Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH

Article abstract of DOI:10.1016/j.tet.2020.131128

Salicylaldehyde derivatives and their imines are important building blocks in organic and supramolecular chemistry. In an effort to expand structural diversity in the current work we changed ortho-OH in salicylaldehyde to NH of amide/sulfonamide and investigated the effect of resulting intramolecular hydrogen bonds on imine dynamic covalent chemistry (DCC). A suite of ortho-aminobenzaldehydes were readily synthesized, and X-ray and NMR data validated the existence of NH?O intramolecular hydrogen bonds. The formation and exchange of imines were then studied in acetonitrile, and the acidity of OH/NH significantly influenced the thermodynamics and kinetics of imine reactions. Furthermore, the role of OH/NH?N hydrogen bonds on imines was elucidated by the shift of aldehyde exchange equilibrium. Finally, the formation of imines was achieved in aqueous solutions. The mechanistic insights could pave the way for future applications in assembly and labelling.

Full text of DOI:10.1016/j.tet.2020.131128

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Modulation of imine chemistry with intramolecular hydrogen
bonding: Effects from ortho-OH to NH
,
b
,
,
b
,
,
c
,
, c, *
Zelin Feng a 1, Shuaipeng Jia a 1, Hang Chen b **, Lei You b
a College of Chemistry, Fuzhou University, Fuzhou 350116, PR China
b State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR
China
c University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Salicylaldehyde derivatives and their imines are important building blocks in organic and supramolec-
ular chemistry. In an effort to expand structural diversity in the current work we changed ortho-OH in
salicylaldehyde to NH of amide/sulfonamide and investigated the effect of resulting intramolecular
hydrogen bonds on imine dynamic covalent chemistry (DCC). A suite of ortho-aminobenzaldehydes were
readily synthesized, and X-ray and NMR data validated the existence of NH⋯O intramolecular hydrogen
bonds. The formation and exchange of imines were then studied in acetonitrile, and the acidity of OH/NH
Received 14 January 2020
Received in revised form
1 March 2020
Accepted 13 March 2020
Available online xxx
significantly influenced the thermodynamics and kinetics of imine reactions. Furthermore, the role of
Keywords:
Imine bond
Hydrogen bond
Dynamic covalent chemistry
Component exchange
Salicylaldehyde
OH/NH⋯N hydrogen bonds on imines was elucidated by the shift of aldehyde exchange equilibrium.
Finally, the formation of imines was achieved in aqueous solutions. The mechanistic insights could pave
the way for future applications in assembly and labelling.
© 2020 Elsevier Ltd. All rights reserved.
1. Introduction
as well as associated imine exchange [6], has been integrated into
many research endeavors, such as assemblies [7], catalysis [8], and
Building on the reversible formation and exchange of covalent
bonds, the field of dynamic covalent chemistry (DCC) has been
flourishing over the past decade [1] and has found wide applica-
tions in the creation of molecular assemblies[2], identification of
receptors [3], and modulation of functional materials [4]. Recently,
the interplay between different dynamic covalent reactions (DCRs)
and the combination of reversible covalent and supramolecular
sensing [9]. Therefore, there is continuous interest in developing
new motifs and exploring different ways to control the imines
despite their rich history.
Among the most fundamental supramolecular interactions,
hydrogen bonds play a critical role in chemistry and biology, and
are in the backbone of nature and synthetic materials [10]. In light
of their strong directivity, tunable strength, and sensitivity to
environment [10] hydrogen bonds have been frequently incorpo-
rated into dynamic assemblies [11]. Of particular interest are sali-
cylaldehyde derivatives and their imines, which are key building
blocks in organic synthesis and supramoecular chemistry [12]. The
imine of salicylaldehyde is stabilized through resonance-assisted
hydrogen bonding and enamine/imine tautomerism (Fig. 1a) [13].
By taking use of those effects covalent organic frameworks exhib-
iting enhanced stability were build, with utility in gas storage,
separation, and catalysis [14]. In addition, the aforementioned
hydrogen bond and tautomerism are closely associated with fluo-
rescence signaling mechanism of excited state intramolecular
proton transfer [15]. Moreover, salicylaldehyde analogs were
employed for the chirality recognition of primary amines and la-
beling of peptides/proteins [16]. In addition, a variety of salen
interactions are capturing significant attention, as
a vessel
composed of multiple dynamic bonding forces can generate
structural and functional diversity and therefore build up system-
atic complexity [5]. As one class of the most employed reversible
covalent bonds, the condensation of a carbonyl, commonly an
aldehyde, and a primary amine to afford an imine (i.e. a Schiff base)
* Corresponding author. State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou 350002, PR China.
** Corresponding author. State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou 350002, PR China.
E-mail addresses: chenhang@fjirsm.ac.cn (H. Chen), lyou@fjirsm.ac.cn (L. You).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tet.2020.131128
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128

2
Z. Feng et al. / Tetrahedron xxx (xxxx) xxx
aminobenzaldehydes were prepared, and the formation and ex-
change of their imines were investigated in detail. The effect of
hydrogen bonding on imine DCC was elucidated, and the creation of
imines in aqueous solutions was further studied, providing struc-
tural and mechanistic insights for future design.
2. Results and discussions
2.1. Design and synthesis
As model compounds acetyl and methanesulfonyl derived 2-
aminobenzaldehydes (2A and 3A) were chosen in conjunction
with their corresponding water soluble counterparts (5A and 6A,
Fig. 2a). Salicylaldehyde (1A) and its analog 4A were employed as
controls. The associated imines of aldehydes 1Ae6A were termed
as 1Ie6I. The synthesis of aldehydes is shown in Fig. 2b. 2A and 3A
were furnished by the condensation of formyl chloride/meth-
anesulfonyl chloride with protected amine PA, followed by acidic
hydrolysis of acetal to afford the aldehyde. In order to improve the
water solubility, an acetic acid group was attached in 5A and 6A.
Analogous acetylation, subsequent nucleophilic substitution with
ethyl 2-bromoacetate, and then ester hydrolysis afforded desired
5A. The same method to synthesis aldehyde 6A failed, likely due to
the different reactivity of NH in sulfonamide and amide. Instead, a
sequence composed of the incorporation of acetic acid unit and
then sulfonylation gave 6A successfully. The aldehyde 4A was
prepared via etherification of 2,4-dihydroxybenzaldehyde. The
final products were fully characterized by 1H NMR and 13C NMR, as
well as mass spectrometry (Figs. S1eS12).
Fig. 1. The change from salicylaldehyde and its imine (a) to ortho-aminobenzaldehydes
and associated imines (b).
complexes contributed to the development of coordination as-
sembly and asymmetric catalysis [17].
Considering the importance of ortho-OH in salicylaldehyde (1A)
[12e17], we wondered about the replacement of OH with NH
(Fig. 1b). As compared to salicylaldehyde, the NH of amide/sulfon-
amide would also serve as a hydrogen bond donor for aldehyde/
imine, but has the advantage of structural variability through facile
modification of carboxylic acids/sulfonic acids. Furthermore, the
tunable acidity of NH could accordingly affect its capability of
forming hydrogen bonds, thereby providing a handle for ensuing
DCR with primary amines. In the current work, a suit of ortho-
In order to reveal the structural characteristics, especially the
existence of intramolecular hydrogen bonding, single-crystal X-ray
Fig. 2. (a) The design of aldehydes 1Ae6A and their imines 1Ie6I; (b) The synthesis of aldehydes. Reagents and conditions: (a) (i) pyridine, CH2Cl2, 0 ꢀC; (ii) TFA, room temperature;
(b) NaOH, CH3OH, room temperature; (c) (i) ethyl bromoacetate, K2CO3, DMF, room temperature; (ii) NaOH, CH3OH, room temperature; (d) (i) ethyl bromoacetate, K2CO3, DMF; (ii)
SOCl2, refluxing; (e) (i) PA, pyridine, CH2Cl2, 0 ꢀC; (ii) TFA, room temperature; (f) NaOH, CH3OH, room temperature; (g) K2CO3, CH3CN, refluxing.
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128

Z. Feng et al. / Tetrahedron xxx (xxxx) xxx
3
diffraction analysis was conducted (Table S1). Taking 3A as an
example, the aldehyde and sulfonamide NH are coplanar with the
benzene ring (Fig. 3). A distance of 1.97 Å was found between NH
and aldehyde oxygen (NH⋯O), suggesting an attractive interaction.
Table 1). An analogous downfield shift of OH/NH in 1I and 3I was
apparent in relative to 1A and 3A, respectively (Table 1). These
findings point toward intramolecular hydrogen bonding within
1Ie3I.
Furthermore, the NH peak of 3A appeared at 10.5 ppm in CD3CN
(Fig. 3). Such a downfield position is also in consistence with the
presence of an intramolecular hydrogen bond. For comparison, the
OH or NH proton of 1A and 2A was found around 11.0 ppm (Table 1),
again matching intramolecular hydrogen bonding. Molecular
modeling also confirmed the presence of an intramolecular
hydrogen bond within 1Ae3A. In all, evidences were collected to
support hydrogen bonding in both solid state and solution.
The kinetics of imine formation was next followed. To gauge the
reactivity the reactions were run in CD3CN without molecular
sieves (Figs. S16eS18). Aldehydes 1A and 3A had the same ten-
dency, with the reaction completed in about 1 h (1.2 equiv. 1-
butylamine). However, the rate of imine formation of aldehyde
2A was much slower than that of 1A and 3A (Fig. 4), and it took
about 30 h to equilibrate even with more 1-butylamine (2.2 equiv.).
The difference in rates can be explained from the perspective of
intramolecular acid catalysis: the stronger acidity of OH in 1A and
NH in 3A results in the acceleration of imine formation, while the
NH in 2A would play a minor role due to its lower acidity, leading to
the sluggish kinetics. Phenol, methanesulfonamide, acetamide have
a pKa of 18.0, 17.5, and 25.5 in DMSO, respectively [18], and the
sequence of pKa values falls in line with the trend of rates.
2.2. Imine formation
With aldehydes in place their dynamic covalent reactions
(DCRs) with primary amines were then performed in the presence
of molecular sieves. Gratifyingly, the individual reactions of alde-
hydes 1Ae3A with 1-butylamine afforded the desired imine
products (1Ie3I) in nearly quantitative yield (Figs. S13eS15). For
example, the formyl resonance of 3A at 10.0 ppm disappeared, with
the emergence of a new peak around 8.4 ppm, indicative the for-
mation of imine. Moreover, the NH proton of 3I resided around
12.7 ppm, significantly different from the value in 3A (10.5 ppm,
2.3. Imine exchange
The next goal was to check the reversibility of imine chemistry.
Toward this end, component exchange of amines was investigated.
Taking 3A as an example, its reaction was first conducted with 1-
butylamine, and cyclohexylamine was then added into the
mixture (Fig. 5A). After the equilibrium was reached there was a
decrease in the amount of imine incorporating 1-butylamine, with
the concomitant appearance of cyclohexylamine derived imine (c
of Fig. 5A). An equilibrium constant (K) of 1.90 was obtained, in
favoring of the imine of 1-butylamine and also in agreement with
steric effect. These findings indicate that amine exchange was
occurring, thereby demonstrating the dynamic nature of the sys-
tem. Moreover, the opposite sequence of amine addition (d of
Fig. 5A) as well as the one-pot amine exchange (e of Fig. 5A)
afforded the same equilibrium position, further validating the
reversibility. Similar results on dynamic amine exchange were also
obtained with 1A (Figs. S22-S24) and 2A (Figs. S25eS27).
To dissect the contribution of hydrogen bonding interactions on
imine DCC, aldehyde exchange experiments were further per-
formed. The equilibrium of aldehyde exchange could serve as a
barometer to probe the relative affinity of aldehydes 1e3 toward
amines. The stepwise aldehyde exchange was attempted, as
Fig. 3. 1H NMR spectrum (CD3CN) and X-ray structure of 3A.
Table 1
Summary of chemical shift values (d, in ppm) of aldehyde/imine CH and OH/NH of
1e3 in CD3CN.
Structure
Y
Compound Number
d
(CHY)
d (OH/NH)
O
NBu
1A
1I
9.93
8.44
10.94
13.65
O
NBu
2A
2I
9.93
8.42
10.97
12.83
O
NBu
3A
3I
9.94
8.44
10.50
12.74
Fig. 4. Kinetic profile of the creation of imines 1Ie3I from individual reactions of
1Ae3A (15 mM) and 1-butylamime (1.2 equiv. for 1A and 3A; 2.2 equiv. for 2A) at
25 ꢀC.
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128

4
Z. Feng et al. / Tetrahedron xxx (xxxx) xxx
Fig. 5. (A) Amine exchange: (a) the reaction of 3A with 1-butylamine (1.2 equiv.); (b) the reaction of 3A with cyclohexylamine (1.2 equiv.); (c) the addition of cyclohexylamine (1.2
equiv.) into (a); (d) the addition of 1-butylamine (1.2 equiv.) into (b); (e) the reaction of 3A with 1-butylamine (1.2 equiv.) and cyclohexylamine (1.2 equiv.). (B) Sequential aldehyde
exchange: (a) 1A; (b) the reaction of 1A with 1-butylamine (1.0 equiv.); (c) 3A; (d) the reaction of 3A with 1-butylamine (1.0 equiv.); (e) the addition of 1A (1.0 equiv.) into (d). (C)
One-pot aldehyde exchange: (a) 1A; (b) the reaction of 1A with 1-butylamine (1.0 equiv.); (c) 3A; (d) the reaction of 3A with 1-butylamine (1.0 equiv.); (e) the reaction of 1A, 3A (1.0
equiv.), and 1-butylamine (1.0 equiv.). (D) Proposed mechanism of sequential amine exchange and aldehyde exchange. Solvent: CD3CN.
aforementioned amine exchange. For example, 1A was added into
preformed 3I (Fig. 5B). The aldehyde exchange was notoriously
slow, and only a small amount of 1I were apparent in 1H NMR
spectra even after one year (e of Fig. 5B and Fig. S38). Similar slow
sequential aldehyde exchange was found with other aldehyde
combinations (Figs. S31eS34). These observations were rational-
ized with the stabilizing effect of intramolecular hydrogen bonding
on imine, which renders hydrolysis of imine difficult. The decom-
position of imine to recover the original aldehyde and amine could
be required for its reaction with the second aldehyde to complete
the sequential aldehyde exchange. In contrast, amine exchange
could proceed via a transimination pathway, circumventing the
hydrolysis of imine (Fig. 5D).
The competition between salicylaldehyde (1A) and aldehyde
2A/3A for the reaction with 1-butylamine was therefore run in one-
pot. The equilibrium was readily reached in three days. For
example, with both 1A and 3A present in the reaction mixture, their
imines were detected (Figs. 5C and S40). A K value of 1.84 was
revealed, preferring the imine of salicylaldehyde (1I) and 3A. Imine
1I was dominant for the reaction of 1A, 2A, and 1-butylamine, as
reflected by a K value of 345 and in favor of 1I (Fig. S39). The
competition between 2A and 3A for the reaction with 1-butylamine
also strongly favored the imine of 3A (K around 170) (Fig. S41).
These results suggest that 1A and 3A show comparable affinity for
primary amines, while aldehyde 2A is much worse than 1A and 3A.
The trend approximately echoes the sequence of OH/NH acidity and
reinforces the critical role of hydrogen bonding on the thermody-
namic stability of imines.
Inspired by significantly different outcomes between sequential
and one-pot aldehyde exchanges, the lability of imines in aqueous
media was explored. Water was added into preformed imine
products in acetonitrile to give a solvent mixture (3:1 CD3CN/D2O),
and NMR spectra were tracked to gain a deeper understanding of
the stability of imines toward the hydrolysis and regeneration of
the initial reactants (Figs. S42eS44). After 7 days very little
decomposition of imine was found (less than 5%). We thereby
inferred that hydrogen bond can modulate the stability of imine in
mixed solvents, although the use of water facilitates the reverse
reaction, albeit to a small degree.
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128

Z. Feng et al. / Tetrahedron xxx (xxxx) xxx
5
Table 2
2.4. Imine formation in aqueous solutions
Summary of the yield of imine formation in aqueous media.
Finally, the formation and exchange of imines were explored in
purely aqueous media. In recent years studies on supramolecular
chemistry in water, the working environment of nature, are
generating intensive interest [19]. Reactions of 4A, 5A, and 6A and
1-butylamine in water (Figs. S45eS48) gave imines 4I, 5I, and 6I
with a yield of 63%, 35%, and 42%, respectively (Fig. 6a and Table 2).
Interestingly, the equilibrium was rapidly reached after 5 min for
5A and 6A, while it took 50 min for the reaction of 4A to equilibrate
(Fig. 6a). One rationalization comes from partial deprotonation of
OH in 4A in basic aqueous media, compromising intramolecular
acid catalysis. On the other hand, the stronger acidity of NH of 5A
and 6A in water than in acetonitrile could contribute to their
relatively fast kinetics. The competition between 4A and 6A for the
reaction with 1-butylamine was feasible, giving a K value of 3.70
and favoring 4I (Figs. 6b and S51). Such a finding is in agreement
with the trend of yield for imine formation reactions.
Aldehyde
Structure
D2O
pH 7.0
Buffer
pH 7.4
Buffer
pH 8.0
Buffer
4A
63%
39%
NRa
45%
52%
5A
6A
a
35%
42%
NR
NR
20%
22%
26%
NR stands for no reaction.
The buffer solutions (50 mM, PBS buffer) of 4A, 5A, and 6A at
different pH were then prepared, and their reactions with 1-
butylamine were monitored. Aldehydes 4 and 6 afforded their
corresponding 1-butylamine derived imines with a yield of 45% and
21% at pH 7.4, respectively (Table 2 and Figs. S52 and S56). However,
no imine of 5 was detected under similar condition (Fig. S55). These
results are reminiscent of the trend of aldehyde exchange in
acetonitrile, as the acidity and hydrogen bonding ability of OH/NH
have a pronounced impact on the reactivity and stability of imine
DCC. As the pH increased, there was an enhancement in the yield of
the imine (Table 2). As the case of reactions in water, the imine
formation in buffer proceeded more quickly for 6A than 4A
(Figs. S53 and S57). Therefore, both thermodynamics and kinetics
of imine chemistry can be tuned in aqueous solutions.
3. Conclusions
In summary, a suite of salicylaldehyde analogs were prepared,
and their associated imine chemistry was explored in detail. The
presence of intramolecular NH⋯O hydrogen bond was supported
by X-ray and NMR data. The formation of imines was then studied
in acetonitrile, and the acidity of OH/NH was found to significantly
impact the thermodynamics and kinetics of imine reactions.
Moreover, the reversibility of system was verified by amine ex-
change, and the extent of aldehyde exchange equilibrium provided
insights for the modulation of imine through intramolecular
hydrogen bonding. Finally, the formation and exchange of imines
were realized in aqueous media, showing application potential in
biolabelling. The current platform complements salicylaldehyde
and its imines and further demonstrates the ability of neighboring
supramolecular interactions for dictating imine chemistry.
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded on a 400 MHz
Bruker Biospin Avance III spectrometer. The chemical shifts (d) for
1H NMR spectra, given in ppm, are referenced to the residual proton
signal of the deuterated solvent. Mass spectra were recorded on a
Bruker IMPACT-II spectrometer. The pH value was measured on a
Sartorius PB-10 pH meter. All reagents were obtained from com-
mercial sources and were used without further purification, unless
indicated otherwise.
Fig. 6. (a) Kinetic profile of the creation of imines 4Ie6I from individual reactions of
4Ae6A (15 mM) and 1-butylamime (2.2 equiv. for 5A and 6A; 1.2 equiv. for 4A) in D2O
at 25 ꢀC; (b) The competition between 4A (1.0 equiv.) and 6A (1.0 equiv.) for the re-
action with 1-butylamine (2.0 equiv.) in D2O.
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128

6
Z. Feng et al. / Tetrahedron xxx (xxxx) xxx
4.2. DCRs in acetonitrile
washed with saturated NaHCO3, dried with anhydrous Na2SO4, and
concentrated in vacuo. The residue was then purified by column
chromatography (silica gel, PE/EA ¼ 4:1) to afford the title com-
Dynamic covalent reactions (DCRs) were performed in situ in the
presence of molecular sieves (3 Å) in CD3CN at room temperature
(25 ꢀC) without isolation and purification. For imine formation
reactions, to an aldehyde (~15 mM, 1.0 equiv.) in CD3CN (0.60 mL),
was added an amine (RNH2, 1.2 equiv.). For aldehyde exchange
reactions two aldehydes (~15 mM each, 1.0 equiv.) were mixed with
1-butylamine (1.0 equiv.) in CD3CN. For amine exchange reactions,
the aldehyde (~15 mM each, 1.0 equiv.) was first mixed with one
primary amine (1.2 equiv.) in CD3CN (0.60 mL), and after equili-
bration the second amine (1.2 equiv.) was added. The mixture was
stirred and then characterized by 1H NMR and ESI-MS after the
equilibrium was reached. Integrals from 1H NMR spectra (alde-
hydes and imines) were used for the calculation of equilibrium
constants. See figure captions for specific conditions if necessary.
pound as a white solid (0.48 g, 80%). 1H NMR (CDCl3):
d 10.60 (s,
1 H), 9.92 (s, 1 H), 7.76 (t, J ¼ 7.6, 1.2 Hz, 2 H), 7.65 (t, J ¼ 6.6 1 H), 7.28
(dd, J ¼ 10.9, 4.2 Hz, 1 H), 3.13 (s, 3 H). 13C NMR (CDCl3)
d 195.2,
140.3, 136.6, 136.3, 123.1, 121.7, 117.0, 40.4. ESI-HRMS: m/z calcd for
C8H9NO3SNa [M þ Naþ]: 222.0201; found: 222.0201.
4.4.4. 4-((2,5,8,11-tetraoxatridecan-13-yl)oxy)-2-
hydroxybenzaldehyde (4A)
To
a
suspension of 2,5,8,11-tetraoxatridecan-13-yl 4-
methylbenzenesulfonate (0.40 g, 1.0 equiv.) and potassium car-
bonate (0.31 g, 2.0 equiv.) in anhydrous CH3CN (10.0 mL), was
added 2,4-dihydroxybenzaldehyde (0.19 g, 1.2 equiv.) under N2 at-
mosphere. The reaction was refluxed overnight. After the reaction
was cooled to room temperature, the solution was washed with
dilute hydrochloric acid and extracted with ethyl acetate. The
combined organic layer was washed with saturated NaHCO3, and
brine solution and then dried with anhydrous Na2SO4. After the
removal of solvent under vacuum and further purification by col-
umn chromatography (silica gel, PE/EA ¼ 1:1), the title compound
4.3. DCRs in aqueous solution
For imine formation in water, the aldehyde (~15 mM) and 1-
butylamine were dissolved in D2O (0.60 mL). For aldehyde ex-
change reaction two aldehydes (~15 mM each, 1.0 equiv.) were
mixed with 1-butylamine (2.0 equiv.) in D2O. For imine formation
in 50 mM phosphate buffer (PB) in D2O, the stock solutions of al-
dehydes 4A, 5A, and 6A (15 mM) were prepared in PB buffer,
respectively, and the desired pH (7.0, 7.4, or 8.0) was adjusted with
concentrated NaOH or HCl solution. To an aldehyde (15 mM, 1.0
equiv.) solution in PB buffer, was added 1-butylamine (1.2 equiv.).
The mixture was equilibrated at room temperature (25 ꢀC) and
characterized by 1H NMR and ESI-MS. See figure captions for spe-
cific conditions if necessary.
was obtained as a brown oil (0.20 g, 55%). 1H NMR (D2O):
d 9.56 (s,
1H), 7.49 (d, J ¼ 5.6 Hz, 1H), 6.52 (dd, J ¼ 6.8, 1.2 Hz, 1H), 6.36 (d,
J ¼ 2.4 Hz, 1H), 4.12 (t, J ¼ 4.0 Hz, 2H), 3.77 (t, J ¼ 4.0 Hz, 2H),
3.63e3.61 (m, 2H), 3.57e3.49 (m, 8H), 3.45e3.42 (m, 2H), 3.2 (s,
3H). 13C NMR (D2O):
d 195.9, 165.7, 162.5, 136.0, 115.4, 108.5, 101.3,
71.6, 70.9, 69.7, 69.5, 69.4, 69.3, 68.7, 67.4, 57.9. ESI-HRMS: m/z calcd
for C16H24O7Na [M þ Naþ]: 351.1420; found: 351.1421.
4.4.5. N-(2-formylphenyl)-4-hydroxybenzamide (7A)
A solution of the PA (0.50 g, 1.0 equiv.) and pyridine (0.30 mL, 1.2
equiv.) in dry dichloromethane (DCM, 30 mL) was cooled in an ice
bath, and a solution of 4-(chlorocarbonyl)phenyl acetate (0.90 g, 1.5
equiv.) in DCM (5.0 mL) was added dropwise. Upon completion
after 2 h, the solution was washed with dilute trifluoroacetic acid,
and the mixture was extracted with ethyl acetate. The combined
organic layer was then washed with saturated NaHCO3, dried with
anhydrous Na2SO4, and concentrated in vacuo. The crude product
was dissolved in methanol (5.0 mL), and 2 M NaOH (5.0 mL) was
added for the hydrolysis of the ester. After stirring overnight the
mixture was extracted with ethyl acetate, and the combined
organic layer was washed with brine solution, dried with anhy-
drous Na2SO4, and concentrated in vacuo. The residue was then
purified by column chromatography (silica gel, PE/EA ¼ 3:1) to
afford the title compound as a white solid (0.35 g, 48%). 1H NMR
4.4. Synthesis
The synthetic route and structures of the target compounds are
shown in Fig. 2.
4.4.1. 2-(1,3-dioxolan-2-yl)aniline (PA)
The reported procedure [20] was used to afford the title com-
pound as a yellow oil.
4.4.2. N-(2-formylphenyl)acetamide (2A)
A solution of the PA (0.50 g, 1.0 equiv.) and pyridine (0.30 mL, 1.2
equiv.) in dry dichloromethane (DCM, 30 mL) was cooled in an ice
bath, and a solution of acetyl chloride (0.35 mL, 1.5 equiv.) in DCM
(5.0 mL) was added dropwise. Upon completion after 1 h, the so-
lution was washed with dilute trifluoroacetic acid, and the mixture
was extracted with ethyl acetate. The combined organic layer was
washed with saturated NaHCO3, dried with anhydrous Na2SO4, and
concentrated in vacuo. The residue was then purified by column
chromatography (silica gel, petroleum ether (PE)/ethyl acetate
(EA) ¼ 4:1) to afford the title compound as a white solid (0.40 g,
(DMSO‑d6):
d 11.68 (s, 1H), 10.35 (s, 1H), 10.04 (s, 1H), 8.55 (d,
J ¼ 8.0 Hz, 1H), 7.96 (dd, J ¼ 7.6, 1.6 Hz, 1H), 7.86 (d, J ¼ 8.0 Hz, 2H),
7.73 (td, J ¼ 7.6, 1.6 Hz, 1H), 7.35 (t, J ¼ 7.2 Hz, 1H), 6.95 (d, J ¼ 8.0 Hz,
2H). 13C NMR (DMSO‑d6):
d 196.7, 165.6, 161.9, 141.0, 136.4, 135.8,
129.9, 124.9, 123.9, 123.7, 120.5, 116.1. ESI-HRMS: m/z calcd for
C
14H11NO3Na [M þ Naþ]: 264.0637; found: 264.0638.
81%). 1H NMR (CDCl3):
d 11.13 (s, 1 H), 9.92 (s, 1 H), 8.76 (d,
J ¼ 8.4 Hz, 1 H), 7.70 (dd, J ¼ 7.6, 1.2 Hz, 1 H), 7.64 (td, J ¼ 7.2, 1.6 Hz,
4.4.6. 2-(4-((2-formylphenyl)carbamoyl)phenoxy)acetic acid (5A)
To a suspension of N-(2-formylphenyl)-4-hydroxybenzamide
(0.50 g, 1.0 equiv.) and potassium carbonate (0.43 g, 1.5 equiv.) in
anhydrous DMF (10.0 mL), a solution of ethyl bromoacetate (0.42 g,
1.2 equiv.) in DMF (3.0 mL) was added dropwise. The reaction was
stirred at room temperature overnight. Afterwards H2O was added,
and the mixture was extracted with ethyl acetate. The combined
organic layer was washed with brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude product was dissolved in
methanol (5.0 mL), and 2 M NaOH (5.0 mL) was added for the hy-
drolysis of the ester. After stirring overnight the mixture was
extracted with ethyl acetate, and then the combined organic layer
1 H), 7.25 (td, J ¼ 6.6, 1.2 Hz, 1 H), 2.26 (s, 3 H). 13C NMR (CDCl3)
d
195.6, 169.7, 140.9, 136.3, 136.1, 122.9, 121.5, 119.8, 25.4. ESI-HRMS:
m/z calcd for C9H9NO2Na [M þ Naþ]: 186.0531; found: 186.0532.
4.4.3. N-(2-formylphenyl)methanesulfonamide (3A)
A solution of the PA (0.50 g, 1.0 equiv.) and pyridine (0.30 mL, 1.2
equiv.) in dry dichloromethane (DCM, 30 mL) was cooled in an ice
bath, and a solution of acetyl chloride (0.45 mL, 1.5 equiv.) in DCM
(5.0 mL) was added dropwise. Upon completion after 1 h, the so-
lution was washed with dilute trifluoroacetic acid, and the mixture
was extracted with ethyl acetate. The combined organic layer was
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128

Z. Feng et al. / Tetrahedron xxx (xxxx) xxx
(e) A. Herrmann, Chem. Soc. Rev. 43 (2014) 1899e1933.
7
was washed with brine solution, dried with anhydrous Na2SO4, and
concentrated in vacuo. The residue was then purified by column
chromatography (silica gel, PE/EA ¼ 1:1) to afford the title com-
[2] (a) J.F. Reuther, J.L. Dees, I.V. Kolesnichenko, E.T. Hernandez, D.V. Ukraintsev,
R. Guduru, M. Whiteley, E.V. Anslyn, Nat. Chem. 10 (2018) 45e50;
(b) G. Zhang, M. Mastalerz, Chem. Soc. Rev. 43 (2014) 1934e1947;
(c) Y. Jin, Y. Hu, W. Zhang, Nat. Rev. Chem. 1 (2017), 0056;
(d) X. Feng, X. Ding, D. Jiang, Chem. Soc. Rev. 41 (2012) 6010e6022;
(e) S.-Y. Ding, W. Wang, Chem. Soc. Rev. 42 (2013) 548e568;
(f) S.P. Black, J.K.M. Sanders, A.R. Stefankiewicz, Chem. Soc. Rev. 43 (2014)
1861e1872;
pound as a white solid (0.39 g, 63%). 1H NMR (DMSO‑d6):
d 11.69 (s,
1H),10.06 (s,1H), 8.53 (d, J ¼ 8.0 Hz,1H), 7.99e7.96 (m, 3H), 7.76 (td,
J ¼ 8.0, 1.2 Hz, 1H), 7.38 (td, J ¼ 7.6, 1.6 Hz, 1H), 7.15 (d, J ¼ 8.0 Hz,
2H), 4.84 (s, 2H). 13C NMR (DMSO‑d6):
d 196.5, 170.3, 165.4, 161.5,
(g) T. Hasell, A.I. Cooper, Nat. Rev. Mater. 1 (2016) 16053;
(h) C. Qian, Q.-Y. Qi, G.-F. Jiang, F.-Z. Cui, Y. Tian, X. Zhao, J. Am. Chem. Soc. 139
(2017) 6736e6743.
140.8, 136.3, 135.6, 129.7, 127.0, 124.2, 123.9, 120.7, 115.3, 65.1. ESI-
HRMS: m/z calcd for C16H13NO5Na [M þ Naþ]: 322.0691; found:
322.0691.
[3] (a) M. Mondal, A.K. Hirsch, Chem. Soc. Rev. 44 (2015) 2455e2488;
ꢁ
€
(b) R. Caraballo, H. Dong, J.P. Ribeiro, J. Jimenez-Barbero, O. Ramstrom, Angew.
Chem. Int. Ed. 49 (2010) 589e593;
4.4.7. Ethyl 2-(4-(chlorosulfonyl)phenoxy)acetate
The reported procedure [21] was used to afford the title com-
pound as a colorless viscous liquid.
(c) R.M. Miller, V.O. Paavilainen, S. Krishnan, I.M. Serafimova, J. Taunton, J. Am.
Chem. Soc. 135 (2013) 5298e5301;
(d) O. Shyshov, R.-C. Brachvogel, T. Bachmann, R. Srikantharajah, D. Segets,
F. Hampel, R. Puchta, M. von Delius, Angew. Chem. Int. Ed. 56 (2017) 776e781.
[4] (a) E. Moulin, G. Cormos, N. Giuseppone, Chem. Soc. Rev. 41 (2012)
1031e1049;
4.4.8. 2-(4-(N-(2-formylphenyl)sulfamoyl)phenoxy)acetic acid (6A)
A solution of the PA (0.50 g, 1.0 equiv.) and pyridine (0.30 mL, 1.2
equiv.) in dry dichloromethane (DCM, 30 mL) was cooled in an ice
bath, and a solution of ethyl 2-(4-(chlorosulfonyl)phenoxy)acetate
(1.27 g, 1.5 equiv.) in DCM (5.0 mL) was added dropwise. Upon
completion after 2 h, the solution was washed with dilute tri-
fluoroacetic acid, and the mixture was extracted with ethyl acetate.
The combined organic layer was then washed with saturated
NaHCO3, dried with anhydrous Na2SO4, and concentrated in vacuo.
The crude product was dissolved in methanol (5.0 mL), and 2 M
NaOH (5.0 mL) was added for the hydrolysis of the ester. After
stirring overnight the mixture was extracted with ethyl acetate, and
the combined organic layer was washed with brine solution, dried
with anhydrous Na2SO4, and concentrated in vacuo. The residue
was then purified by column chromatography (silica gel, PE/
EA ¼ 1:1) to afford the title compound as a yellow solid (0.20 g,
(b) R. Deng, M.J. Derry, C.J. Mable, Y. Ning, S.P. Armes, J. Am. Chem. Soc. 139
(2017) 7616e7623;
(c) F. della Sala, E.R. Kay, Angew. Chem. Int. Ed. 54 (2015) 4187e4191;
(d) W. Edwards, N. Marro, G. Turner, E.R. Kay, Chem. Sci. 9 (2018) 125e133.
[5] (a) A. Wilson, G. Gasparini, S. Matile, Chem. Soc. Rev. 43 (2014) 1948e1962;
(b) J. Li, P. Nowak, S. Otto, J. Am. Chem. Soc. 135 (2013) 9222e9239;
(c) D.A. Roberts, B.S. Pilgrim, J.R. Nitschke, Chem. Soc. Rev. 47 (2018) 626e644;
(d) J.F. Reuther, S.D. Dahlhauser, E.V. Anslyn, Angew. Chem. Int. Ed. 58 (2019)
74e85.
[6] (a) M.E. Belowich, J.F. Stoddart, Chem. Soc. Rev. 41 (2012) 2003e2024;
(b) M. Ciaccia, S. Di Stefano, Org. Biomol. Chem. 13 (2015) 646e654.
[7] (a) Y. Jia, J. Li, Chem. Rev. 115 (2015) 1597e1621;
(b) Y. Liu, Z.-T. Li, Aust. J. Chem. 66 (2013) 9e22.
[8] (a) P.G. Cozzi, Chem. Soc. Rev. 33 (2004) 410e421;
(b) A. Dirksen, S. Dirksen, T.M. Hackeng, P.E. Dawson, J. Am. Chem. Soc. 128
(2006) 15602e15603;
€
(c) F. Schaufelberger, O. Ramstrom, J. Am. Chem. Soc. 138 (2016) 7836e7839.
[9] (a) X. Su, I. Aprahamian, Chem. Soc. Rev. 43 (2014) 1963e1981;
(b) H. Zou, Y. Hai, H. Ye, L. You, J. Am. Chem. Soc. 141 (2019) 16344e16353.
[10] (a) P.A. Kollman, L.C. Allen, Chem. Rev. 72 (1972) 283e303;
(b) G.K. Such, A.P.R. Johnston, F. Caruso, Chem. Soc. Rev. 40 (2011) 19e29;
(c) M. Juanes, R.T. Saragi, W. Caminati, A. Lesarri, Chem. Eur. J. 25 (2019)
11402e11411;
20%). 1H NMR (DMSO‑d6):
d 10.54 (s, 1H), 10.02 (s, 1H), 7.82 (dd,
J ¼ 6.0, 1.6 Hz, 1H), 7.66 (d, J ¼ 8.0 Hz, 2H), 7.59 (td, J ¼ 8.0, 1.2 Hz,
1H), 7.33 (t, J ¼ 8.0 Hz,1H), 7.19 (d, J ¼ 8.0 Hz, 1H), 7.05 (d, J ¼ 8.0 Hz,
(d) J.N.N. Eildal, G. Hultqvist, T. Balle, N. Stuhr-Hansen, S. Padrah, S. Gianni,
K. Strømgaard, P. Jemth, J. Am. Chem. Soc. 135 (2013) 12998e13007;
(e) R. Bu, Y. Xiong, X. Wei, H. Li, C. Zhang, Cryst. Growth Des. 19 (2019)
5981e5997.
2H), 4.78 (s, 2H). 13C NMR (DMSO‑d6):
d 193.6, 170.1, 161.9, 139.4,
135.9, 132.4, 131.1, 129.6, 127.6, 127.5, 125.8, 122.7, 115.7, 65.2. ESI-
HRMS: m/z calcd for C15H13NO6SNa [M þ Naþ]: 358.0361; found:
358.0361.
[11] (a) S. Kitagawa, K. Uemura, Chem. Soc. Rev. 34 (2005) 109e119;
(b) J.-F. Xu, Y.-Z. Chen, D. Wu, L.-Z. Wu, C.-H. Tung, Q.-Z. Yang, Angew. Chem.
Int. Ed. 52 (2013) 9738e9742;
(c) X. Lou, R.P.M. Lafleur, C.M.A. Leenders, S.M.C. Schoenmakers,
N.M. Matsumoto, M.B. Baker, J.L.J. van Dongen, A.R.A. Palmans, E.W. Meijer,
Nat. Commun. 8 (2017) 15420.
Declaration of competing interest
[12] (a) K. Maher, Inter. Multi. Res. Rev. 7 (2015);
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
(b) K. Li, Y. Xiang, X. Wang, J. Li, R. Hu, A. Tong, B.Z. Tang, J. Am. Chem. Soc. 136
(2014) 1643e1649;
ꢁ
(c) F. Esteban, W. Cieslik, E.M. Arpa, A. Guerrero-Corella, S. Díaz-Tendero,
ꢁ
ꢁ
J. Perles, J.A. Fernandez-Salas, A. Fraile, J. Aleman, ACS Catal.
8 (2018)
1884e1890.
Acknowledgement
[13] (a) C.M. Metzler, A. Cahill, D.E. Metzler, J. Am. Chem. Soc. 102 (1980)
6075e6082;
We thank National Natural Science Foundation of China
(21672214), the Recruitment Program of Global Youth Experts, and
the Strategic Priority Research Program (XDB20000000) and the
Key Research Program of Frontier Sciences (QYZDB-SSW-SLH030)
of the Chinese Academy of Sciences for funding.
(b) J. Crugeiras, A. Rios, E. Riveiros, J.P. Richard, J. Am. Chem. Soc. 131 (2009)
15815e15824;
(c) A.E. Felten, G. Zhu, Z.D. Aron, Org. Lett. 12 (2010) 1916e1919.
[14] (a) S. Kandambeth, A. Mallick, B. Lukose, M.V. Mane, T. Heine, R. Banerjee,
J. Am. Chem. Soc. 134 (2012) 19524e19527;
(b) X. Han, Q. Xia, J. Huang, Y. Liu, C. Tan, Y. Cui, J. Am. Chem. Soc. 139 (2017)
8693e8697;
(c) S. Yan, X. Guan, H. Li, D. Li, M. Xue, Y. Yan, V. Valtchev, S. Qiu, Q. Fang, J. Am.
Chem. Soc. 141 (2019) 2920e2924;
(d) M. Zhang, L. Li, Q. Lin, M. Tang, Y. Wu, C. Ke, J. Am. Chem. Soc. 141 (2019)
5154e5158.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131128.
[15] (a) H. Houjou, H. Shingai, K. Yagi, I. Yoshikawa, K. Araki, J. Org. Chem. 78
(2013) 9021e9031;
(b) A.C. Sedgwick, L. Wu, H.-H. Han, S.D. Bull, X.-P. He, T.D. James, J.L. Sessler,
B.Z. Tang, H. Tian, J. Yoon, Chem. Soc. Rev. 47 (2018) 8842e8880;
(c) H. Xi, Z. Zhang, W. Zhang, M. Li, C. Lian, Q. Luo, H. Tian, W.-H. Zhu, J. Am.
Chem. Soc. 141 (2019) 18467e18474.
References
[1] (a) S.J. Rowan, S.J. Cantrill, G.R.L. Cousins, J.K.M. Sanders, J.F. Stoddart, Angew.
Chem. Int. Ed. 41 (2002) 898e952;
[16] (a) J.M. Gilmore, R.A. Scheck, A.P. Esser-Kahn, N.S. Joshi, M.B. Francis, Angew.
Chem. Int. Ed. 45 (2006) 5307e5311;
(b) J.-M. Lehn, Chem. Soc. Rev. 36 (2007) 151e160;
(c) Y. Jin, C. Yu, R.J. Denman, W. Zhang, Chem. Soc. Rev. 42 (2013) 6634e6654;
(d) Q. Ji, R.C. Lirag, O.S. Miljanic, Chem. Soc. Rev. 43 (2014) 1873e1884;
(b) S.L. Pilicer, P.R. Bakhshi, K.W. Bentley, C. Wolf, J. Am. Chem. Soc. 139 (2017)
1758e1761;
ꢀ
ꢁ
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128

8
Z. Feng et al. / Tetrahedron xxx (xxxx) xxx
(c) D.P. Murale, S.C. Hong, S.-y. Jang, J.-S. Lee, Chembiochem 19 (2018)
2545e2549.
[17] (a) S. Shaw, J.D. White, Chem. Rev. 119 (2019) 9381e9426;
(b) J.C. Pessoa, I. Correia, Coord. Chem. Rev. 388 (2019) 227e247.
[18] F.G. Bordwell, Acc. Chem. Res. 21 (1988) 456e463.
[19] (a) S. Ulrich, Acc. Chem. Res. 52 (2019) 510e519;
(b) M.J. Langton, C.J. Serpell, P.D. Beer, Angew. Chem. Int. Ed. 55 (2016)
1974e1987.
[20] Z.A. De los Santos, C. Wolf, J. Am. Chem. Soc. 138 (2016) 13517e13520.
[21] Y. Li, Z. Li, F. Li, Q. Wang, F. Tao, Org. Biomol. Chem. 3 (2005) 2513e2518.
Please cite this article as: Z. Feng et al., Modulation of imine chemistry with intramolecular hydrogen bonding: Effects from ortho-OH to NH,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131128