Inhibition and Stabilization: Cucurbituril Induced Distinct Effects on the Schiff Base Reaction

Article abstract of DOI:10.1021/acs.joc.6b02971

The different effects of cucurbit[7]uril (CB[7]) on the Schiff base reactions in aqueous solution were explored by ¹H NMR spectroscopy and single X-ray crystallography. With CB[7], the condensation reaction of aldehyde and primary amine is dramatically inhibited. In contrast, the presence of CB[7] does tremendously stabilize iminium cation in water through ion-dipole interactions. A single crystal structure of the complex of iminium ion 7 with CB[7] grown in water is reported.

Full text of DOI:10.1021/acs.joc.6b02971

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Note
Inhibition and Stabilization: Cucurbituril Induced
Distinct Effects on the Schiff Base Reaction
Wanjun Gong, Jun Ma, Zhiyong Zhao, Fang Gao, Feng Liang, Haijun Zhang, and Simin Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02971 • Publication Date (Web): 23 Feb 2017
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Inhibition and Stabilization: Cucurbituril Induced Distinct Ef-
fects on the Schiff Base Reaction
Wanjun Gong, Jun Ma, Zhiyong Zhao, Fang Gao, Feng Liang, Haijun Zhang, Simin Liu*
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The State Key Laboratory of Refractories and Metallurgy, School of Chemistry and Chemical Engineering, Wuhan University of Science and
Technology, Wuhan 430081, China
ABSTRACT: The different effects of cucurbit[7]uril (CB[7]) on
the Schiff base reactions in aqueous solution were explored
1
by H NMR spectroscopy and single Xꢀray crystallography.
With CB[7] the condensation reaction of aldehyde and primary
amine is dramatically inhibited. In contrast the presence of
CB[7] does tremendously stabilize iminium cation in water
through ionꢀdipole interactions. A single crystal structure of
the complex of iminium ion 7 with CB[7] grown in water is reported.
It is always at the heart of synthetic chemistry to develop
novel, cleaner, more efficient and selective reactions. To
this end, there has been a recent explosion of interest in
the use of microenvironments to simulate the catalyst
prowess of enzymes.1ꢀ3 Appearing in the late 1990s,
nanoꢀreactors (NRs) have attracted considerable attenꢀ
tion because of their ability to control reaction processes.
Moreover within supramolecular chemistry numerous
successes in this area have been achieved using differꢀ
ent kinds of hosts. For example, selfꢀassemblies such as
cages and “soft ball” have been found to catalyze organꢀ
ic reactions.4ꢀ7 In addition, other cyclic hosts such as
crown ethers, cyclodextrins and calixarenes have been
also used in different kind of reactions.8ꢀ10
more, imines are also important enzymatic intermediates
in vivo such as the reaction of a common enzyme cofacꢀ
tor PLP and a lysine residue.24 In this work we investiꢀ
gate the effects of CB[n] on the reversible Schiff base
reaction and the stability of iminium cations using 1H
NMR spectroscopy and single Xꢀray crystallography.
Among the macrocyclic hosts, cucurbit[n]uril (CB[n], n
= 5ꢀ8, 10, Scheme 1a) possess a hydrophobic cavity
and two identically open portals with 2n carbonyl
oxygens. These structural features lead to outstanding
molecular recognition properties towards cationic and
neutral guests.11ꢀ13 CB[n] have showed an exquisite abilꢀ
ity as nanoꢀreactors, catalyst, and to the stabilization of
highly reactive species.14ꢀ17 Relatedly, several groups
have focused on the use of CB[n] as protective agent in
different reactions.18,19
The Schiff base reaction (Scheme 1b), discovered by
German chemist Hugo Schiff,20 is a well known and wildꢀ
ly utilized reaction in numerous domains.21ꢀ23 Furtherꢀ
Scheme 1. Structure of CB[n] (a), Schiff base reaction (b) and
structure of iminium cation compounds (c).
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tons on both 1 and 2 shifted upfield as a consequence of
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the encapsulation of two substrates within CB[7] (Figure
S1, Table S1). Despite the relatively larger peaks (11%)
reflecting more substrates converted to imine, the perꢀ
centage of imine is still smaller compared to those withꢀ
out CB[7] (47%) (Figure S1, S2). Although CB[7] can
bind the guests in both weaker and stronger basic condiꢀ
tion, obviously it prefers to bind the protonated amine 2,
which is why more imine formed with the increase of pD
in the presence of CB[7].
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Since protonation of 2 is unfavorable to reaction we
sought to probe this inhibition by determining the pKa
values of 2 in the absence and presence of CB[7]
(UV/Vis titration). As excepted, encapsulation within
CB[n] led to an increase in the pKa of the amino guest:25
a pKa shift of 2 from 9.7 to 12.1 (Figure S3). The mechaꢀ
nism of inhibition is therefore quite clear. In a relatively
weaker basic condition (pD = 9.6), the reaction of free 2
proceeds because it is only partially protonated. Howevꢀ
er, in the presence of CB[7] the amino group of 2 is alꢀ
most fully protonated due to the increase of its pKa.
Hence 2 cannot act as a nucleophile and attack the carꢀ
bonyl carbon atom of 1, so that the reaction is fully inhibꢀ
ited (Scheme 2). In contrast, in strongly basic condition
(pD = 13.6), both neutral 1 and 2 competitively bind with
CB[7], which reduces the chance of their encounter due
to the encapsulation inside CB[7]. Moreover, the electroꢀ
negative oxygen on the carbonyl groups of CB[7] could
stabilize the electropositive carbon on the aldehyde
group of 1 by electrostatic interactions and so reduce the
reactivity of substrate 1 (Scheme 2).26
Figure 1. Partial 1H NMR spectra (600 MHz, D2O) for a) 1 (2.0 mM);
b) 5 min after addition of 1 (2.0 mM) to 2 (2.0 mM); c) 20 min after
addition of 1 (2.0 mM) to 2 (2.0 mM); d) 2 (2.0 mM); e) 1:1.1 mixꢀ
ture of 2 (2.0 mM) and CB[7]; f) 1 day after addition of 1 (2.0 mM)
to a 1:1.1 mixture of 2 (2.0 mM) and CB[7] (pD = 9.6); g) 1h after
addition of 1 (2.0 mM) to a 1:1.1 mixture of 2 (2.0 mM) and CB[7] in
pD = 11.5.
The condensation reaction of benzaldehyde (1) and
benzylamine (2) with/without CB[7] was first explored by
1H NMR. In the absence of CB[7], a new peak at ~ 8.4
ppm corresponding to the imine product emerged after
adding 1 to the solution of 2, indicating the occurrence of
the reaction (Figure 1a, 1b). Within 20 minutes, the conꢀ
tent of imine increased to 35% (Figure 1c). Separately,
when CB[7] was added to the solution of 2, the signals
for the aromatic protons of 2 underwent significant upꢀ
field shifts (∆δ = 0.5 ~ 0.7 ppm), whereas those from the
methylene signal underwent a less significant upfield
shift (∆δ = 0.15 ppm) (Figure 1d, 1e). These shifts are
suggestive of the encapsulation of 2 within CB[7] (fast
1
exchange on H NMR time scale). After addition of 1 to
the solution of this complex, the signals of 2 shifted
slightly downfield due to weak competitive binding of 1
(pD = 9.6) (Ka for both 1 and 2 with CB[7] can be found
in Table S1). Importantly, no peak at ~ 8.4 ppm was obꢀ
served even after the mixture was left for 1 day, indicatꢀ
ing the reaction between 1 and 2 is fully inhibited by the
presence of CB[7] at pD 9.6 (Figure 1f). To obtain a
comprehensive understanding of the role of CB[7], the
reaction was carried out at different pD. Although a small
peak at ~ 8.4 ppm emerged after 1h at pH 11.5, the conꢀ
tent of imine (7%, according to equation 1) did not inꢀ
crease even after 1 day (Figure 1g). When a strong
basic solution (pD = 13.6) was used, all signals of proꢀ
Scheme 2. Plausible mechanism of CB[7]ꢀmediated Schiff base
reaction.
To gather more information of the influence of CB[7]
on the reaction, the hydrolysis of imine at various pD
was also explored. We found that in the absence of CB[7]
the percentages of imine at pD = 13.6, 12.5, 11.5 were
47%, 43% and 36%, whereas in the presence of CB[7]
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the values were 22%, 16%, and 9% (compare Figure
The binding H NMR of iminium cation 7 with CB[7] is
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S4a with S4b, S4c with S4d, S4e with S4f). Apparently
the presence of CB[7] promoted the hydrolysis of imine
at all pD values examined. Alone with previous inhibition
effect, this promotion on the hydrolysis could be attributꢀ
ed to the higher binding affinity between CB[7] and the
hydrolysis products 1 and 2.
shown in Figure 2. Like the other iminium cations, hyꢀ
drolysis of 7 can be observed in few minutes by 1H NMR
(Figure 2a). According to the split of the NMR signals on
CB[7] in Figure 2c, the 1:1 inclusion complex CB[7]•7
exhibits slow exchange on the 1H NMR time scale.
Given the encapsulation of iminium cations inside
CB[7], we then focus on the stabilization of these high
activity species upon encapsulation. The hydrolysis of 3ꢀ
The inhibition effect on the Schiff base reaction by
CB[7] lead us to postulate about reactions involving secꢀ
ondary amine that form iminium cations.27ꢀ30 The Rayꢀ
mond group has developed a route to generate and staꢀ
bilize these species in aqueous solution by trapping the
product in an assembled cage host,31 which suggested
that CB[n] could play the same role owing to its high
binding affinity towards organic cations. Unfortunately
we did not observe that CB[7] can generate these speꢀ
cies in aqueous solution. However CB[7] does promote
the stabilization of iminium cations. Several iminium catꢀ
ions with different size and shape were synthesized by
the condensation of ketones and secondary amine
(Scheme 1c).32
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1
7 was monitored by H NMR spectroscopy in deuterium
oxide. All 1H NMR spectra demonstrate that without
CB[7], iminium cations hydrolyzed quickly to its correꢀ
sponding ketone and amine (Figure 2a, 2b and Figure
S5ꢀS8). However, in the presence of CB[7] either no
peaks correlating to ketone and amine could be obꢀ
served, or only very small peaks were evident that did
not change over time. Apparently, in some cases hydrolꢀ
ysis was observed before the iminium cation was encapꢀ
sulated by CB[7]. The lifetimes of 3ꢀ7 were calculated by
NMR signal integration (Figure S9, according to equation
2). In all cases with CB[7] there was no evidence of hyꢀ
drolysis after 1 day, and for the complex CB[7]•7, no
obvious hydrolysis was observed even after two weeks.
The binding of iminium cations with CB[7] was investiꢀ
1
gated by H NMR (Figure 2, S5ꢀS8), and the complexaꢀ
tionꢀinduced chemical shift changes (CIS, ∆δ = δbound
ꢀ
δfree) exhibited by guest protons were calculated to unꢀ
derstand binding behavior.12,15,33 CIS values (Table S2)
reveal that all iminium cation compounds can be encapꢀ
sulated within the cavity of CB[7]. Since the positively
charged nitrogen is located in the middle the guest both
the α and β moieties (Scheme 1c) on the guest could
conceivably bind to CB[7]. According to the CIS values,
it is evident that for iminium cation 4, both similarly sized
moieties have equal affinity for the binding site of CB[7].
A binding model of iminium cation 4 within CB[7] is
showed in Scheme 3. This model explains that why the
signals for all protons on both five number rings of 4 unꢀ
derwent significant upfield shifts.34 To explain the CIS
data for all guests the packing coefficient (PC)35 of each
moiety (Table S3) were calculated. For example, for
iminium cation 3 both the CIS and the PC values for proꢀ
tons on the α moiety are much larger than those on the β
moiety. Correspondingly for those having β moieties with
larger PC, their CIS values on β moiety are obviously
larger than those on α moiety, especially for 7 which has
β moiety with a nearly perfect PC value (52.68).35
Figure 2. Partial 1H NMR spectra (600MHz, D2O) of: a) 7 (1.0 mM)
(partially hydrolyzed); b) fully hydrolyzed 7 (1.0 mM); c) CB[7]•7
(1.0 mM) for 1 day.
The single crystal of CB[7]•7 was successfully obꢀ
tained assisted by adding a small amount of KI to the
aqueous solution of host and guest. This provided direct
evidence of the encapsulation and stabilization of iminiꢀ
um ion 7 (Figure 3).36 The nature of the bound guest was
confirmed by: 1) the short bond length of N=C (1.298 Å
for N86=C145 verses 1.506 Å and 1.540 Å for N86–C141
and N86–C144 respectively); 2) the planar array of the four
atoms covalently linked to N86 and C145. Also apparent
from the structure was that all seven oxygens on one
ureidyl carbonyl portal of CB[7] are involved in forming
C=O———N+ ionꢀdipole interactions with the positively
charged nitrogen atom on the guest 7. The average disꢀ
tance from oxygen on the ureidyl carbonyl portal to niꢀ
Scheme 3. Kinetic binding model of iminium cation 4 with CB[7].
3
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trogen on guest 7 was ~ 4.23 (7) Å, which is slightly
Page 4 of 5
1
shorter than ~ 4.38 (7) Å found in a CB[7] complex with
an attomolar dissociation constant reported by Isaacs.37
Furthermore, the positively charged nitrogen atom is
exactly located on the plane composed of seven oxꢀ
ygens on the portal of CB[7], which maximizes the ionꢀ
dipole interactions between CB[7] and the guest. Further
inspection reveals that the average distance from oxyꢀ
gen on the ureidyl carbonyl portal to C145 (carbon on 2
position in 2ꢀadamantanone) on guest 7 (~ 4.39 (7) Å) is
very close to that of C152 (carbon on 6 position in 2ꢀ
adamantanone) to the adjacent oxygens on CB[7] (~
4.43 (7) Å) (Figure S10). The results imply in this case
that the 2ꢀadamantyl “perfectly” fits in the cavity of CB[7].
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Experiment Section
General information: CB[6] and CB[7] were syntheꢀ
sized and separated according to literature procedures.38
Other compounds used in this study were purchased
from commercial suppliers and were used without further
1
purification. H NMR spectra were collected on Agilent
600 MHz DD2 spectrometers and chemical shifts were
recorded in parts per million (ppm). UV/Vis measureꢀ
ment was performed on a SHIMADZU UVꢀ3600 instruꢀ
ment with 1 cm pathlength cells at 298 K. The Xꢀray inꢀ
tensity data were measured on a Bruker APEXꢀII CCD
system (Data collection temperature was 203K).
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General procedure for iminium cation compounds
synthesis: All the iminium cations (as perchlorate salt)
were prepared according to the literature.32 To a solution
of ketone (10 mmol) and pyrrolidine (10 mmol) in toluene
(25 mL) was added ammonium perchlorate (10 mmol).
The solution was heated to reflux with continuous reꢀ
moval of the water formed. After cooling down in iceꢀ
water bath, the precipitated product was collected by
filtration, washed with ether (3 × 10mL), and dried in
vacuum.
Figure 3. Representation of the Xꢀray crystal structures of the
inclusion complex CB[7]•7: a) top view and b) side view.
The binding and stabilization of iminium cations were
further extended to smaller CB[6] (Figure S11ꢀS16). To
our surprise, although CB[6] has the capacity to hold an
aromatic group, no obviously chemical shift changes
from the protons of the iminium cations could be obꢀ
served from the 1H NMR spectra. Nevertheless, by moniꢀ
toring the progress of the hydrolysis of iminium cations,
we found that even though inferior to CB[7], CB[6] inꢀ
deed provided protection to iminium ions from hydrolysis
in aqueous solution. We assume that once upon mixed,
iminium cations stay at the portals of CB[6] due to the
strong ionꢀdipole interactions, which slows down the hyꢀ
drolysis.
Hydrolysis of imine experiment: 1 (2.0 mM) and 2 (2.0
mM) was mixed in D2O/NaOD (pD > 13.6) and left overꢀ
night. Then the solution was divided into two parts and
one was added with 1.1 equivalent of CB[7]. To above
solutions was added DCl to adjust pD, and all samples
were monitored by 1H NMR until there was no any
change on 1H NMR spectra.
Calculation of lifetime of iminium cations: Due to the
high reactivity of iminium cations to H2O, the concentratꢀ
ed solution of iminium cations was prepared in CD3OH.
However when added to the aqueous solution of CB[7],
quick hydrolysis of iminium cation was still observed beꢀ
fore it was stabilized by the encapsulation inside CB[7].
In order to simplify the calculation, the first percentage
for the complex is set up to 100% and the subsequent
values are calculated based on this value.
In summary, we have demonstrated that CB[7] can
play an important role in Schiff base reactions ꢀ inhibiting
the condensation reaction of aldehyde and primary
amine. Although CB[7] could not help to generate iminiꢀ
um cation in aqueous condition, it does stabilize them by
hostꢀguest interaction. Also, for the first time we report
on the crystal structure of an encapsulated iminium ion
grown in water. This preliminary finding further point out
that CB[n] are able to control the reaction process, either
obverse or reverse effect. Stabilization of highly unstable
iminium ions in water with CB[n] could lead to a new way
to switch some reactions involving highly active intermeꢀ
diates from organic condition to aqueous condition.
Calculation equation:
[imine]
ꢀ ꢁ
imine %= [imine] + [aldehyde]
1
ꢂiminium caitonꢃ
iminium cation %= ꢂiminium caitonꢃ + ꢂamineꢃ
ꢀ ꢁ
2
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(13) Barrow, S. J.; Kasera, S.; Rowland, M. J.; del Barrio, J.;
Supporting Information
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Crystallographic data for CB[7]•7
9
AUTHOR INFORMATION
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Corresponding Author
Email: liusimin@wust.edu.cn
ACKNOWLEDGMENT
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This work was financially supported by the National Natꢀ
ural Science Foundation of China (No. 21472143 &
21604066), Thousand Youth Talents Program of China
(No. D1118031), and Program for Innovative Teams of
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