A pillar[5]arene with an amino-terminated arm stabilizes the formation of aliphatic hemiaminals and imines

Article abstract of DOI:10.1039/c9cc01947b

We report a new mono-armed pillar[5]arene with the amino-substituent self-included in the pillarene cavity, which can stabilize the hemiaminals and imines formed from the reaction of aliphatic amines and aldehydes as monitored by mass spectroscopy.

Full text of DOI:10.1039/c9cc01947b

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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A pillar[5]arene with an amino-terminated arm stabilizes
the formation of aliphatic hemiaminals and imines
Xu-Sheng Du,a Qiong Jia,a Chun-Yu Wang,b Kamel Meguellati*a and Ying-Wei Yang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report a new mono-armed pillar[5]arene with the amino- co-workers observed the hemiaminal intermediates in an enzyme
mechanism at an atomic resolution.38 Fujita and co-workers
observed a transient hemiaminal trapped in a porous network via X-
ray analysis.39,40 Yaghi and co-workers employed metal-organic
frameworks to stabilize hemiaminals.41 Rebek and co-workers
reported the use of macrocycles in the stabilization of
hemiaminals,42,43 and the calculation by Li and co-workers is also of
great importance to complement the complexity during the
formation of imines.44 However, it still remains challenging to
characterize aliphatic imines and hemiaminals by analytical
methods such as electrospray ionization mass spectrum (ESI-MS).
To the best of our knowledge, no MS data for aliphatic hemiaminals
and imines have ever been reported due to their instability in the
conditions of ESI-MS. Thus, we are highly interested in developing a
strategy to stabilize aliphatic hemiaminals and imines in the isolated
state and trace these active species by ESI-MS.
substituent self-included in the pillarene cavity, which can
stabilize the hemiaminals and imines formed from the
reaction of aliphatic amines and aldehydes as monitored by
mass spectroscopy.
Pillar[n]arenes, first reported by Ogoshi and co-workers in 2008,1
have advanced significantly and shown many interesting
applications in supramolecular assembly,2-4 advanced functional
materials,5-11 molecular machinery,12-14 etc.,15-21 due to the unique
rigid cylindrical structure with a particular ring size and an electron-
rich cavity, ease and diversity of functionalization, and appreciable
host-guest properties. Among them, pillar[5]arene and its
derivatives are still the most widely investigated ones partly due to
the relatively high yielding of synthesis. Pillar[5]arene can form
host–guest inclusion complexes with electron poor species and
neutral molecules such as linear alkanes, but not with branched or
cyclic alkanes with large steric hindrance.11,12,22 On the basis of this
property, we developed some strategies for the efficient syntheses
of mono-ester and bis-ester arm functionalized pillar[5]arene
derivatives via a one-pot reaction,23-25 holding great potentials in
the construction of functional materials by facile modification.
On the other hand, imine bond formation is currently one of
the most widely used reactions that play a vital role in the dynamic
combinatorial (or covalent) chemistry (DCC)26-34 and macrocyclic
chemistry.35, 36 The process of imine bond formation has generally
been considered to occur in a stepwise manner, among which the
hemiaminal intermediate has received much attention to help
further understand its real mechanism.37 Some direct observations
of active hemiaminals have been reported. For example, Wilson and
Inspired by our previous work on the synthesis of a stable
functionalized pseudo[1]rotaxane in high yield by the aminolysis of
monoester-based copillar[5]arene,23 we envision that it is of great
possibility to find a suitable supramolecular nanoreactor to stabilize
the formation of aliphatic hemiaminals and imines by properly
functionalizing and optimizing a pillar[5]arene host to endow itself
not only a stable self-included structure but also a reactive motif
that fully sits in the centre of the cavity. We started with the
synthesis of an analogue, ethoxyl-based copillar[5]arene (ECP5A),
a
International Joint Research Laboratory of Nano-Micro Architecture Chemistry
(NMAC), College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun
130012, P. R. China. Email: kamel_m@jlu.edu.cn; ywyang@jlu.edu.cn
b
State Key Laboratory of Supramolecular Structure and Materials, Jilin University,
2699 Qianjin Street, Changchun 130012, P. R. China
Electronic Supplementary Information (ESI) available: Experimental section,
characterization data including 1H NMR spectra, 13C NMR spectra, 2D NMR spectra,
mass spectra of related compounds. See DOI: 10.1039/x0xx00000x
Scheme 1 Chemical structures of a) the aldehydes and b)
DEP5A; c) Synthetic route to the nanoreactor (R).
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methylbutylaldehyde (G2), and caproaldehyde (G3) were chosen for
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DOI: 10.1039/C9CC01947B
comparison. As a prototype, DEP5A was used as the candidate to
evaluate the DCLs. Firstly, the stoichiometry of DEP5A (host) and
the selected aldehydes (guest) was determined to be 1:1 by Job’s
plot method (Fig. S13-18, Table S1-3, ESI†). Secondly, the binding
constants between hosts and guests have also been investigated.
We used a mixture of three aldehydes and DEP5A for 1H NMR
titration (Fig. 2a). From the non-linear curve-fitting, the binding
constant of G3 and DEP5A was calculated to be 49 M-1 (Fig. 2b), in
accordance with the reported value,47 and the binding constant
between G1 (or G2) and DEP5A was too small to be measured (Fig.
S19-20, Table S4, ESI†). These results clearly provide a direct
evidence that aryl or branched aldehydes cannot enter the cavity of
pillar[5]arene while linear aldehydes can.
To further confirm this conclusion, an aromatic amine, i.e., p-
anisidine (PA), was introduced to the mixture of aldehydes, and the
molar ratio of PA to other aldehydes was 1:3. In the absence of
DEP5A, the decay of G3 and the formation of imine G3iPA were
found to be slow (Fig. 3a, Fig. S21-24, Table S5†). However, in the
presence of DEP5A at a concentration of 100 mM, the decay of
both G1 and G2 had obvious rate enhancement, and in sharp
contrast, the proportion of G3 stayed very stable and no
corresponding imine G3iPA was detected (Fig. 3b, Fig. S25, Table
S6†). More interestingly, further analysis of our NMR studies in Fig.
3b suggested a competitive reaction, aldol reaction, where PA acted
as a catalyst and DEP5A as a co-catalyst.48-50 Firstly, G2iPA formed
immediately with the decay of G2 within a period of 6 minutes.
Subsequently, the G2iPA decreased with the decay of G2, and
accordingly the detection by 1H NMR indicated that a new aldehyde
appeared (around δppm 9.64), which came from the side aldol
Fig. 1 Partial NOESY spectrum (600 MHz, CDCl3, 298 K) of R.
Fig. 2 a) Partial 1H NMR titration spectra (400 MHz, CDCl3, 298 K) of
three aldehydes (G1, G2, and G3) at an equal concentration of 4
mM upon addition of DEP5A. b) The non-linear curve-fitting for the
complexation of G3 (4 mM) and DEP5A in CDCl3 at 298 K.
reaction where the representative chemical shift values of –CHO of
52
aldol products lied in δppm 9.71-9.6251,
(Fig. S26-27, ESI†).
Furthermore, the total amount of G2iPA and G2 that participated in
the observed aldol reaction was not equal to the total amount of G2
as in Fig. 3b. This phenomenon can be ascribed to the formation of
the uncontrolled intermediates (Scheme S1, ESI†).
which was subsequently subjected to solvolysis by ethylenediamine
to get R (Scheme 1). Interestingly, DEP5A (Fig. S3-5, ESI†) as one of
the by-products was separated in the one-pot reaction where
ECP5A was synthesized. ECP5A was characterized by 1H and 13C
NMR spectroscopy, and mass spectroscopy (Fig. S6-8, ESI†). In its 1H
NMR spectrum, the δppm values of the ethyl protons belonging to
the ester group were upfield shifted to 2.49 (-CH2-) and -1.30 (-CH3)
in CDCl3 at room temperature, suggesting the presence of a self-
For comparison, five-fold higher concentration of 1,4-
diethoxybenzene monomer was used in the reaction system to
replace DEP5A and thus to rule out the importance of
supramolecular host DEP5A with a suitable cavity. As in Fig. 3c, Fig.
S28, Table S7†, the reaction rate between reactant G3 and the
product G3iPA was obviously enhanced in the presence of high
concentration of 1,4-diethoxybenzene, and the effects on the decay
of G1 and the formation of G1iPA were hardly observed. On one
hand, these comparative studies of DEP5A and the 1,4-
dimethoxybenzene monomer allow us to conclude that DEP5A acts
as not only a shielder via host-guest inclusion complexation in the
process of imine formation but also a specific catalyst that could
promote the formation of a side aldol reaction. This catalytic
1
included structure. R was analysed by H NMR spectroscopy, 13C
NMR spectroscopy, mass spectroscopy, and 2D NMR spectroscopy
including HSQC and NOESY in CDCl3 (Fig. S9-12, ESI†). In Fig. 1, the
NOE cross-peaks between –CH2- that belongs to the
ethylenediamine moiety and the backbone protons of the
pillar[5]arene suggested that a self-included conformation of R in
CDCl3, similar to the reported crystals of an analogue of R.45
Subsequently, some analogous aldehydes have been selected
to demonstrate the strategy of dynamic combinatorial libraries
(DCLs) that has been widely used in the search of novel systems
with astonishing functionalities,46 because we believe that some
representative aryl or branched aldehydes, on the contrary to linear
aldehydes, are not able to enter the cavity of R. Therefore, three
kinds of aldehydes, that is, benzaldehyde (G1), 2-
property of DEP5A might originate from
a strain-induced
reactivity.53 On the other hand, the lower reversibility of an aldol
reaction, compared with imine formation, is a driving force for the
rate enhancement of the decay of G1 and G2.
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R
and the hemiaminal [G5h +H]+ was corrected as 108V3ie.6w2A0rt5ic,lewOhnliicnhe
DOI: 10.1039/C9CC01947B
are the same with the exact mass, 1065.5835 and 1083.5941,
R
respectively. And an experimental mass of the hemiaminal [G5h
+H]+ was also observed as 1083.5828. Herein, two main reasons
weigh in the stabilization of unstable imines and hemiaminals
formed from aliphatic amine, R, and aldehydes. On one hand, the
imine formation most likely happens within the confined cavity of R
where the limited size of cavity excludes a molecule of water
involved in the transition state (Scheme S2, ESI†), thus making the
imines form slow and keep a comparative higher concentration of
hemiaminals. On the other hand, the hydrophobic cavity of
pillar[5]arene makes the reversible hydrolysis of imine difficult due
to the hindrance of the entrance of water molecule. As a
comparison, we also traced the imines and hemiaminals formed
from aliphatic aldehydes and monomeric amine, the counterpart of
R
without pillarene cavity, showing no targeted signals of
corresponding imines and hemiaminals at all by ESI-MS in the same
conditions.
Fig. 3 Comparative studies of the constituent distribution of DCLs by
400 MHz at 25 °C, where each aldehyde (G1, G2, G3) of equal
concentration (4 mM) in CDCl3 was added a) in the absence of
DEP5A or its monomer, or in the presence of b) DEP5A (25 equiv.,
 aldol product); c) the monomer (125 equiv.); d) R (3 equiv.). PA
in a, b, and c is 4 mM (1.0 equiv.).
Table 1 Unstable imines and hemiaminals detected by ESI-MS.
With the above information in hand, R is expected to play a
powerful role in the segregation of G1, G2 and G3 in the imine
formation because it can host non-hindered chemical reagents in its
self-included version. Results of the constituent distribution of DCLs
in the presence of R are discussed. When the molar ratio of the
total three aldehydes to R was 3:1, it is G3 that only reacts with the
amino group (Fig. S29, Table S8, ESI†). To double-check hardly could
G2 react in this system, the molar ratio of mixed aldehydes to R was
reset as 1:1, and surprisingly it was still G3 that decayed and the
corresponding imine G3iR was formed (Fig. 3d, Fig. S30, Table S9,
ESI†). This could be explained by the fast exchange between the
self-included and its free form of R in CDCl3 that was extremely
faster than imine formation, thus resulting in a stable self-included
form of R in the DCLs, and only G3 that could also be included in the
cavity of pillarenes reacted. In addition, from Fig. 3d, we notice that
the decay of G3 and the formation of corresponding imine G3iR are
not complete and the reaction reaches a steady state within 20 min,
which are attributed to a direction between the reactive formyl
group and R for host-guest recognition and the equilibrium of the
reactants, the intermediate hemiaminal, and the imine product.
We hypothesized that our system could stabilize imines and
hemiaminals for their direct detection by ESI-MS. So four kinds of
aliphatic aldehydes, G3, benzenepropanal (G4), phenylacetaldehyde
(G5), and 3,3-dimethylbutyraldehyde (G6) with different space
effects were selected to react with R in a controlled method.
Surprisingly, several groups of active imines and hemiaminals were
detected as summarized in Table 1 and Fig. S31-S43, ESI†. Fig.4
demonstrates the reaction of R and G5. The exact mass of [R+H]+ is
963.5365, and the experimental mass is 964.0109. The systematic
error is 0.4744. So the imine [G5iR +H]+ was corrected as 1065.6061
Fig. 4 ESI-MS of the reaction mixture of R and G5. The exact mass of
[R+H]+ is 963.5365, and the experimental mass is 964.0109. The
systematic error is 0.4744. The mass of imine, [G5iR +H]+, is
R
corrected as 1065.6061. The mass of hemiaminal, [G5h +H]+, is
corrected as 1083.6205, and an experimental mass is observed as
1083.5828.
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Table of Contents Entry
A self-included mono-amino substituted pillar[5]arene efficiently stabilizes the
hemiaminal and imine formation from the reaction of aliphatic amines and aldehydes.