Highly Chemoselective Solvent-Free Synthesis of 1,3,5-Triaryl-1,5-diketones: Crystallographic Investigation and Intramolecular Weak Bifurcated H Bonds Involving Aliphatic C-H Group

Article abstract of DOI:10.1055/s-0039-1690224

Several 1,3,5-triaryl-1,5-diketones have been chemoselectively synthesized under solvent-free conditions. It was found that intramolecular weak bifurcated H-bonds interaction of aliphatic C-H group plays a decisive role in the structural arrangement of 3-

Full text of DOI:10.1055/s-0039-1690224

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
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Z. Yin et al.
Letter
Synlett
Highly Chemoselective Solvent-Free Synthesis of 1,3,5-Triaryl-1,5-
diketones: Crystallographic Investigation and Intramolecular
Weak Bifurcated H Bonds Involving Aliphatic C–H Group
R
O
O
Zhongyou Yina
Changkun Xionga
Jianxin Guoa
O
grinding
12 examples, 75–86% yield
+ R CHO
Ph
Ph
NaOH/K2CO3 (1:1)
Ph
R = 2,6-Cl2C6H3, 2,4-Cl2C6H3, 2-ClC6H4 3-ClC6H4, 4-ClC6H4, 2-BrC6H4,
2-MeOC6H4, 4-MeOC6H4, 2-MeC6H4, 2-F3CC6H4, 4-F3CC6H4
Xiaoyun Hu*a
Zixing Shanb
0
0
0
0-
0
0
0
2-5
2
5
1-2
5
2
1
Victor Borovkov*a
0
0
0
0-0
0
0
1-7
8
9
8-
0
4
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a College of Chemistry and Materials Science, South-Central Uni-
versity for Nationalities, Wuhan, 430074, P. R. of China
xyhu@mail.scuec.edu.cn
victor.borovkov@scuec.edu.cn
b College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, 430072, P. R. of China
Received: 15.09.2019
Accepted after revision: 10.10.2019
Published online: 24.10.2019
been demonstrated that these weak interactions play a sig-
nificant role in crystal packing,6 host–guest chemistry,7 su-
pramolecular chirality,8 asymmetric organocatalysis,9 and
biochemical phenomena.10
DOI: 10.1055/s-0039-1690224; Art ID: st-2019-u0490-l
Abstract Several 1,3,5-triaryl-1,5-diketones have been chemoselec-
tively synthesized under solvent-free conditions. It was found that intra-
molecular weak bifurcated H-bonds interaction of aliphatic C–H group
plays a decisive role in the structural arrangement of 3-(2,6-dichloro-
phenyl)-1,5-diphenylpentane-1,5-dione in a solid state resulting in sig-
nificant impact on the corresponding bond lengths and dihedral angles.
Also, bifurcated hydrogen bonds were found to be a key
driving force to form the secondary structure of proteins.11
This was firstly proposed by Albrecht and Corey upon re-
vealing the structural disposition of NH and C=O groups in
the crystal structure of -glycine.12 Conventional H bonds
normally comprise a single donor–acceptor pair, while bi-
furcated H bonds include more than one donor or accep-
tor.13 Though various compounds with the bifurcated H
bonds have been studied so far, most of them possessed a
strong hydrogen bonding.14 However, in the case of aliphat-
ic C–H groups, their weak acidity results in almost negligi-
ble interaction with two H-bonding acceptors simultane-
ously. Therefore, there are only few reports on this phe-
nomenon to date. For example, the aromatic C–H···(F–C)2
weak bifurcated hydrogen bonding has been described.15
Also, our group successively discovered the intramolecular
weak bifurcated H bonds between aliphatic Cl and aromatic
C–H as well as aliphatic C–H and aromatic Cl atoms.16
Herein we report two types of intramolecular weak bi-
furcated H bonds, including C=O···H–C···Cl and C–H···(Cl–C)2,
and their significant impact on changing the corresponding
bond lengths and dihedral angles to fix the molecular con-
formation. In order to investigate this phenomenon in de-
tail, a series of 1,3,5-triaryl-1,5-diketones have been syn-
thesized via highly chemoselective synthesis under the sol-
vent-free conditions. It is important to note that these
compounds owing to their specific structure are often used
as versatile synthetic intermediates for many heterocyclic
and polyfunctional compounds.17
Key words solvent-free reaction, intramolecular bifurcated weak
bonds, X-ray crystallographic analysis, highly chemoselective synthesis,
1,5-diketones
From the second half of the last century, an increasing
number of studies has demonstrated that various types of
weak hydrogen bonds (other than conventional hydrogen
bonding) are ubiquitous.1 Particularly, weak H bonds are of
great importance due to their influence on the conforma-
tion of organic compounds and 3D structure of biomacro-
molecules.2 In 1962, the C–H···O interaction was firstly es-
tablished as a hydrogen bond by Sutor based on the ob-
tained crystallographic data.3 In 1982, Taylor and Kennard
proposed two basic crystallographic characteristics of weak
C–H···X (X = O, N, Cl, S) hydrogen bonds upon their system-
atic investigation of neutron diffraction crystal structures.4
These two crystallographic characteristics are as follows: 1)
the distance between the proton and acceptor atoms
should be shorter than the sum of their corresponding van
der Waals radii,5 and 2) the donor-proton-acceptor angle in
the H bond must be at least 90°. Since their seminal work,
various compounds possessing C–H···X (X = O, N, F, Cl, Br,
etc.) weak hydrogen bonds have been discovered, and it has
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z. Yin et al.
Letter
Synlett
In general, solvent-free reactions can not only signifi-
cantly reduce the chemical waste to make synthetic trans-
formations more environmentally benign, but also can im-
prove the rate and selectivity of reactions.18 Our previous
work demonstrated that the reaction medium had a crucial
role in determining chemoselectivity of the reaction be-
tween 2,6-dichlorobenzaldehyde and acetophenone. For
example, an aldol addition product 1 was obtained if this
reaction was catalyzed by a 10% NaOH–EtOH solution
(Scheme 1).17 However, a double-component solid-based
system of K2CO3 and NaOH (3:1 molar ratio) under the sol-
vent-free conditions yielded the corresponding chalcone 2a
and syn-head-to-head dimer of chalcone 3 (Scheme 1).15
Figure 1 A fragment of the 1H NMR (chloroform-d, 400 MHz) spec-
O
OH Cl
trum at 298 K and crystal structure of 4a
10% NaOH/EtOH
Previous work
Cl
teratomic distances between the methine proton H9 and
Cl2 and O1 being 2.453 Å and 2.382 Å, correspondingly, and
the bond angles for O1–H9–C9 and Cl2–H9–C9 being
120.72° and 100.07°, correspondingly. Figure 2 (bottom)
represents another type of the intramolecular weak H
bonds of H8B···Cl1···H10B in 4a. In this case, the distances
1
O
PhOC
Cl
COPh
Cl
O
Cl
NaOH/K2CO3 (1:3)
Previous work
+
+
Cl
Cl
3
Cl
CHO
2a
Cl
Cl
Cl
O
Cl
NaOH/K2CO3 (1:1)
This work
O
Ph
Ph
4a
Scheme 1 Chemoselective transformation of 2,6-dichlorobenzaldhyde
with acetophenone under different conditions
Surprisingly, changing the molar ratio of K2CO3 and
NaOH resulted in the different reaction pathway to give 3-
(2,6-dichlorophenyl)-1,5-diphenylpentane-1,5-dione (4a)
in a high yield. To continue our research, we targeted to
firstly prepare chalcones via the reaction of aromatic alde-
hydes and acetophenone under catalysis of this double-
component solid-base system. Unexpectedly, upon chang-
ing the molar ratio of the solid-base system, the reaction of
2,6-dichlorobenzaldehyde with acetophenone gave 3-(2,6-
dichlorophenyl)-1,5-diphenylpentane-1,5-dione (4a) in a
high yield.
1
The H NMR spectrum of the product exhibited eight
types of proton resonances, of which six types correspond
to the aromatic protons and two sets correspond to one
methine proton and four methylene protons (Figure 1, top).
This spectral pattern clearly corroborates the structure of
4a. To further confirm its structure, the crystallographic
analysis of the product was carried out (Figure 1, bottom). It
shows that there are two molecules of 4a crystallizing in a
typical triclinic system with P-1 space group.
Further insight into the crystallographic data indicated
that 4a possesses two types of the intramolecular weak bi-
furcated H-bonding networks. Figure 2 (top) depicts the in-
tramolecular weak H bonds of O···C–H···Cl in 4a with the in-
Figure 2 Two types of intramolecular weak bifurcated H bonds in 4a
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

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Z. Yin et al.
Letter
Synlett
from Cl1 to the methylene protons H8B and H10B are 2.597
Å and 2.836 Å, respectively, with the bond angles being
112.96° for C8–H8B–Cl1 and 129.09° for C10–H10B–Cl1. It
is of note that the corresponding van der Waals radii for H,5
O,19 and Cl5 are 1.20 Å, 1.40 Å, and 1.75 Å. This clearly
demonstrated the existence of intramolecular weak H
bonding as O···C–H···Cl and C–H···Cl···C–H in 4a according to
the two basic crystallographic characteristics of the weak
C–H···E (E = O, N, Cl, S) H bond stated above.4
Further examination of the crystallographic data indi-
cated that these bifurcated H-bonding interactions dramat-
ically affect the C–Cl and C–O bond lengths (H-bonding ac-
ceptors) in 4a. Hence, as shown in Figure 3, the C23–Cl1 dis-
tance is noticeably longer than that of C19–Cl2. This is
because the fact that Cl1 takes part in two bifurcated weak
H bonds with H8B and H10B, whilst Cl2 participates in only
one weak H bond with H9 involving in weak C9–H9–Cl2 H
bond.
NaOH, K2CO3, and 2,6-dichlorobenzaldehyde showed the
best chemoselectivity to give 4a as the main product in 83%
yield (Table 1, entry 5). When the NaOH loading was de-
creased to 0.2 equiv in the solid-base mixture, only ,-un-
saturated ketone 2a was obtained (Table 1, entry 8), as in
the case of pure K2CO3.
Table 1 Influence of NaOH Loading on Chemoselectivity of the Reac-
tion between 2,6-Dichlorobenzaldehyde with Acetophenone under Sol-
vent-Free Conditionsa
O
Cl
Cl
O
Cl
O
+
Ph
Cl
Ph
O
CHO
solid
NaOH/K2CO3
Cl
Cl
+
2a
4a
grinding
O
Cl
Cl
Ph
Cl
Cl
+
Ph
O
HO
Ph
5a
Entry
NaOH/K2CO3/
aldehyde
Product
Yield of main
product (%)b
1
2
3
4
5
6
7
8
9
2:0:1
3:1:2
2:1:2
1:1:2
1:1:1
1:2:1
1:3:1
1:5:2
0:2:1
5a22
5a
88 (84)
90 (87)
92 (90)
54 (51)
86 (83)
78 (76)
61 (62)
(89)
5a
2a + 4a (main) + 5a
2a + 4a (main) + 5a
2a + 4a (main) + 5a
2a (main) + 4a
2a
Figure 3 Comparison of the bond length of C–O and C–Cl groups par-
ticipating (blue-colored bonds) and nonparticipating (red-colored
bonds) in the intramolecular weak bifurcated H bonds of 4a
2a20
(52)
Furthermore, the bond length of C11–O2, which does
not involve in the intramolecular weak H bonding, is con-
siderable shorter than that of C7–O1, as O1 participates in
formation of the H bond. These results are reasonable, since
H bonding decreases the electron density of Cl and O atoms,
thus inducing the elongation of the corresponding bond
lengths.
Our previous work demonstrated the product diversity
in the reaction between aromatic aldehyde and acetophe-
none catalyzed by the double-component solid-base sys-
tem consisted of K2CO3 and NaOH.20 As shown in Table 1,
this reaction can yield ,-unsaturated ketone 2a, 1,5-dike-
tone 4a, and cyclohexane derivative 5a21 catalyzed by dif-
ferent composition of the double-component base. The al-
kali strength of the mixture plays a decisive role in the reac-
tion pathway and the corresponding product distribution.
Thus, both the >2:1 molar ratio of NaOH and K2CO3 and
pure NaOH gave the same main product 5a (Table 1, entries
1–3). However, it is of note that using just NaOH results in
formation of syrupy dope and consequent difficulty in han-
dling the reaction. Further, upon reducing the concentra-
tion of NaOH, a mixture of 2a, 4a, and 5a was obtained (Ta-
ble 1, entries 4–7). It was found that the 1:1:1 molar ratio of
a For all the reactions, 5 mmol of 2,6-dichlorobenzenealdehyde were used
at room temperature.
b Isolated yields after recrystallization based on 2,6-dichlorobenzaldehyde
at the 1:2 and 1:1.1 (in the brackets) molar ratio of 2,6-dichlorobenzalde-
hyde and acetophenone.
The above results clearly indicated that ,-unsaturated
ketone 2a and 1,5-diketone 4a are the key intermediates for
the formation of cyclohexane derivative 5a, and the reac-
tion pathway is governed by the alkali strength of the base
used. As an additional evidence of this suggestion, the cor-
responding control reactions of 2a and 4a ground in a 1:1
mixture of NaOH and K2CO3 condensation of 2,6-dichloro-
benzenealdehyde with acetophenone provides 2a, which in
turn undergoes Michael addition reaction that yielded the
single product 5a as expected. Based on these results, a
plausible mechanism was proposed (Scheme 2).
Aldol condensation of 2,6-dichlorobenzenealdehyde
with acetophenone to give 4a was performed. The second
Michael addition reaction of 4a with 2a furnishes a linear
triketone intermediate, which was not isolated. Finally, 5a
is formed via the intramolecular aldol reaction of the trike-
tone intermediate, which occurred readily and fleetly. For-
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
Z. Yin et al.
Letter
Synlett
Ph
Cl
O
Cl
Cl
PhCOCH3
PhCOCH3
Ph
O
O
CHO
Aldol condensation
Michael addition
Cl
Cl
4a
Ph
Cl
2a
Cl
Cl
Cl
O
Cl
Ph
Cl
O
Ph
Ph
O
Cl
Cl
H
Ph
Cl
Michael addition
Cl
Ph
Cl
O
Ph
H
O
O
O
Ph
linear triketone intermediate
O
Cl
Cl
Ph
Cl
Cl
Aldol addition
Ph
O
HO
Ph
5a
Scheme 2 A plausible mechanism for the formation of 2a, 4a, and 5a
mation of 5a involves multiple steps of the nucleophilic at-
tack of a carbonyl by carbanions, while the generation of
carbanions in turn is closely related to the corresponding al-
kali strength of the solid-base mixture. If the concentration
of NaOH is decreased, the basicity is not enough to produce
the corresponding carbanion, and the reaction cannot pro-
ceed further, and hence is terminated at the stage of 2a or
4a. This reaction mechanism is in good agreement with the
experimental results obtained. With the optimized condi-
tions in hand and to expand the reaction scope, a series of
aromatic aldehydes were allowed to react with acetophe-
none, as shown in Table 2. One can see that all selected aro-
matic aldehydes at the optimized reaction conditions re-
sulted in the corresponding 1,5-diketone products to con-
firm the chemoselective efficiency of this solid-state
synthetic methodology.
Further studies related to the conformational structure
and weak intramolecular H-bonding interactions of this
type of organic compounds are in progress and will be re-
ported elsewhere in due course.
In summary, two types of intramolecular bifurcated
weak bonds of aliphatic C–H (Cl···C···H···O and C–H···Cl···H–
C) were observed in a crystal of 3-(2,6-dichlorophenyl)-1,5-
diphenylpentane-1,5-dione.23 X-ray crystallographic analy-
sis demonstrated that the bifurcated H bonds dramatically
affected the length of C–Cl and C–O bonds in the crystalline
form. Furthermore, a highly chemoselective synthesis of
1,5-diketones under the solvent-free conditions was devel-
oped. This observation revealed an important role of the
weak bifurcated H bonds in conformation stability and spa-
tial structure of organic molecules.
Table 2 Reaction of Acetophenone with Aromatic Aldehydes under
Solvent-Free Conditionsa
R
O
O
O
grinding
+ R CHO
Ph
Ph
NaOH/K2CO3 (1:1)
Ph
4
Entry
R
Main product 4
Yield (%)b
1
2
2,6-Cl2C6H3
2,4-Cl2C6H3
2-ClC6H4
4a
4b
4c
4d
4e
4f
86
84
81
79
83
80
76
75
77
79
83
85
3
4
3-ClC6H4
5
4-ClC6H4
Funding Information
6
2-BrC6H4
National Natural Science Foundation of China (Grant No.21302233);
Natural Science Foundation of Hubei Province (Grant No.
2012FFB07410); Fundamental Research Funds for the Central Univer-
sities (CZY18010), and start-up research grant (YZZ16005) from
7
2-FC6H4
4g
4h
4i
8
2-MeOC6H4
4-MeOC6H4
2-MeC6H4
2-F3CC6H4
4-F3CC6H4
9
South-Central University for Nationalities.
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Supporting Information
a All the reactions were carried out at 5 mmol scale by using a 1:1 solid mix-
ture of NaOH and K2CO3 at room temperature.
Supporting information for this article is available online at
b Yields were obtained after recrystallization for the reactions in a 1:2 molar
ratio of aromatic aldehydes and acetophenone.
https://doi.org/10.1055/s-0039-1690224.
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References and Notes
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1102.
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(23) General Procedure
To a mixture of aromatic aldehydes (5 mmol) and acetophenone
(11 mmol) a fine powder of NaOH (5 mmol) and K2CO3 (5
mmol) was added. The reaction mixture was ground at room
temperature until it became incompact solid (generally 20–30
min). After the solid was treated with water, the water-insolu-
ble solid was recrystallized in ethanol.
3-(2,6-Dichlorophenyl)-1,5-diphenylpentane-1,5-dione (4a)
Mp 125–128 °C, 86% yield, white solid. 1H NMR (400 MHz,
CDCl3):  = 8.03–7.93 (m, 4 H), 7.54 (d, J = 7.4 Hz, 2 H), 7.45 (t, J =
7.6 Hz, 4 H), 7.33 (d, J = 7.9 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 7.06
(14) (a) Tzeli, D.; Tsoungas, P. G.; Petsalakis, I. D.; Kozielewicz, P.
Struct. Chem. 2017, 28, 925. (b) Thomas, J.; Liu, X.; Jäger, W.; Xu,
Y. Angew. Chem. Int. Ed. 2015, 54, 11711. (c) Preimesberger, M.
R.; Majumdar, A.; Aksel, T.; Sforza, K.; Lectka, T.; Barrick, D.;
Lecomte, J. T. J. Am. Chem. Soc. 2015, 137, 1008.
(15) Caccamese, S.; McMillan, J. A.; Montaudo, G. J. Org. Chem. 1978,
43, 2703.
(t, J = 8.0 Hz, 1 H), 5.07 (p, J = 7.1 Hz, 1 H), 3.84–3.65 (m, 4 H). 13
C
NMR (100 MHz, CDCl3):  = 198.3, 138.3, 136.9, 136.7, 134.5,
133.2, 129.9, 128.9, 128.6, 128.3, 128.2, 41.1, 33.3.
Crystal Structure of Compound 4a
C
23H18Cl2O2, MW = 397.27, Dcalc = 1.342 g/cm3; V = 983.0(2) Å3,
(16) (a) Hu, X. Y.; Shan, Z. X.; Soloshonok, V. A. Cryst. Growth Des.
2012, 12, 33. (b) Hu, X. Y.; Guo, J. X.; Yin, Z. Y.; Shan, Z. X. Chem-
istrySelect 2018, 3, 3309.
triclinic; Z = 2; space group P-1, a = 9.4157(12), b = 10.3008(14),
c = 10.9517(15),  (Mo K) = 0.345 mm–1, –11 ≤ h ≤ 12, –13 ≤ k ≤
13, –14 ≤ l ≤ 14, F(000) = 412, GOF = 1.059, T = 296 (2) K; CCDC
1904249.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E