Interplay between n→π? Interactions and Dynamic Covalent Bonds: Quantification and Modulation by Solvent Effects

Article abstract of DOI:10.1021/jacs.9b01006

Orbital donor-acceptor interactions play critical roles throughout chemistry, and hence, their regulation and functionalization are of great significance. Herein we demonstrate for the first time the investigation of n→π? interactions through the strategy of dynamic covalent chemistry (DCC), and we further showcase its use in the stabilization of imine. The n→π? interaction between donor X and acceptor aldehyde/imine within 2-X-2′-formylbiphenyl derivatives was found to significantly influence the thermodynamics of imine exchange. The orbital interaction was then quantified through imine exchange, the equilibrium of which was successfully correlated with the difference in natural bond orbital stabilization energy of n→π? interactions of aldehyde and its imine. Moreover, the examination of solvent effects provided insights into the distinct feature of the modulation of n→π? interaction with aprotic and protic solvents. The n→π? interaction involving imine was enhanced in protic solvents due to hydrogen bonding with the solvent. This finding further enabled the stabilization of imine in purely aqueous solution. The strategies and results reported should find application in many fields, including molecular recognition, biological labeling, and asymmetric catalysis.

Full text of DOI:10.1021/jacs.9b01006

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Article
The Interplay Between n##* Interaction and Dynamic Covalent
Bond: Quantification and Modulation by Solvent Effects
Hao Zheng, Hebo Ye, Xiaoxia Yu, and Lei You
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 May 2019
Downloaded from http://pubs.acs.org on May 10, 2019
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The Interplay Between n→π* Interaction and
Dynamic Covalent Bond: Quantification and
Modulation by Solvent Effects
a, c
a, b
a, c
a, b, *
Hao Zheng, Hebo Ye, Xiaoxia Yu, and Lei You
a. State Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou 350002, China.
b. University of Chinese of Academy of Sciences, Beijing 100049, China.
c. College of Chemistry and Material Science, Fujian Normal University,
Fuzhou 350007, China.
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Table of Contents
1. General Methods.…………………………………………S3
2
. Synthesis and Characterization
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(1) Synthesis of 1(X) and 1(p-X)……………………S3-S8
(
2) Synthesis of water soluble compounds…….... S8-S10
(3) NMR spectrum of synthetic compounds……S11-S13
4) Crystal structures of 1(X)…………..…….……….S14
3. Dynamic Covalent Reactions
1) Imine formation……………………..………..S15-S29
(
(
(2) Imine exchange.………………………..……..S30-S41
4
. Correlation with n→π* Interaction……….………S42-S46
5. Solvent Effect
1) Solvent effect on thermodynamics…………..S47-S51
(2) Solvent effect on kinetics……………………..S52-S57
3) Solvent effect on n→π* interaction ……..…..S57-S58
6. Imine Formation in Aqueous Phase……………….S59-S66
(
(
7
. References………………………………………………..S67
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. General Methods
1H NMR and 13C NMR spectra were recorded on a 400 MHz Bruker Biospin
Avance III spectrometer or a 400 MHz JEOL JNM-ECZ400S spectrometer. The
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chemical shifts (δ) for H 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. Crystallographic data was collected on a Mercury single
crystal diffractometer at room temperature. The structures were solved with direct
methods by using SHELXS-97 and refined with the full-matrix least-squares
technique based on F2. Deuterium solvents were purchased from Aldrich. All other
reagents were obtained from commercial sources and were used without further
purification, unless indicated otherwise. The experimental details of dynamic
covalent reactions, computational studies, and imine formation in water are shown
in page S15, S42, and S59, respectively.
2
. Synthesis and Characterization
(1) Synthesis of 1(X) and 1(p-X)
Br
B(OH)2
X
[
Pd] catalyst
Base
X
O
+
1
,4-Dioxane
O
X = NMe , OMe, SMe, F, Cl, Br, I
1(X)
2
X
B(OH)2
Br
[
Pd] catalyst
Base
O
+
1
,4-Dioxane
O
X
X = NMe , OMe, SMe, F, Cl, Br
1(p-X)
2
Scheme S1. General synthetic routes of 1(X) and 1(p-X).
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'-(methylthio)-[1,1'-biphenyl]-2-carbaldehyde: To a mixture of
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-bromobenzaldehyde (1.0 mmol, 185 mg), (2-(methylthio)phenyl)boronic acid (1.2
mmol, 202 mg), potassium carbonate (2.0 mmol, 276 mg), and
tetrakis(triphenylphosphine)palladium (0.005 mmol, 58 mg), was added 1,4-dioxane
(
10 mL) under N atmosphere. The reaction was stirred at 80 ℃ for 12 h. After the
2
reaction was cooled to room temperature, H O (25 ml) was added, and the mixture
2
was extracted with ethyl acetate (EA; 25 ml × 3). The combined organic layer was
washed with saturated aqueous NH Cl (50 ml × 3) and dried over anhydrous Na SO .
4
2
4
After removal of solvent under vacuum and further purification performed on the
column chromatography (silica gel, petroleum ether (PE) / EA = 40:1 to 20:1), the
1
title compound was obtained as a white solid (216 mg, 95%). H NMR (DMSO-d ): δ
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.61 (s, 1H), 7.91 (dd, J = 7.7, 1.1 Hz, 1H), 7.77 (td, J = 7.5, 1.3 Hz, 1H), 7.61 (t, J =
.6 Hz, 1H), 7.48 (t, J = 6.6 Hz, 1H), 7.35 (t, J = 8.2 Hz, 2H), 7.32-7.23 (m, 2H), 2.36
1
3
(
s, 3H). C NMR (CDCl ): δ 191.9, 143.8, 138.3, 136.3, 133.9, 133.9, 131.0, 130.4,
3
1
29.0, 128.5, 127.0, 124.7, 124.6, 15.5. ESI-HRMS: m/z calcd for C H OSNa [M +
14 12
+
Na ]: 251.0501; found: 251.0501.
2
'-methoxy-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS1
1
was used to afford the title compound as a white crystal (yield: 90%). H NMR
1
(
CDCl ): δ H NMR (CDCl ) δ 9.81 (s, 1H), 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.67 (td, J
3
3
=
7.5, 1.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.48-7.42 (m, 1H), 7.39 (d, J = 7.7 Hz,
1H), 7.32 (dd, J = 7.5, 1.7 Hz, 1H), 7.11 (t, J = 7.0 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H),
3.77 (s, 3H).
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'-(dimethylamino)-[1,1'-biphenyl]-2-carbaldehyde: The reported
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procedure was used to afford the title compound as a yellow solid (yield: 96%). H
NMR (CD CN): 9.54 (s, 1H), 7.88 (dd, J = 7.7, 1.2 Hz, 1H), 7.74 (td, J = 7.5, 1.4 Hz,
3
1
H), 7.52 (t, J = 7.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.42 (td, J = 7.9, 1.7 Hz, 1H), 7.38
(
dd, J = 7.5, 1.6 Hz, 1H), 7.23-7.14 (m, 2H), 2.37 (s, 6H).
2'-fluoro-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS3
1
was used to afford the title compound as a colorless oil (yield: 60%). H NMR
(DMSO-d ): δ 9.83 (s, 1H), 7.96 (d, J = 7.3 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.65 (t,
6
J = 7.5 Hz, 1H), 7.56-7.46 (m, 3H), 7.38-7.32 (m, 2H).
2
'-chloro-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS3
1
was used to afford the title compound as a white solid (yield: 55%). H NMR (CDCl ):
3
δ 9.83 (s, 1H), 8.07 (dd, J = 7.8, 1.1 Hz, 1H), 7.70 (td, J = 7.5, 1.4 Hz, 1H), 7.58 (t, J
=
7.6 Hz, 1H), 7.55-7.51 (m, 1H), 7.45-7.39 (m, 2H), 7.37 (m, 2H).
'-bromo-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS3
2
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was used to afford the title compound as a yellow solid (yield: 63%). H NMR
(
DMSO-d ): δ 9.71 (s, 1H), 7.95 (dd, J = 7.7, 1.1 Hz, 1H), 7.81-7.74 (m, 2H), 7.65 (t,
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J = 7.5 Hz, 1H), 7.52 (td, J = 7.5, 1.1 Hz, 1H), 7.47-7.35 (m, 3H).
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'-iodo-[1,1'-biphenyl]-2-carbaldehyde: The reported procedure was
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used to afford the title compound as a drab solid (yield: 57%). H NMR (DMSO-d ):
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δ 9.68 (s, 1H), 8.00 (dd, J = 7.9, 0.9 Hz, 1H), 7.95 (dd, J = 7.8, 1.1 Hz, 1H), 7.78 (td,
J = 7.5, 1.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.53 (td, J = 7.5, 1.1 Hz, 1H), 7.41 (dd,
J = 7.6, 1.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.21 (td, J = 7.7, 1.7 Hz, 1H).
4
'-(dimethylamino)-[1,1'-biphenyl]-2-carbaldehyde: The reported
S5
1
procedure was used to afford the title compound as a yellow solid (yield: 97%). H
NMR (CDCl ): δ 10.03 (s, 1H), 7.99 (dd, J = 7.8, 1.2 Hz, 1H), 7.60 (td, J = 7.7, 1.5
3
Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H),
6.81 (d, J = 8.8 Hz, 2H), 3.03 (s, 6H).
4'-methoxy-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS5
1
was used to afford the title compound as a white solid (yield: 95%). H NMR (CDCl ):
3
δ 10.02 (s, 1H), 8.05 (dd, J = 7.8, 1.1 Hz, 1H), 7.66 (td, J = 7.5, 1.5 Hz, 1H), 7.52 (t, J
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H), 3.88 (s, 3H).
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'-(methylthio)-[1,1'-biphenyl]-2-carbaldehyde:
The
reported
S6
1
procedure was used to afford the title compound as a white solid (yield: 96%). H
NMR (CDCl ) δ 9.99 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.49
3
(t, J = 7.4 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.33 (q, J = 8.3 Hz, 4H), 2.55 (s, 3H).
4
'-fluoro-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS3
1
was used to afford the title compound as a white solid (yield: 58%). H NMR (CDCl )
3
δ 9.97 (s, 1H), 8.05 – 8.00 (m, 1H), 7.64 (td, J = 7.5, 1.4 Hz, 1H), 7.51 (t, J = 7.6 Hz,
1
H), 7.42 (d, J = 7.7 Hz, 1H), 7.35 (m, 2H), 7.17 (t, J = 8.6 Hz, 2H).
4
'-chloro-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS3
1
was used to afford the title compound as a white solid (yield: 70%). H NMR (CDCl )
3
δ 9.97 (s, 1H), 8.03 (dd, J = 7.8, 1.3 Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.52 (t, J
=
7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 7.7, 0.9 Hz, 1H), 7.32 (d, J = 8.4
Hz, 2H).
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was used to afford the title compound as a yellow solid (yield: 66%). H NMR
(
CDCl ) δ 9.97 (s, 1H), 8.03 (dd, J = 7.8, 1.1 Hz, 1H), 7.68 – 7.59 (m, 3H), 7.52 (t, J
3
=
7.6 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.27 – 7.25 (m, 2H).
(2) Synthesis of water soluble compounds
Br
B(OH)2
X
Pd(PPh3)4
K CO
1. BrCH2CH2Br
K2CO3
X
X
O
2
3
+
O
1,4-Dioxane
O
2. NMe3
OH
O
OH
NMe Br
3
X = H, OMe
O
3
(X)
O
1
. BrCH CH Br
2
2
K CO
2
3
2. NMe3
O
OH
NMe Br
3
5
Scheme S2. General Synthetic routes of water soluble compounds 3(X) and 5.
2
-((2-formyl-2'-methoxy-[1,1'-biphenyl]-4-yl)oxy)-N,N,N-
trimethylethan-1-aminium bromide: To suspension
-hydroxy-2'-methoxy-[1,1'-biphenyl]-2-carbaldehyde (1.0 mmol, 228 mg) and
potassium carbonate (3.0 mmol, 414 mg) in 10 ml anhydrous DMF, was added
,2-dibromoethane (2.0 mmol, 376 mg) was added dropwise. The reaction was stirred
a
of
4
1
at 90 ℃ until the starting material was completely consumed. After the reaction was
cooled to room temperature, H O (50 mL) was added, and the mixture was extracted
2
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with EA (25 ml × 3). The combined organic layer was washed with brine (50 ml × 3),
dried over anhydrous Na SO , and concentrated under vacuum. Toluene (7 mL), a
2
4
solution of trimethylamine (2 M in THF, 3 mL) was added to the resulting residue,
and the mixture was transferred to a sealed tube. The reaction was stirred at 60 ℃
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for 2 days, and H O (20 mL) was next added. The aqueous layer was washed with PE
2
(20 ml × 3) and EA (20 ml × 3), concentrated under vacuum, and dried to afford the
1
title compound as a white solid (389 mg, 96%). H NMR (D O): δ 9.57 (s, 1H),
2
7
.50-7.47 (m, 2H), 7.37-7.30 (m, 3H), 7.15 (t, J = 6.6 Hz, 2H), 4.58 (br, 2H), 3.85 (t,
13
J = 4.5 Hz, 2H), 3.71 (s, 3H), 3.26 (s, 9H). C NMR (D O): δ 194.9, 156.7, 155.8,
2
1
5
34.8, 134.2, 132.8, 131.1, 130.2, 125.6, 121.5, 121.3, 111.5, 111.3, 64.9, 62.1, 55.2,
+
+
4.0. ESI-HRMS: m/z calcd for C H NO [M ]: 314.1751; found: 314.1751.
1
9
24
3
2
-((2-formyl-[1,1'-biphenyl]-4-yl)oxy)-N,N,N-trimethylethan-
1
-aminium bromide: To a suspension of 4-hydroxy-[1,1'-biphenyl]-2-carbaldehyde
(1.0 mmol, 198 mg) and potassium carbonate (3.0 mmol, 414 mg) in 10 ml anhydrous
DMF, was added 1,2-dibromoethane (2.0 mmol, 376 mg) was added dropwise. The
reaction was stirred at 90 ℃ until the starting material was completely consumed.
After the reaction was cooled to room temperature, H O (50 mL) was added, and the
2
mixture was extracted with EA (25 ml × 3). The combined organic layer was washed
with brine (50 ml × 3), dried over anhydrous Na SO , and concentrated under vacuum.
2
4
Toluene (7 mL), a solution of trimethylamine (2 M in THF, 3 mL) was added to the
resulting residue, and the mixture was transferred to a sealed tube. The reaction was
stirred at 60 ℃ for 2 days, and H O (20 mL) was next added. The aqueous layer was
2
washed with PE (20 ml × 3) and EA (20 ml × 3), concentrated under vacuum, and
1
dried to afford the title compound as a yellowish solid (360 mg, 95%). H NMR
(
D O): δ 9.73 (s, 1H), 7.50-7.43 (m, 5H), 7.36-7.31 (m, 3H), 4.53 (br, 2H), 3.83 (br,
2
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3
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H), 3.24 (s, 9H). C NMR (D O): δ 193.9, 156.5, 139.4, 136.7, 133.5, 132.3, 130.0,
2
+
1
28.4, 127.9, 121.4, 111.7, 64.9, 62.1, 54.0. ESI-HRMS: m/z calcd for C H NO
2
1
8
22
+
[
M ]: 284.1645; found: 284.1645.
0
1
2
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9
0
4
-hydroxy-2'-methoxy-[1,1'-biphenyl]-2-carbaldehyde: The reported
S7
1
procedure was used to afford the title compound as a white solid (yield: 90%). H
NMR (DMSO-d ): δ 9.98 (br, 1H), 9.55 (s, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.25 (d, J =
6
7
.2 Hz, 1H), 7.21-7.18 (m, 2H), 7.12-7.05 (m, 3H), 3.67 (s, 3H).
-hydroxy-[1,1'-biphenyl]-2-carbaldehyde: The reported procedureS8
4
1
was used to afford the title compound as a yellowish solid (yield: 92%). H NMR
(DMSO-d ): δ 10.05 (br, 1H), 9.81 (s, 1H), 7.50 - 7.41 (m, 3H), 7.41 - 7.36 (m, 3H),
6
7
.35 - 7.28 (m, 2H), 7.16 (dd, J = 8.2, 2.2 Hz, 1H).
2
-(4-formylphenoxy)-N,N,N-trimethylethan-1-aminium
S9
bromide: The reported procedure was used to afford the title compound as a white
1
solid (yield: 98%). H NMR (D O): δ 9.77 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.16 (d, J
2
=
8.4 Hz, 2H), 4.61 (br, 2H), 3.86 (t, J = 4.1 Hz, 2H), 3.24 (s, 9H).
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(
3) NMR spectrum of synthetic compounds
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1
1
1
1
1
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Figure S1. H NMR spectrum of 1(SMe) in DMSO-d .
6
13
Figure S2. C NMR spectrum of 1(SMe) in CDCl .
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Figure S3. H NMR spectrum of 3(OMe) in D O.
2
1
3
Figure S4. C NMR spectrum of 3(OMe) in D O.
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Figure S5. H NMR spectrum of 3(H) in D O.
2
13
Figure S6. C NMR spectrum of 3(H) in D O.
2
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(
4) Crystal structures of 1(X)
0
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Figure S7. Crystal structure of 1(OMe) (a) and 1(SMe) (b).
Table S1. Summary of crystallographic data for 1(OMe) and 1(SMe).
1(OMe)
1(SMe)
Formula
Formula weight
T / K
C H O
C H OS
1
4
12
2
14 12
212.24
100
228.30
293
Crystallization solvent
Color
Cyclohexane
Colorless
monoclinic
P 1 21 1
7.6256(4)
7.4766(3)
9.9777(5)
90.00
108.663(2)
90.00
538.95(4)
2
Cyclohexane
Colorless
monoclinic
P 1 21/c 1
10.530(4)
7.555(3)
15.466(6)
90.00
105.601(5)
90.00
1185.1(8)
4
Crystal system
Space group
a / Å
b / Å
c / Å
α / °
β / °
γ / °
V / Å3
Z
-3
D / g cm
1.308
0.087
224.0
1.280
0.247
480.0
x
μ / mm-1
F(000)
θ range / º
GOF on F2
R1 [I > 2σ(I)]
2.950 to 25.414
1.294
2.7167 to 27.5126
1.049
0.0269
0.0970
0.0359
wR (all data)
0.1029
2
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3
. Dynamic Covalent Reactions
Dynamic Covalent Reactions (DCRs) were performed in situ in CD CN without
3
isolation and purification. To a stirred solution of 1 (20 mM, 1.0 equiv.) in CD CN
3
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(0.60 mL), were added 1-butylamine (22 mM, 1.2 equiv.) and activated 3 Å molecular
sieves (MS, 4-8 mesh). The mixture was stirred at room temperature overnight and
1
characterized by H NMR and ESI-MS. For imine exchange, another aldehyde (20
1
mM, 1.0 equiv.) was then added, and the exchange was monitored by H NMR. For
competition experiments, both aldehydes (20 mM each, 1.0 equiv.) were mixed with
1-butylamine (24 mM, 1.2 equiv.) in CD CN (0.60 mL), and the mixture was stirred
3
1
overnight and characterized by H NMR. To ensure reproducibility all competition
experiments were performed twice.
(1) Imine formation
1
Figure S8. H NMR spectrum of the reaction of 1(H) and 1-butylamine in CD CN.
3
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Figure S9. ESI-MS spectrum of the reaction of 1(H) and 1-butylamine in CD CN.
3
1
Figure S10. H NMR spectrum of the reaction of 1(OMe) and 1-butylamine in
CD CN.
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Figure S11. H NMR spectra of the reaction between 1(OMe) (20 mM, 1.0 equiv.)
and 1-butylamine (24 mM, 1.2 equiv.) in CD CN at varied time. The reaction was
3
complete in 300 min.
Figure S12. ESI-MS spectrum of the reaction of 1(OMe) and 1-butylamine in
CD CN.
3
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Figure S13. H NMR spectrum of the reaction of 1(NMe ) and 1-butylamine in
2
CD CN.
3
Figure S14. ESI-MS spectrum of the reaction of 1(NMe ) and 1-butylamine in
2
CD CN.
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Figure S15. H NMR spectrum of the reaction of 1(SMe) and 1-butylamine in
CD CN.
3
Figure S16. ESI-MS spectrum of the reaction of 1(SMe) and 1-butylamine in
CD CN.
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Figure S17. H NMR spectrum of the reaction of 1(F) and 1-butylamine in CD CN.
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Figure S18. ESI-MS spectrum of the reaction of 1(F) and 1-butylamine in CD CN.
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Figure S19. H NMR spectrum of the reaction of 1(Cl) and 1-butylamine in CD CN.
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Figure S20. ESI-MS spectrum of the reaction of 1(Cl) and 1-butylamine in CD CN.
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Figure S21. H NMR spectrum of the reaction of 1(Br) and 1-butylamine in CD CN.
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Figure S22. ESI-MS spectrum of the reaction of 1(Br) and 1-butylamine in CD CN.
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Figure S23. H NMR spectrum of the reaction of 1(I) and 1-butylamine in CD CN.
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Figure S24. ESI-MS spectrum of the reaction of 1(I) and 1-butylamine in CD CN.
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Figure S25. H NMR spectrum of the reaction of 1(p-NMe ) and 1-butylamine in
2
CD CN.
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Figure S26. ESI-MS spectrum of the reaction of 1(p-NMe ) and 1-butylamine in
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Figure S27. H NMR spectrum of the reaction of 1(p-OMe) and 1-butylamine in
CD CN.
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Figure S28. ESI-MS spectrum of the reaction of 1(p-OMe) and 1-butylamine in
CD CN.
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Figure S29. H NMR spectrum of the reaction of 1(p-SMe) and 1-butylamine in
CD CN.
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Figure S30. ESI-MS spectrum of the reaction of 1(p-SMe) and 1-butylamine in
CD CN.
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Figure S31. H NMR spectrum of the reaction of 1(p-F) and 1-butylamine in CD CN.
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Figure S32. ESI-MS spectrum of the reaction of 1(p-F) and 1-butylamine in CD CN.
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Figure S33. H NMR spectrum of the reaction of 1(p-Cl) and 1-butylamine in
CD CN.
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Figure S34. ESI-MS spectrum of the reaction of 1(p-Cl) and 1-butylamine in CD CN.
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Figure S35. H NMR spectrum of the reaction of 1(p-Br) and 1-butylamine in
CD CN.
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Figure S36. ESI-MS spectrum of the reaction of 1(p-Br) and 1-butylamine in
CD CN.
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