Pillar[5]arenes with an introverted amino group: A hydrogen bonding tuning effect

Article abstract of DOI:10.1039/c2ob27044g

Pillar[5]arenes with introverted amino groups were produced through aminolysis. X-ray analysis demonstrated that the intramolecular hydrogen bonding induced the amino group toward the inner space of the cavity. The kinetic studies and molecular modelings revealed that the hydrogen bonding also contributed to the acceleration of the aminolysis through stabilizing the intermediate.

Full text of DOI:10.1039/c2ob27044g

Organic &
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Pillar[5]arenes with an introverted amino group: a
hydrogen bonding tuning effect†
Cite this: Org. Biomol. Chem., 2013, 11,
248
Lei Chen, Zhiming Li, Zhenxia Chen and Jun-Li Hou*
Received 19th October 2012,
Accepted 7th November 2012
DOI: 10.1039/c2ob27044g
www.rsc.org/obc
Pillar[5]arenes with introverted amino groups were produced induce the formation of tubular structures.12a These hydrogen
through aminolysis. X-ray analysis demonstrated that the intra- bondings might also be used to locate functional groups
molecular hydrogen bonding induced the amino group toward inwardly. To achieve this, the mono-activated ester functiona-
the inner space of the cavity. The kinetic studies and molecular lized pillar[5]arene 1 was prepared from 212b (Scheme 1). The
modelings revealed that the hydrogen bonding also contributed possibility for the formation of introverted pillar[5]arene (IP)
to the acceleration of the aminolysis through stabilizing the through the aminolysis of 1 was investigated by employing
intermediate.
α,ω-alkyldiamine (DA-n, n: carbon number) and alkylmono-
amine (MA-n) as substrates (Scheme 2a).
Introverted synthetic cavities, such as Rebek’s introverted cavi-
tands,1 feature inwardly directed functional groups that are
regarded as exclusive attributes of proteins and displayed prop-
erties of selective recognition,2 trapping reactive intermedi-
ates3 and efficient catalysis.4 Pillar[5]arene represents a new
kind of synthetic cavity that exhibits pillar conformation.5 The
substituents on the pillararene point to two opposite direc-
tions, which may lead to the formation of longer unique
tubular cavities.6 These cavities are open at both ends7 and
thus different from the self-assembled molecular capsules,
cages and cavitands.8 The unique tubular structures have been
demonstrated to be novel useful supramolecular hosts9 and
applied in the construction of new supramolecular polymers,10
molecular devices,11 artificial transmembrane channels,12 as
well as chemical and physical responding materials.13 At the
current stage, the functionalization of pillar[5]arene usually
occurred at either or both sides of the macrocycle. Arranging a
functional group inward of pillar[5]arene might generate a new
kind of functional group introverted cavity. Herein, we report
the first synthesis of pillar[5]arenes that bear an introverted
amino group through accelerated aminolysis, which was tuned
by intramolecular hydrogen bonding.
Scheme 1
We recently reported that the intramolecular hydrogen
bondings between the side-chains on pillar[5]arene could
Department of Chemistry, Fudan University, Shanghai, 200433, P.R. China.
E-mail: houjl@fudan.edu.cn; Fax: +86 21 65643712; Tel: +86 21 65105744
†Electronic supplementary information (ESI) available: Synthetic procedures
and characterization data, data for kinetic studies, 2D COSY and NOESY
1H NMR specta of IP-A-3, X-ray crystal structure for IP-DA-3 (CIF file). CCDC
903417. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2ob27044g
Scheme 2
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Fig. 2 X-ray crystal structure of IP-DA-3. (a) Side view; (b) top view. The moiety
including the hydrogen bonded amide group is highlighted with a stick model.
The hydrogen atoms except the one on the amide nitrogen atom are omitted
for clarity. d = 2.39 Å.
Fig. 1 Partial 1H NMR spectra showing the reaction of 1 (4.0 mM) with (a)
DA-3 (80 mM) and (b) MA-3 (160 mM) in CDCl3 at 298 K.
Fig. 3 Kinetic measurements for the reaction of 1 with (a) DA-3 and (b) MA-3.
[1]0 is the initial concentration of 1 (= 4.0 mM); [1] is the concentration of 1 at
time t. The solid line represents linear simulation of measured data points, of
that the slope is the reaction rate constants (k).
The aminolysis of 1 with DA-3 and MA-3 was monitored by
using in situ H NMR experiments (Fig. 1). Mixing the phenol
ester 1 (4.0 mM) and DA-3 (80 mM) in deuterated chloroform
1
(CDCl3) at 298 K resulted in the reaction proceeding smoothly,
as revealed by the resonance intensity of H1 on 1 decreasing Fig. S7†). The propyl group of IP-MA-3 was also introverted as
and Ha on phenol increasing (Fig. 1a). Furthermore, in the indicated by its upfield shifted Hβ and Hγ signals and the
NOEs signals of Hβ and Hγ with Ar-H (see ESI, Fig. S10 and
upfield area, two sets of new signals were exhibited in the
range of 0–1.0 ppm, which were assigned to Hβ and Hγ and S11†). The reaction of 3 with A-3 under the same conditions
shifted upfield gradually with the reaction proceeding. The was fairly slow and was complete only after ten days
(Scheme 2b). For the three reactions, the amino substrates
reaction was complete over the course of 95 min. The for-
mation of IP-DA-3 in the mixture was verified by high-resolu- were in large excess. Thus, it is reasonable to assume that the
tion ESI-MS (HR ESI-MS) and by comparing the 1H NMR reactions were of pseudo-first order, which was also verified by
the linear plots of ln([1]0/[1]) or ln([3]0/[3]) against time (Fig. 3
spectrum of the final reaction mixture with the authentic
sample (see ESI, Fig. S4†). X-ray crystal structure analysis‡ of and ESI, Fig. S13–22†). The reaction rate constants (k), the
IP-DA-3 showed that the amide bond formed intramolecular slope of the linear plots, for the reactions of 1 + DA-3, 1 + MA-3
and 3 + MA-3 were calculated to be 3.6 ( 0.3) × 10−4, 2.1 ( 0.2)
hydrogen bonding with the adjacent oxygen atoms and the
γ-aminopropyl group introverted toward the center of the pillar × 10−5 and 2.8 ( 0.2) × 10−6 s−1, respectively.
[5]arene cavity (Fig. 2). Under the strong shielding effect of the
The rate constants for the reactions of 1 with different
DA-ns and A-ns were also measured and the results are shown
1
tubular cyclophane, the H NMR signals of Hβ and Hγ shifted
upfield. In acetone-d6, a competitive solvent for the formation in Table 1. For the reactions of DA-n (n = 2–7), the values of
of hydrogen bonding, the signals of Hβ and Hγ in the range of k varied apparently with the different chain length of DA-n, and
DA-4 showed the highest rate constants of 4.4 ( 0.1) × 10−4 s−1
,
0–1.0 ppm were absent from the 1H NMR spectrum, indicating
that hydrogen bonding is the main force for keeping the stab- corresponding to a half-life-time (t1/2) of 26 min, which indi-
ility of the introverted structure.
cates a quick reaction. However, for the reaction of A-n, the
chain length has little influence on the reaction rate. The fact
The reaction of 1 and MA-3 in CDCl3 at the same concen-
tration and temperature was much slower than the reaction of that k1+DA-n > k1+MA-n > k3+MA-n indicates that aminolysis of 1
1 with DA-3 (Scheme 2a). The reaction was complete over the could be dramatically accelerated by the reaction with DA-n
and A-n. Similar to the introverted alkyl groups of IP-DA-3 and
course of 1500 min to produce IP-MA-3 which was also verified
by HR ESI-MS and the authentic sample (Fig. 1b and ESI, IP-MA-3, the alkyl groups of all the other products of the
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Table 1 The reaction rate constants (k) and half-life-times (t1/2) of the reactions
between 1 or 3 and different amino derivativesa
Run
Substratesb
k (s−1
)
t1/2
1
2
3
4
5
6
7
8
9
10
1 + DA-2
1 + DA-3
1 + DA-4
1 + DA-5
1 + DA-6
1 + DA-7
1 + MA-3
1 + MA-4
1 + MA-6
3 + MA-3
6.4 ( 0.3) × 10−5
3.6 ( 0.3) × 10−4
4.4 ( 0.1) × 10−4
4.3 ( 0.2) × 10−5
2.5 ( 0.1) × 10−5
2.1 ( 0.3) × 10−5
2.1 ( 0.2) × 10−5
1.8 ( 0.2) × 10−5
1.5 ( 0.3) × 10−5
2.8 ( 0.2) × 10−6
3 h
32 min
26 min
4 h
8 h
9 h
9 h
10 h
12 h
3 d
Fig. 5 Geometry optimized structures (hyperchem, semi-empirical, AM1) of
aminolysis intermediate (a) T⊥(DA-3) and (b) T⊥(MA-3). d1 = 2.29 Å; d2 = 2.22 Å;
a The reactions were run in CDCl3 at 298 K. b [1] = [3] = 4.0 mM; [DA-n]
= 80 mM; [MA-n] = 160 mM.
d3 = 2.85 Å; d4 = 2.37 Å; d5 = 2.31 Å.
formed between the amino group and the adjacent oxygen
atoms.
It is generally recognized that the aminolysis of the phenol
ester involves a zwitterionic tetrahedral intermediate (T⊥) and
the expulsion of phenol is the rate-determining step.14 To
further explore the driving force for the acceleration of amino-
lysis, molecular modeling on the tetrahedral intermediate of
the reaction of 1 with DA-3 and MA-3 was carried out and the
results are shown in Fig. 5. For both T⊥s, the N–Hs close to the
zwitterions were found to form hydrogen bonding with the
adjacent oxygen atoms, which stabilize the intermediate and
thus the aminolysis was accelerated compared to the reaction
of 2 with A-3. On T⊥(DA-3), an additional hydrogen bonding
formed between the primary amino group and the oxygen
atom on the pillar[5]arene backbone. This hydrogen bonding
caused T⊥(DA-3) to be more stable than T⊥(MA-3) and thus
kDA-3 is larger than kMA-3. The tendency for formation of hydro-
gen bonding by the primary amino group on T⊥(DA-n)
decreased with the increase of the chain length of DA-n. As a
result, the k values varied in a large range for the reaction of
the DA-n series. In conclusion, we have reported the synthesis
of amino group introverted pillar[5]arene which was tuned by
intramolecular hydrogen bonding. The hydrogen bonding not
only stabilized the introverted structure, but also accelerated
the aminolysis through stabilizing the intermediate of the
reaction. It is envisioned that the chiral space will be generated
by using chiral alkylamines as substrates, which was under
investigation.
Fig. 4 Partial 1H NMR spectra of IP-DA-n (n = 2–7) and IP-MA-n (n = 3, 4, 6)
highlighted the proton signals of introverted side chains. The assignment of the
proton signals of CH2NH2 and CH3 based on their integration and non-anisotro-
pic properties.
IP-DA-n and IP-MA-n series are introverted as indicated by
their upfield shifted 1H NMR signals in the range of
0–2.5 ppm (Fig. 4). Among the series of IP-DA-n, the signal of
CH2NH2 of IP-DA-4 showed the largest upfield shifting com-
pared to the chemical shift of CH2NH2 in DA-4, indicating that
IP-DA-4 might be the one in which the CH2 connecting to the
terminal amino group is closest to the center of the cavity. The
position of the amino group in the cavity could be adjusted by
using DA-ns of different length as substrates. The values for
chemical shift change of CH3 on the introverted side-chain of
IP-MA-n were much smaller than that of CH2NH2 on IP-DA-n
due to the fast flipping of the side-chain in and out of the
cavity (Fig. 4). The fast flipping led to the integration of the
introverted side-chain being lower than expected. The reason
why the introverted structure of IP-DA-n is more stable than
IP-MA-n might be the contribution of hydrogen bonding
This work was supported by NSFC (20902012 and
91027008), Program for Changjiang Scholars and Innovative
Research Team in University (IRT1117), STCSM (09ZR1402700,
10PJ1401200).
Notes and references
‡Crystallographic data of IP-DA-3 (CCDC 903417): C76H94N2O29·(CHCl3),
Mr = 1618.93, monoclinic, space group P2(1)/n, a = 18.958 (4), b = 21.804 (5),
c = 20.210 (5) Å; α = 90, β = 91.004 (4), γ = 90°; V = 8353 (3) Å3; Z = 4, λ = 0.71073 Å;
T = 296 (2) K; 39 475 reflections collected, 14 656 unique reflections (Rint = 0.1029);
R1 = 0.1409, wR2 = 0.3690 [I > 2σ(I)]; R1 = 0.2456, wR2 = 0.4131 (all data).
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