Reactivity-based dynamic covalent chemistry: Reversible binding and chirality discrimination of monoalcohols

Article abstract of DOI:10.1021/jo502801g

In an effort to develop reactivity-based dynamic covalent bonding and to expand the scope and application of the dynamic covalent chemistry, in situ-generated simple generic iminium ions were utilized for the dynamic covalent binding of monoalcohols with high affinity. Hammett analysis was conducted to manipulate the equilibrium and correlate with the reactivity of reactants. The structural features of aldehydes and secondary amines were identified, and both polar and steric effects have significant impact on the binding. In particular, the substrates which can participate in π-π and polar-π interactions are able to afford apparent equilibrium constants in the magnitude of 10⁴ M^-2, demonstrating the power of weak supramolecular forces to stabilize the dynamic covalent assembly. The generality of the assembly was validated with a series of mono secondary alcohols. To showcase the practicality of our system, chirality discrimination and ee measurement of chiral secondary alcohols were achieved.

Full text of DOI:10.1021/jo502801g

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Article
Reactivity Based Dynamic Covalent Chemistry: Reversible
Binding and Chirality Discrimination of Mono-Alcohols
Yuntao Zhou, Hebo Ye, and Lei You
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502801g • Publication Date (Web): 12 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Reactivity Based Dynamic Covalent Chemistry: Reversible
Binding and Chirality Discrimination of MonoꢀAlcohols
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Yuntao Zhou,a,b,‡ Hebo Ye,a,‡ and Lei You*,a
a State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fujian, 350002, P. R. China. Eꢀmail: lyou@fjirsm.ac.cn
b College of Chemistry, Fuzhou University, Fujian, 350116, P. R. China.
Abstract: In an effort to develop reactivity based dynamic covalent bonding, and to expand the scope and
application of the dynamic covalent chemistry, in situꢀgenerated simple generic iminium ions were
utilized for the dynamic covalent binding of monoꢀalcohols with high affinity. Hammett analysis was
conducted to manipulate the equilibrium and correlate with the reactivity of reactants. The structural
features of aldehydes and secondary amines were identified, and both polar and steric effects have
significant impact on the binding. In particular, the substrates which can participate in πꢀπ and polarꢀπ
interactions are able to afford equilibrium constants in the magnitude of 104 Mꢀ2, demonstrating the power
of weak supramolecular forces to stabilize the dynamic covalent assembly. The generality of the assembly
was validated with a series of mono secondary alcohols. To showcase the practicality of our system,
chirality discrimination and ee measurement of chiral secondary alcohols were achieved.
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Introduction
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Dynamic covalent chemistry (DCC)1 is increasingly popular for the construction of complex
assembling structures,2 creation of novel chemosensors,3 and modulation of stimuli responsive materials.4
In order to achieve the aforementioned goals, it is of great significance to discover reversible covalent
interactions with high affinity. Compared to the widespread use of dynamic imine formation with primary
amines and carbonyls as well as metal complexes of these imines,5 the use of iminium ions for
thermodynamically driven systems has been rarely reported despite the fact that iminium ion is widely
employed in asymmetric organocatalysis that is generally under kinetic control.6 Because of their high
reactivity, iminium ions can undergo a variety of transformations, such as nucleophilic additions, and
hence, the utilization of iminium ions in DCC would expand the diversity and complexity of the
assembling architectures and have potential applications in a variety of contexts, such as sensing3c, 7 and
labeling.8
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Monoꢀalcohols are one of the most common functional groups in chemistry. Moreover, they are the
targets of many asymmetric reactions.9 As a result, it is of importance to develop alcohol receptors.
However, due to monoꢀalcohols’ poor nucleophilicity and weak coordinating ability, their molecular
recognition is challenging. For example, the use of electronꢀwithdrawing groups was employed to enhance
the binding affinity of carbonyl receptors to monoꢀalcohols to create hemiacetals, but only to a small
extent.10 Anslyn11 and Lehn12 reported separately the formation of hemiacetals from
pyridineꢀ2ꢀcarboxaldehyde (2ꢀPA) analogs and the stabilization of products with Brønsted or Lewis acids.
In another study, Lehn and Hermann explored the reversible formation of cyclic aminals and the release of
volatile carbonyl compounds from them.13 Anslyn and You used specially designed tris(pyridine) based
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iminium for the binding and chirality recognition of alcohols with the formation of stable metal complexes
as the driving force.14
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We are initiating a project of reactivity based dynamic covalent chemistry. Toward this end, simple
generic iminium ions were exploited for alcohol binding, and the modulation of binding properties as well
as chirality differentiation of chiral alcohols was investigated. Understanding the details should open the
opportunity for the use of other reactive intermediates in dynamic assembly systems, thereby further
expanding the scope and application of DCC.
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Results and discussion
Model and Experiment Design
Due to the lability of iminium ions, in situ assembly reactions of an aldehyde, a secondary amine, and
an alcohol were run (Figure 1). In addition to the desired hemiaminal ether (
1
), the competing reaction to
create aminal
2
is likely. We postulated that once formed after the elimination of water from hemiaminal
4
the iminium ion (
3) would rapidly react with alcohol and amine to afford
1
and
2, respectively. However,
the hemiaminal ether functionality is thermodynamically unfavourable, and can easily reverse back to the
reactants. Nꢀacylation15 as well as cyclization16 is normally used to stabilize the hemiaminal ether. Instead
of relying on elegant design, we conceived that the equilibrium could be manipulated through the
structural features of the assembling component. In short, we sought a dynamic covalent system in which
the reactivity of the iminium ion, the reversibility of the reaction, and the stability of the assembly can be
balanced.
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Figure 1. Proposed reaction mechanism of hemiaminal ether (1) formation.
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To test our hypothesis, ethanol was chosen as a model alcohol. A series of aromatic aldehydes were
screened, with both electronꢀpoor and electronꢀrich cases included. Aliphatic aldehydes were not chosen
because of interfering enamine formation. For secondary amines, both arylꢀ and alkylꢀsubstituted ones as
well as acyclic and cyclic ones with varied bulkiness were explored. The multiꢀcomponent reactions were
performed at room temperature in CD3CN for 24 h in the presence of 3 Å molecular sieves (MS) and 0.1
equiv. of methanesulfonic acid, and the mixture was characterized by 1H NMR. No further increase in the
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percentage of
1 was detected after 24 h. To quantify the binding strength, the apparent equilibrium
constant (Kapp) was derived through NMR integrals and mass balance of aldehydes (see details in ESI).
The component distribution (yield) of the aldehyde, heminaminal ether, and aminal was also calculated
from their equilibrium concentrations.
Modulation of Binding Affinity
The features and trends of aldehydes that affect the binding affinity significantly were then examined
using diethylamine as a model amine (Table 1. For component distribution, see Table S1). With
benzaldehyde analogs, the Kapp value increase as the electrophilicity of aldehydes is enhanced. For
example, 4ꢀmethoxyꢀbenzaldehyde gave the poorest reaction (K ~8.49 Mꢀ2), while 4ꢀnitroꢀbenzylaldehyde
afforded a binding constant of 4160 Mꢀ2, greater than benzaldehyde by 177ꢀfold. The plot of logarithm of
equilibrium constants of dynamic covalent reactions with para or meta substituted benzaldehydes against
Hammett parameter σ gave a linear relationship with a sensitivity constant (ρ) of 2.75 (r2 = 0.975, Figure
2a). This result further supports the observed trend of aldehyde electrophilicity toward addition reactions.
Table 1. The apparent equilibrium constant of the multiꢀcomponent assembly of aldehydes,
secondary amines, and ethanol.
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NR1R2
O
H
N
CH3SO3H
CH3CH2OH
+
Ar
+
R1
R2
Ar
CD3CN/3ÅMS
OCH2CH3
1
6
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Aldehyde 5
Amine 6
Kapp/Mꢀ2 Aldehyde 5
Amine 6
Kapp/Mꢀ2
461
4160
2020
397
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2380
541
182
77.0
81.9
23.5
8.49
1050
29.0
7950
821
6890
946
11200
5540
77500
15600
17300
2000
7530
12100
3740
1280
437
4020
b
508
a
4.0
2.8
p-OCH
3
p-NO
2.6
2.4
2.2
2.0
1.8
1.6
1.4
3.5
3.0
2.5
2.0
1.5
1.0
0.5
2
p-CH
3
m
-CN
p-CN
m
-Br
p-H
m-Cl
m-OCH
3
p-H
slope =2.75
2
slope= -1.36
2
p-OCH
m,p-Cl
R
=0.975
0.6
R
= 0.987
0.0
3
-0.4 -0.2 0.0
0.2
0.4
0.8
-0.4
-0.2
0.2
0.4
0.6
σ
σ
Figure 2. (a) Hammett plot of the reaction of substituted benzaldehydes, diethylamine, and ethanol; (b) Hammett
plot of the reaction of 2ꢀPA, Nꢀmethylaniline analogs, and ethanol.
Having explored benzaldehyde derivatives, we next turned to heterocycle substituted aromatic
aldehydes. Formylpyridines with different substitution pattern were investigated. Among these three,
pyridineꢀ4ꢀcarboxaldehyde (4ꢀPA) afforded the strongest binding (K ~5540 Mꢀ2), while 2ꢀPA (K~1050
Mꢀ2) and 3ꢀPA (K~946 Mꢀ2) gave similar results. For 2ꢀPA and 4ꢀPA, resonance interaction between
electronegative nitrogen and α position of carbonyl leads to an increase in electrophilicity. However, there
was a fiveꢀfold increase of binding constant for 4ꢀPA over 2ꢀPA. This difference is likely due to less
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stability of 2ꢀPA derived assembly as a result of repulsion between electron lone pairs on three
neighboring heteroatoms (N, N, and O, Figure 3). In order to generate a broad range for screening of
secondary amines, 2ꢀPA was employed.
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Figure 3. The interaction of electron lone pairs within 4ꢀPA and 2ꢀPA derived assembly.
A variety of secondary amines were then tested. For Nꢀmethylaniline analogs, the amine bearing an
electronꢀdonating
p
ꢀOCH3 was the best (K ~461 Mꢀ2), while no desired product was detected with
Nꢀmethylꢀ4ꢀnitroaniline. The equilibrium constants correlate well with the nucleophilicity of amines with
the reaction better promoted by stronger nucleophiles. A linear relationship was obtained when logK was
plotted against the Hammett value σ (ρ = ꢀ1.36, r2 = 0.987, Figure 2b). For Nꢀmethylꢀ3,4ꢀdichloroaniline,
the sum of the corresponding Hammett parameter of
mꢀCl and pꢀCl was utilized for analysis. Aminal 2
was not detected for the reactions with these aromatic amines or diethyl amine (Table S1).
In general, aliphatic amines afforded stronger binding affinity than their aromatic counterparts, and
similar trend regarding nucleophilicity was observed (Table 1). Moreover, steric interactions have
significant effects on the reversible reactions described herein. For example, the reaction of piperidine (K
~7950 Mꢀ2) gave a much larger equilibrium constant than diethylamine (K ~1050 Mꢀ2). Meanwhile, the
interference with aminal formation was much more pronounced for cyclic amines, such as piperidine and
morpholine, whose reaction mixtures contained 36% and 53% aminal 2, respectively (Table S1). To
minimize the side product, bulkier amines were used as sterically congested aminal would be disfavored.
For example, the assembly with 2ꢀmethylpiperidine afforded the hemiaminal ether in good yields (71%),
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and aminal
2
was not observed. However, 2ꢀmethylpiperidine also gives a smaller binding constant (821
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Mꢀ2). Hence, a delicate balance between reactivity and sterics must be established.
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The Effect of π Interactions
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One surprising result was obtained with benzylamine derivatives. An equilibrium constant of 12100
Mꢀ2, that is a 24ꢀfold enhancement compared to Nꢀmethylpropylamine (508 Mꢀ2), was found for
multiꢀcomponent assembly with Nꢀmethylbenzylamine. Such a sharp increase in binding affinity can’t be
explained with simple inductive effects since phenyl is slightly electronꢀwithdrawing while 1ꢀpropyl is
electronꢀdonating. We postulated that the assembly is stabilized through πꢀπ stacking interaction between
pyridine and phenyl planes (Figure 4a).17 The use of intramolecular π interactions to stabilize acyclic
dynamic covalent assemblies has been rarely reported. The placement of the pyridine and phenyl unit here
is similar to that of two phenyl groups of 1,8ꢀdiarylnaphthalenes in which the sandwich conformation is
favored over the edge to face orientation.18 To gauge the possibility of and gain further insights into
proposed π interactions within dynamic covalent assemblies, computational studies were conducted
(Figure 4a). Although not perfectly parallel, the two interacting arenes can adopt an orientation between
parallelꢀstacking and parallelꢀoffset arrangements.19
Figure 4. (a) Proposed and computational structures of πꢀπ interaction between pyridine and phenyl planes. (b)
Proposed and computational structures of polarꢀπ interactions between pyridine plane and methoxy group. The
electrostatic potential maps were also shown.
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Inspired by this finding, we tested other secondary amines with nearby functionalities that can
participate in π interactions. First, more benzylamine analogs were explored. Nꢀmethylꢀ3ꢀfluoroaniline
and 3ꢀ[(methylamino)methyl]pyridine gave an equilibrium constant of 11200 and 7530 Mꢀ2, respectively.
Second, we conceived that polarꢀπ interaction20 would have a similar impact as πꢀπ stacking, and hence,
several amines with nearby polar groups were examined. N,N,N’ꢀtrimethylꢀ1,3ꢀpropanediamine and
(2ꢀmethoxyethyl)methylamine afforded a yield of more than 80% with only residue amounts of aminals.
The binding constant is 1280 Mꢀ2 and 3740 Mꢀ2, respectively, significantly higher than that of
Nꢀmethylpropylamine. For (2ꢀmethoxyethyl)methylamine, molecular modeling reveals that in one isomer
the methoxy group is in close contact with the pyridine plane (Figure 4b).
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Expansion of Substrate Scope
Having identified the structural features of both aldehyde and secondary amines, we next set out to
expand the scope of the assembly. First, 4ꢀPA was employed to conduct the multiꢀcomponent assembly.
Representative amines were chosen to cover a broad range of chemical space: alkyl, aromatic, cyclic, and
hetero atom substitution (Table 1). It was found that 4ꢀPA showed stronger affinity than 2ꢀPA in all cases,
and
N,N,N’ꢀtrimethylꢀ1,3ꢀpropanediamine,
(2ꢀmethoxyethyl)methylamine,
as
well
as
Nꢀmethylbenzylamine are the best with an equilibrium constant in the magnitude of 104 Mꢀ2.
The dynamic covalent multiꢀcomponent assembly was then run with 4ꢀPA
,
(2ꢀmethoxyethyl)methylamine, and a suit of structurally diverse secondary alcohols, and the results are
listed in Table 2. 2ꢀpropanol afforded ~80% of the desired hemiaminal ether with a binding constant of
9700 Mꢀ2. For other secondary alcohols tested (2ꢀbutanol, 3ꢀmethylꢀ2ꢀbutanol, 1ꢀphenylethanol,
1ꢀphenylꢀ1ꢀpropanol, and cyclohexanol), similar extent (~80%) of the assembly was created, confirming
the binding capability of this simple system.
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The aldehyde as well as its associated iminium ion intermediate is enantiotopic, and the addition of
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chiral alcohols (100%
R or S) would lead to a pair of diastereomers. As a result, four stereoisomers would
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be generated with racemic chiral secondary alcohols. However, due to the principles of stereochemistry,
there are two pairs of enantiomers in the mixture, and hence, only two sets of resonances were observed in
1H NMR. To quantify the stereoselectivity for chiral alcohol derived assembly, the diastereomeric ratio
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(
dr) was calculated with the integral ratio of the corresponding CH of the newly formed stereocenter (i.e.
aldehyde H). For 2ꢀbutanol, 3ꢀmethylꢀ2ꢀbutanol, and 1ꢀphenylꢀ1ꢀpropanol, the dr value was around 1.5
(Table 2).
Table 2. The yield, binding constant, and dr value of the reaction of 4ꢀPA, (2ꢀmethoxyethyl)methylamine,
and secondary alcohols.
Alcohol
Yield of 1/%
Kapp/Mꢀ2
9700
4770
4220
8610
3480
7270
dr
ꢀ
81
78
79
83
78
85
1.47
1.54
1.09
1.48
ꢀ
Only a modest dr value (~1.1) was found for 1ꢀphenylethanol. This is in sharp contrast with
previously reported tris(pyridine) substituted iminium based assembly, in which 1ꢀphenylethanol afforded
the largest dr value (~2.2) among the chiral alcohols tested here.14d We reasoned that the steric effect of
phenyl group in 1ꢀphenylethanol derived assembly is much less pronounced due to πꢀπ interaction
between pyridine and phenyl of the alcohol (Figure S24). Such a rationalization is also supported by the
fact that there are two values of Charton steric parameter for phenyl (0.57 and 1.66),21 and the inꢀplane Ph
(0.57) is more appropriate to describe the steric interactions here than the outꢀofꢀplane Ph (1.66). The
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steric parameter of methyl (0.52) is very close to that of the inꢀplane Ph, leading to a small dr value. This
result is also in consistence with the similar equilibrium constant for 2ꢀpropanol and 1ꢀphenylethanol
(Table 2).
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Investigation of Intermediates
Reaction intermediates were then explored as a means of probing the mechanism of the dynamic
covalent assembly. To capture hemiaminal 4, molecular sieves were not used. The reaction was conducted
in the absence or in the presence of 1 equiv. of ethanol without molecular sieves. Without alcohol, both
the hemiaminal and aminal were detected, and the latter had a higher percentage than the former (Figure
5a). With 1 equiv. of ethanol, the hemiaminal ether appeared, though aldehyde, hemiaminal, and aminal
all existed (Figure 5b). The corresponding iminium ion was also observed in ESI mass spectrum, further
supporting the pathway shown in Figure 1.
Figure 5. 1H NMR spectra of the reaction of 4ꢀPA and (2ꢀmethoxyethyl)methylamine without (a) or with (b) 1
equiv. of ethanol. Molecular sieves were not used.
Chirality Discrimination
To demonstrate the application potential of this dynamic covalent assembly, chiral iminium ions
were employed to differentiate enantiomers of chiral secondary alcohols. Chirality plays a vital role in the
development of asymmetric transformations, and as a result, the detection of chirality is generating
significant interest within organic and supramolecular chemistry community.22 NMR spectroscopic
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methods have been commonly employed,23 but preꢀderivatization of the analytes is often required,
especially for weakly coordinating guest, such as monoꢀalcohols. To take advantage of the highꢀaffinity
dynamic covalent assembly described herein and avoid additional synthesis as well as isolation, an in situ
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derivatization with a commercially available chiral auxiliary
Sꢀ2ꢀ(methoxyꢀmethyl)pyrrolidine was
conducted. One reason for the selection of this amine is its structural similarity with
(2ꢀmethoxyethyl)methylamine. Moreover, facile recovery of the analytes could be achieved due to the
dynamic nature of our assembly.
The assembly of 4ꢀPA, Rꢀ1ꢀphenylethanol, and Sꢀ2ꢀ(methoxymethyl)pyrrolidine afforded two
diastereomers (yield ~86%), and the proton on the hemiaminal ether carbon was at 5.43 and 5.13 ppm,
respectively (see SI). The dr value was 2.8. For Sꢀ1ꢀphenylethanol, the methine protons shifted to 5.22 and
5.19 ppm, with a dr value of 3.2 (yield ~86%). The change in dr is due to differential chirality induction as
a result of varied stability of created diastereomeric assemblies. When a racemic sample was tested, four
separated methine peaks were observed, further supporting the discrimination (Figure 6). The
corresponding methine proton peaks from
R or S alcohol derived hemiaminal ether 1 were assigned by
comparison with the NMR of the assembly from two enantiomerically pure alcohols, respectively (see SI).
To examine the generality of the assay, more chiral secondary alcohols were studied to span a range
of chemical space of substitutions on the stereocenter, including linear alkyl (2ꢀbutanol), branched alkyl
(3ꢀmethylꢀ2ꢀbutanol), cyclic aliphatic (menthol), and aromatic (1ꢀphenylꢀ1ꢀpropanol). Furthermore,
bifunctional substrates (methyl lactate and methyl melate) were explored. The dynamic reactions were run
with both enantiomers and racemic sample of these alcohols (yield more than 60%, Table 3), and the
R
or
S
stereoisomers were successfully differentiated (Figure 6). For alcohols with two sp3 carbons attached on
the α carbon
(
2ꢀbutanol, 3ꢀmethylꢀ2ꢀbutanol, and menthol), NMR peaks of the proton on the hemiaminal
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ether carbon from
R alcohol derived assembly fell between those from S alcohol derived assembly. For
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alcohols with one or two sp2 carbons attached on the α carbon
(1ꢀphenylethanol, 1ꢀphenylꢀ1ꢀpropanol,
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methyl lactate, and methyl melate), the opposite trend was observed.
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Figure 6. Partial 1H NMR spectra of the reaction of 4ꢀPA, Sꢀ2ꢀ(methoxymethyl)pyrrolidine and racemic 2ꢀbutanol,
3ꢀmethylꢀ2ꢀbutanol, menthol, 1ꢀphenylethanol, 1ꢀphenylꢀ1ꢀpropanol, methyl lactate, or methyl melate. The peaks
of the proton (marked in red) on the hemiaminal ether carbon from R or S alcohol derived assemblies were
labelled.
Table 3. Discrimination of enantiomers of chiral secondary alcohols: chemical shifts, dr values, yield, and
ratio of R and S alcohol derived assembly for different racemic chiral alcohols.
a
b
c
d
R1R2OH
δ/1R
δ/1S
dr/1R
dr/1S
1R%/1S%e
Yield/%
75
5.48/5.35 5.50/5.29
5.48/5.36 5.50/5.27
5.52/5.52 5.60/5.26
5.43/5.13 5.22/5.19
5.40/5.05 5.19/5.14
5.63/5.41 5.48/5.46
5.63/5.52 5.59/5.56
2.4
3.0
0.95
2.1
ꢀ
4.0
4.3
3.2
2.4
2.3
1.9
0.87
0.93
0.85
0.84
0.17
1.00
80
61
86
79
72
66
2.8
3.0
1.7
1.9
OH
O
O
Note: a and b, chemical shift (in ppm) of the proton on the hemiaminal ether carbon from R and S alcohol derived
assembly, respectively; c and d, diastereomeric ratio of R and S alcohol derived assembly, respectively; e,
concentration ratio of R and S alcohol derived assembly.
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The integrals of methine protons in four diastereomers of hemiaminal ethers (Figure 6) were obtained.
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First, the dr value for
case with 1ꢀphenylethanol,
1ꢀphenylethanol, 1ꢀphenylꢀ1ꢀpropanol, and methyl lactate afforded different dr. The dr value for
ꢀmenthol was not available due to overlap of the NMR peaks. Furthermore, there is a reversal of the
R
or
S
alcohol derived assembly was calculated (dr
/1R and dr/1S in Table 3). As the
R
or enantiomer of the percentage of 2ꢀbutanol, 3ꢀmethylꢀ2ꢀbutanol,
S
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R
trend of dr for 1ꢀphenylꢀ1ꢀpropanol compared to 1ꢀphenylethanol. Considering that the only difference
between 1ꢀphenylꢀ1ꢀpropanol and 1ꢀphenylethanol is one methylene group, this result demonstrates the
sensitivity of our system toward subtle structural changes. Second, the percentage of total integral of
R or
S
alcohol derived assembly (1R% and 1S%, respectively) was obtained, and their ratio (1R%/1S%) is listed
in Table 3. For racemic 2ꢀbutanol, 3ꢀmethylꢀ2ꢀbutanol, menthol, 1ꢀphenylethanol, 1ꢀphenylꢀ1ꢀpropanol,
and methyl lactate, 1R%/1S% is less than 1. For racemic methyl melate, the value of 1R%/1S% is 1.0, in
agreement with the result that the
R or S isomer of methyl melate afforded identical dr value.
Having achieved the discrimination of two enantiomers of a series of chiral alcohols, quantitative
correlation of NMR integrals with enantiomeric composition was explored using 1ꢀphenylethanol as a
model. 1H NMR titration experiment was performed with 3 equiv. of alcohol samples at eleven ee values
covering the whole range (−100, −80, −60, −40, −20, 0, 20, 40, 60, 80, and 100%, Figure 7a). The
existence of all four stereoisomers at all ee values except −100 and 100 further supports that the assembly
is thermodynamically driven. The value of 1R% and 1S% was calculated through NMR integrals and
plotted against real ee values to generate the calibration curve. A slight curvature was notable. We
rationalize this observation as different 1R%/1S% as a function of ee because of varied stabilities of their
respective diastereomers. Nevertheless, the linear fit of the calibration curve was excellent (R2 = 0.996,
Figure 7b). The six unknown samples were tested with the linear fitting, and the average absolute error for
ee was 3.0% (Table 4).
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Figure 7. (a) 1H NMR titration experiment of 1ꢀphenylethanol with various ee; (b) The average ee calibration line
for 1ꢀphenylethanol.
Table 4. Calculated ee values and the associated absolute errors for 1ꢀphenylethanol.
1R%a
94.2
82.5
60.4
22.7
12.1
2.5
1S%b
5.8
Calcd. eec
93.1
Real. ee
90
Abs. Error
3.1
17.5
39.6
77.3
87.9
97.5
70.0
68
2.0
26.1
30
3.9
ꢀ48.4
ꢀ69.4
ꢀ88.2
ꢀ46
2.4
ꢀ70
0.6
ꢀ94
5.8
Note: a and b, calculated from 1H NMR integrals; c, calculated from the calibration lines in Figure 7b use 1R% or
1S
%
.
Conclusions
In summary, a dynamic multiꢀcomponent covalent assembly has been developed for the binding and
chirality differentiation of monoꢀalcohols. The system is based on the reactivity of simple generic iminum
ions. Both aldehydes and secondary amines have significant impact on the binding affinity, and linear free
energy relationship based Hammett analysis was utilized to manipulate the equilibrium. The structural
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features as well as polar and steric effects were identified, with pyridineꢀ4ꢀcarboxyaldehyde as the best
aldehyde and Nꢀmethylbenzylamine and (2ꢀmethoxyethyl)methylamine amongthe best amines. Notably,
weak supramolecular interactions, such as πꢀπ and polarꢀπ contacts, significantly stabilize the assembly.
The dynamic covalent assembly afforded the desired product in high yield for a broad range of
monoꢀalcohols. Moreover, chirality discrimination was achieved with an enantiopure secondary amine,
and the ee values were determined with high accuracy. Future efforts will focus on the use of the assembly
to create complex architectures.
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Experimental Section
General. 1HꢀNMR spectra were recorded on a 400MHz spectrometer. ESIꢀmass spectra were obtained on
an ion trap mass spectrometer. Commercially available reagents were used without further purification
。
The Multiꢀcomponent assembly reaction. Assembly reactions were performed in situ in d3ꢀacetonitrile
without isolation and purification. To a stirred solution of an aldehyde (50ꢀ55 mM, 1 equiv.), a secondary
amine (1.2 equiv.), an alcohol (3.0 equiv.) and methanesulfonic acid (0.1 equiv.) in d3ꢀacetonitrile (0.6
mL), were added activated 3 Å molecular sieves (4 to 8 mesh). The mixture was stirred at room
1
temperature overnight. The assembly solution was characterized by HꢀNMR and ESIꢀMS. For chirality
analysis, chiral secondary alcohols with different ee values were used.
Molecular modeling. All calculations were performed using the Gaussian 09 packages and Spartan 10
(Version: 1.01). For structures with proposed π interactions, conformer calculations were run by MMFF in
Spartan 10 by searching the whole potential energy surface (PES), and the one with lowest energy was
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selected for further geometry optimization. Geometry optimization and frequency analysis were run using
density functional theory method (M06ꢀ2X). The basis set of CCPVDZ was employed. A solvent model
for acetonitrile (polar continuum model, PCM) was used. The final structures were confirmed by vibration
calculations without imaginary vibrational frequencies.
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ASSOCIATED CONTENT
Supporting Information
Component distribution at equilibrium, and selected 1H NMR and ESI mass spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
lyou@fjirsm.ac.cn
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
Acknowledgements
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We thank The Recruitment Program of Global Youth Experts and National Science Foundation of Fujian
Province, China (2014J05024) for financial support. We also thank Dr. Eric Anslyn of The University of
Texas at Austin for helpful discussions.
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ACS Paragon Plus Environment