: dichloromethane, e: chloroform, f: tetrahydrofuran, g: 1,4-dioxane, h: toluene)
a solution of amine 2 (8 mg, 32.4 µmol) in 2 mL of solvent (a-h) was added dropwise. After
stirring for 2 days at room temperature an analytical aliquot of the reaction mixture was taken
for analysis by MALDI MS. The precipitate (a, b, c, e, f, g) was separated from the mother
liquor by filtration and the solvent of the mother liquor was removed under reduced pressure
1
(
10 mbar, 50°C). The precipitate and the residue were investigated independently by H NMR
spectroscopy. For reactions (d) and (h) no precipitate formation was observed and the solvent
1
was removed under reduced pressure (10 mbar, 50°C) and the residue was investigated by H
NMR spectroscopy. Since the precipitates did not contain side products after isolation the yield
1
could be calculated by mass of the precipitate. If solvent signals were visible in the H NMR
the yield was corrected by subtraction of the amount of solvent in the sample. The amount for
1
the cage left in the solution was estimated from the H NMR by using 1,3,5-trimethoxybenzene
(>99%) as internal standard (ca. 50 mass% of crude). See figures S46 and S47 in supporting
1
information for H NMR spectra.
Cage formation experiment of compound 4 with TFA
After dissolving aldehyde 1 (10 mg, 52.6 µmol) in 2 mL of solvent which contained 2 mol%
TFA per amine unit (a: methanol, b: ethanol, c: acetonitrile, d: dichloromethane, e: chloroform,
f: tetrahydrofuran, g: 1,4-dioxane, h: toluene) a solution of amine 2 (9 mg, 36.1 µmol) in 2 mL
of solvent (a-h) was added dropwise. After 2 days stirring at room temperature an analytical
aliquot of the reaction mixture was taken for analysis by MALDI MS. The precipitates (a, b, c,
e, f, g) were separated from the mother liquors by filtration and the solvent of the mother liquor
was removed under reduced pressure (10 mbar, 50°C). Since the precipitate did not contain side
products after isolation the yield could be calculated by mass of the precipitate. If solvent
1
signals were visible in the H NMR the yield was calculated by subtraction of the amount of
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solvent in the sample. For reaction (d) and (h) the solvent was removed under reduced pressure
1
(10 mbar, 50°C) and the residue was investigated by H NMR. The amount of cage left in the
1
solution was estimated from the H NMR by using 1,3,5-trimethoxybenzene (>99%) as
1
standard (ca. 50 mass% of crude). See figures S48 and S49 in supporting information for H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR spectra.
Cage formation experiment of compound 5 without TFA
After dissolving aldehyde 1 (11 mg, 57.9 µmol) in 2 mL of solvent (a: methanol, b: ethanol, c:
acetonitrile, d: dichloromethane, e: chloroform, f: tetrahydrofuran, g: 1,4-dioxane,
h: toluene) a solution of amine 3 (6 mg, 41.0 µmol) in 2 mL of solvent (a-h) was added dropwise
After 2 days stirring at room temperature an analytical aliquot of the reaction solution was taken
for analysis by MALDI MS. The precipitates (c, f, g) were separated from the mother liquors
by filtration and the solvent of the mother liquor was removed under reduced pressure (10 mbar,
5
0°C). Since the precipitate did not contain side products after isolation the yield could be
1
calculated by mass of the precipitate. If solvent signals were visible in the H NMR the yield
was calculated by subtraction of the amount of solvent in the sample. For reaction a, b, d, e, h
the solvent was removed under reduced pressure (10 mbar, 50°C) after the reaction and the
1
residue was investigated by H NMR. The amount of the cage left in the solution was estimated
1
from the H NMR by using 1,3,5-trimethoxybenzene (>99%) as standard (ca. 50 mass% of
1
crude). See figures S50 and S51 in supporting information for H NMR spectra.
Cage formation experiment of compound 5 with TFA
After dissolving aldehyde 1 (11 mg, 57.9 µmol) in 2 mL of solvent which contained 2 mol%
TFA per amine (a: methanol, b: ethanol, c: acetonitrile, d: dichloromethane, e: chloroform, f:
tetrahydrofuran, g: 1,4-dioxane, h: toluene) a solution of amine 2 (7 mg, 47.9 µmol) in 2 mL of
solvent (a-h) was added dropwise. After 2 days stirring at room temperature an analytical
aliquot of the reaction solution was taken for analysis by MALDI MS. The precipitates (c, f, g)
were separated from the mother liquors by filtration and the solvent of the mother liquor was
removed under reduced pressure (10 mbar, 50°C). For reactions a, b, d, e, h the solvent was
1
removed under reduced pressure (10 mbar, 50°C) and the residue was investigated by H NMR
spectroscopy. Since the precipitate did not contain side products after isolation the yield could
1
be calculated by mass of the precipitate. If solvent signals were visible in the H NMR the yield
was calculated by subtraction of the amount of solvent in the sample. The yield for the cage left
1
in the solution was estimated from the H NMR by using 1,3,5-trimethoxybenzene (>99%) as
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2
2
2
2
2
2
2
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5
5
6
1
standard (ca. 50 mass% of crude). See figures S52 and S53 in supporting information for H
NMR spectra.
Cage-to-cage scrambling experiment of cages 4 and 4-d27 without TFA
Cage compounds 4 (1 mg, 1 µmol) and 4-d27 (1 mg, 1 µmol) were immersed/dissolved in 250
µL of solvent (a: methanol, b: ethanol, c: acetonitrile, d: dichloromethane, e: chloroform, f:
tetrahydrofuran, g: 1,4-dioxane, h: toluene) and stirred at room temperature. After 7 days an
analytical sample was taken out of the reaction solution. After removing the solvent of this
sample the residue was mixed with a pre-prepared DCTB solution in THF and investigated by
MALDI MS. After 7 days, water (1 µL) was added to the reaction mixture and stirred for
another 7days at room temperature. The reaction mixture was investigated again by MALDI
MS as described above. See figures S54 and S55 in supporting information for mass spectra.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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0
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0
1
2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cage-to-cage scrambling experiment of cages 4 and 4-d27 with TFA
Cage compounds 4 (1 mg, 1 µmol) and 4-d27 (1 mg, 1 µmol) were immersed/dissolved in 250
µL of solvent containing 2 mol% TFA (a: methanol, b: ethanol, c: acetonitrile, d:
dichloromethane, e: chloroform, f: tetrahydrofuran, g: 1,4-dioxane, h: toluene) and stirred at
room temperature. After 7 days an analytical sample was taken out of the reaction solution.
After removing the solvent of this analytical sample, the residue was mixed with a pre-prepared
solution of DCTB in THF and investigated by MALDI MS. To the reaction mixture water (1
µL) was added and stirred for another 7days at room temperature. The reaction mixture was
investigated by MALDI MS as described above. See figures S56 and S57 in supporting
information for mass spectra.
Cage-to-cage scrambling experiment of cages 5 and 5-d27 without TFA
Cage compounds 5 (1 mg, 1.33 µmol) and 5-d27 (1 mg, 1.28 µmol) were dissolved/immersed
in 332 µL of solvent (a: methanol, b: ethanol, c: acetonitrile, d: dichloromethane, e: chloroform,
f: tetrahydrofuran, g: 1,4-dioxane, h: toluene) and stirred at room temperature. After 7 days an
analytical sample was taken out of the reaction solution. After removing the solvent of this
analytical sample the residue was mixed with a pre-prepared DCTB solution in THF and
investigated by MALDI MS. To the reaction mixture water (1 µL) was added and stirred for
another 7d at room temperature. The reaction mixture was investigated again by MALDI MS
as described above. See figures S58 and S59 in supporting information for mass spectra.
Cage-to-cage scrambling experiment of cages 5 and 5-d27 with TFA
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Page 29 of 36
The Journal of Organic Chemistry
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Cage compounds 5 (1 mg, 1.33 µmol) and 5-d27 (1 mg, 1.28 µmol) were dissolved in 332 µL
of solvent containing 2 mol% TFA (a: methanol, b: ethanol, c: acetonitrile, d: dichloromethane,
e: chloroform, f: tetrahydrofuran, g: 1,4-dioxane, h: toluene) and stirred at room temperature.
After 7 days an analytical sample was taken out of the reaction solution. After removing the
solvent of this analytical sample the residue was mixed with a pre-prepared DCTB solution in
THF and investigated by MALDI MS. To the reaction mixture water (1 µL) was added and
stirred for another 7d at room temperature. The reaction mixture was again investigated by
MALDI MS as described above. See figures S60 and S61 in supporting information for mass
spectra.
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Aldehyde exchange experiment with cage 4 and aldehyde 1-d9 without TFA
To cage 4 (8 mg, 8.33 µmol) and aldehyde 1-d9 (7 mg, 35.2 µmol) was added 2 mL of solvent
(a: methanol, b: ethanol, c: acetonitrile, d: dichloromethane, e: chloroform, f: tetrahydrofuran,
g: toluene) and the reaction mixture was stirred at room temperature. After 7 days an analytical
sample was taken from the reaction solution and investigated by MALDI MS. From reaction a,
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b, c, e, f, g the precipitate was separated by filtration and investigated by H NMR. The solvent
of the mother liquor was removed under reduced pressure (10 mbar, 50°C) and the residue was
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analyzed by H NMR. For reaction d, h no precipitate was observed and the solvent was
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removed under reduced pressure (10 mbar, 50°C). The residue was investigated in H NMR.
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See figures S62, S63, S64, S65 and S66 in supporting information for mass and H NMR
spectra.
Aldehyde exchange experiment with cage 4 and aldehyde 1-d9 with TFA
To cage 4 (8 mg, 8.33 µmol) and aldehyde 1-d9 (7 mg, 35.2 µmol) 2 mL of solvent was added
with 2 mol% TFA per imine bond (a: methanol, b: ethanol, c: acetonitrile, d: dichloromethane,
e: chloroform, f: tetrahydrofuran, g: toluene) and the reaction mixture was stirred at room
temperature. After 7 days an analytical sample was taken out of the reaction mixture and
investigated by MALDI TOF MS. From reactions a, b, c, e, f, g the precipitate was separated
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by filtration and investigated by H NMR. The solvent of the mother liquor was removed under
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reduced pressure (10 mbar, 50°C) and the residue was analyzed in H NMR. For reaction d, h
no precipitate was observed and the solvent was removed under reduced pressure (10 mbar,
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50°C). The residue was investigated by H NMR. See figures S67, S68, S69, S70 and S71 in
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supporting information for mass and H NMR spectra.
Aldehyde exchange experiment with cage 5 and aldehyde 1-d9 without TFA
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