A new series of C-6 unsubstituted tetrahydropyrimidines: Convenient one-pot chemoselective synthesis, aggregation-induced and size-independent emission characteristics

Article abstract of DOI:10.1002/chem.201203012

A new series of C-6 unsubstituted tetrahydropyrimidines 6 have been directly synthesized via a convenient urea-catalyzed chemoselective five-component reaction (5CR) under mild conditions. Compounds 6 show typical aggregation-induced emission enhancement (AIEE) characteristics because they are practically no emissive in solution but emit blue or green fluorescence in aggregates with fluorescence yield up to 93 %. One of the 5CR products, 6 aa, exhibits blue- and green-fluorescence aggregates (bf- and gf-aggregates). The bf- and gf-aggregates are prepared under different conditions and proved to result from different J-aggregations by single-crystal X-ray analysis. In addition, the bf- and gf-aggregates of 6 aa show unusual size-independent emission (SIE) characteristics because their maximum emission wavelengths in different sizes (suspension particles, film, powder and crystals) are the same, 434 and 484 nm, respectively. Based on the obtained experimental results, the 5CR mechanism, the origins of AIEE and SIE characteristics are discussed. Copyright

Full text of DOI:10.1002/chem.201203012

DOI: 10.1002/chem.201203012
A New Series of C-6 Unsubstituted Tetrahydropyrimidines: Convenient One-
Pot Chemoselective Synthesis, Aggregation-Induced and Size-Independent
Emission Characteristics
Qiuhua Zhu,[a] Lan Huang,[a] Zhipeng Chen,[a] Sichao Zheng,[a] Longyun Lv,[a]
Zhibo Zhu,[a] Derong Cao,[b] Huanfeng Jiang,*[b] and Shuwen Liu*[a]
Abstract: A new series of C-6 unsubsti-
tuted tetrahydropyrimidines have
5CR products, 6aa, exhibits blue- and
green-fluorescence aggregates (bf- and
gf-aggregates). The bf- and gf-aggre-
gates are prepared under different con-
ditions and proved to result from dif-
ferent J-aggregations by single-crystal
X-ray analysis. In addition, the bf- and
gf-aggregates of 6aa show unusual size-
independent emission (SIE) character-
istics because their maximum emission
wavelengths in different sizes (suspen-
sion particles, film, powder and crys-
tals) are the same, 434 and 484 nm, re-
spectively. Based on the obtained ex-
perimental results, the 5CR mecha-
nism, the origins of AIEE and SIE
characteristics are discussed.
6
been directly synthesized via a conven-
ient urea-catalyzed chemoselective
five-component reaction (5CR) under
mild conditions. Compounds 6 show
typical aggregation-induced emission
enhancement (AIEE) characteristics
because they are practically no emis-
sive in solution but emit blue or green
fluorescence in aggregates with fluores-
cence yield up to 93%. One of the
Keywords: aggregation-induced
emission
· multicomponent reac-
tions · nitrogen heterocycles · size-
independent emission · tetrahydro-
pyrimidine
Introduction
the direct synthesis of diversely substituted tetrahydropyri-
midines is needed in order to explore new potential drug-
like molecules and other valuable properties.
Tetrahydropyrimidines are important heterocycles exhibiting
diverse biological activities.[1] They are also used as impor-
tant intermediates in synthetic and medicinal chemistry.[2]
Some of pyrimidinyl nitronyl nitroxides were found to pos-
sess interesting magnetic properties.[3] The RuII complexes
of tridentate ligands with N,N’-bis(2-pyridyl)-tetrahydropyri-
midinium hexafluorophosphate show red-shifted emission.[4]
However, the reported methods for the synthesis of tetrahy-
dropyrimidine derivatives suffer from disadvantages such as
low overall yields, complex procedures, harsh reaction con-
ditions or limited starting materials.[1,3,5] Therefore, the de-
velopment of convenient and efficient methodologies for
Multi-component reactions (MCRs) have attracted in-
creased attention in synthetic chemistry for their distinct ad-
vantages such as atom economy, simplified workup proce-
dures, high overall yields and molecular diversity products.[6]
We have recently reported an efficient new four-component
reaction (4CR) of but-2-ynedioates 1, primary amines 2 and
4, and formaldehyde 5 for the synthesis of new 1,2,3,6-tetra-
hydropyrimidine-4,5-dicarboxylates 7 [Reaction (1)].[7] Fol-
lowing the methodology, detailed investigations on expand-
ing the scope of the 4CR for asymmetric alkynoates,[8] im-
proving the method and studying the mechanism[9] have
been undertaken. However, the substitution on the C-2/C-6
position of 7 remains a synthetic challenge owing to steric
hindrance and regioselectivity.
[a] Dr. Q. Zhu, L. Huang, Dr. Z. Chen, S. Zheng, L. Lv, Dr. Z. Zhu,
Prof. S. Liu
School of Pharmaceutical Sciences
Southern Medical University
1838 Guangzhou Avenue North;
Guangzhou 510515 (P. R. China)
Fax : (+86)20-61648655
E-mail: liusw@smu.edu.cn
[b] Prof. D. Cao, Prof. H. Jiang
School of Chemistry and Chemical Engineering
State Key Laboratory of Luminescent Materials and Devices
South China University of Technology
381 Wushan Road, Guangzhou 510640 (P. R. China)
E-mail: jianghf@scut.edu.cn
In the past decade, organocatalysts have become a thriv-
ing area in synthesis chemistry for the advantages such as
being stable in air and water, available from biological ma-
terials, inexpensive and easy to prepare, simple to use, and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203012.
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FULL PAPER
non-toxic.[10] As one of important organocatalysts, urea and
its derivatives have attracted much attention in organic syn-
thesis chemistry.[11] We found that the five-component reac-
tion (5CR) of 1, 2, aromatic aldehydes 3, 4 and 5 using urea
as the organocatalyst could chemoselectively provide a
direct and mild synthesis of C-6 unsubstituted tetrahydro-
pyrimidines 6 [(C-2 substituted 7 in Reaction (1)].
a challenge.[27a] It is therefore expected that 6aa possessing
AIEE and SIE characteristics would be very useful for theo-
retical research and practical applications.
Herein we first report the condition optimization, scope
and possible mechanism of the 5CR for the synthesis of 6,
followed by the typical AIEE properties of 6 as well as the
condition influences on the formation, preparation, AIEE
properties, SIE characteristics and molecular stacking
modes (MSM) of 6aa in bf- and gf-aggregates. Furthermore,
the origins of the formation of the bf- and gf-aggregates of
6aa, the AIEE and SIE characteristics are discussed.
Importantly, the 5CR products 6 show unusual character-
istics of aggregation-induced emission enhancement (AIEE)
because they show no fluorescence in solutions but emit
strong blue or green fluorescence in aggregates.[12] Fluores-
cence quantum yield (FF) is an important optical property
parameter of an organic fluorophore. The FF values of con-
ventional fluorophores often decrease at high concentration
or in solid state due to the formation of detrimental exci-
meric species, which is called aggregation-caused quenching
(ACQ).[13] Because fluorophores are usually used as a solid
form in practical applications, such as thin films in the fabri-
cation of organic light-emitting diodes (OLEDs),[14] the
ACQ effect has been a thorny obstruct that must be over-
come. The unusual AIEE phenomenon of pseudoisocyanine
chloride was observed in 1930s by Jelley[15] and Scheibe[16] et
al. independently. Since then, an enormous number of cya-
nine dye aggregates have been studied intensively.[17] Re-
cently, several organic compounds, such as poly(phenylene-
Results and Discussion
Synthesis of diethyl 1,2,3,6-tetrahydro-1,2,3-triphenylpyrimi-
dine-4,5-dicarboxylate (6aa): MCRs are networks of various
reactions. Thus, finding the suitable reaction conditions for a
new MCR is likely to be more difficult than for convention-
al reactions. The condition optimization of the 5CR was car-
ried out for the synthesis of 6aa. We first investigated the in-
fluence of catalysts and solvents on the 5CR (Table 1). The
5CR could give target product 6aa in 10–15% yields in the
presence of AcOH, acidic organocatalysts l-proline, urea or
thiourea (entries 1, 3–5). Trace target product was obtained
using N(Et)3, CuAc2·H2O (favoring the formation of 8a[28]),
FeCl3·6H2O and Pd/C as catalysts (entries 6–9). Although
ACHTUNGTRENNUNG
ethynylene)s,[18] pentaphenylsiloles,[19] 1-cyano-trans-1,2-bis-
(4’-methylbiphenyl)ethylenes,[20] and arylethene deriva-
tives,[21] were also found to exhibit AIEE characteristics.
During the past decade, AIEE fluorophores have shown
their distinct advantages in many areas of application, such
as chemo/biosensors,[22] OLEDs,[23] and others. To the best of
our knowledge, 6 are the only AIE fluorophores synthesized
via an efficient and convenient 5CR. It is well known, a li-
brary of products could be built via a MCR. For example, a
5CR could generate 105 different products using only ten
starting materials for each component through permutations
and combinations. Therefore, the 5CR is expected to be
very useful for the investigation into the structure-fluores-
cence relationships of 6 and for their practical applications.
Another interesting phenomenon is that 6aa was found to
exhibit blue- and green-fluorescence aggregates (bf- and gf-
aggregates) possessing unusual size-independent emission
(SIE) characteristics. Maximum emission wavelength
(lem,max) is another important optical property parameter of
an organic fluorophore. The lem,max values of conventional
organic fluorophores usually change along with aggregate
sizes. For example, lem,max bathochromically shifts with in-
crease in the diameters of wires[24] and in the sizes of parti-
cles.[25] In addition to conventional fluorophores, AIEE fluo-
rophores also usually show the dependence of lem,max values
on aggregate sizes.[19a,20,26] Yao and co-workers have investi-
gated size-dependent optical properties in detail.[25,27] They
thought that organic crystals also exhibit significant size ef-
fects as inorganic semiconductors and metals but with a
greater diversity because of a wide variety of organic molec-
ular structures. Hence the search for ways to control size,
shape and optical properties of organic molecular crystals is
Table 1. Optimization of catalysts and solvents for the 5CR synthesis of
6aa.[a]
Entry Solvent Catalyst
AcOH [equiv] t [h] 6aa
7a
8a
Yield [%][b]
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH l-proline
MeOH urea
MeOH thiourea
MeOH N(Et)3
MeOH CuAc2·H2O
MeOH FeCl3·6H2O
MeOH Pd/C
MeOH l-proline
MeOH urea
2
48
48
48
48
48
48
48
48
48
24
24
24
48
48
48
15
6
13
11
10
71
65
72
73
70
trace
trace
trace
trace
trace
trace trace trace
trace trace 90
trace trace trace
9
trace 89
trace
trace
trace
trace
trace
10
10
11
12
13
14
15
2
2
2
2
2
2
18
20
17
18
10
72
70
73
70
75
MeOH thiourea
EtOH
DMF
DCM
urea
urea
urea
trace 20
5
[a] Reaction mixture A (0.2 mmol of 1a and 0.2 mmol of 2a in 0.2 mL of
MeOH kept for 10 min), 3a (0.3 mmol) and catalyst (0.04 mmol) were
added to reaction mixture B (0.32 mmol of 4a, 0.24 mmol of 38% 5 and
0.4 mmol of AcOH in 1 mL of MeOH kept for 10 min) in sequence, fol-
lowed with stirring at room temperature for desired time. [b] Isolated
yields.
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Q. Zhu, H. Jiang, S. Liu et al.
Table 2. Optimization of reactant amounts and temperature for the 5CR
the 5CR proceeded for shorter time (48 to 24 h) in higher
yield (10–15 to 17–20%) using acidic organocatalysts
(0.2 equiv) in the presence of AcOH (2 equiv) (entries 10–
12), by-product 7a[9] was still the main product (70–73%
yield). Among the screened solvents (entries 11, 13–15),
MeOH was the most suitable solvent for the 5CR
(entry 11).
synthesis of 6aa.[a]
Entry 3a
5
4a Urea
[equiv]
AcOH
[equiv]
T
t
6aa Yield
[8C] [h] [%][b]
1
2
3
4
5
6
7
8
1.6 1.4 1.5 0.2
1.6 1.0 1.5 0.2
1.6 1.2 1.5 0.2
1.6 1.2 1.5 0.2
1.6 1.2 1.5 0.2
1.6 1.2 1.5 0.3
1.6 1.2 1.5 0.1
1.4 1.2 1.5 0.2
2
2
2
4
6
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
ꢀ5
60
24 20
24 17
24 22
24 27
24 24
24 25
24 26
24 18
24 21
24 19
The optimization results on the amounts of reactants,
urea and acetic acid as well as temperature for the synthesis
of 6aa are shown in Table 2. Both 1a and 2a were used as
limiting reactants in the 5CR because 1a and 2a could react
fast and quantitatively.[9] The yield of 6aa could not be sig-
nificantly increased after the amounts of urea, AcOH and
other reactants were optimized respectively (entries 1–11).
When the amounts of 3a and 4a were increased at the same
time, 54% yield of 6aa was obtained (entry 15, Table 2).
The results on temperature optimization (entry 15, 19 and
20) indicate that the 5CR is suitable to be carried out at
room temperature. In addition, under the reaction condi-
tions (RT, 3a/4a/5/urea/AcOH 3.5:3.5:1.4:0.2:4) similar to
that of entry 15, the amounts of 1a/2a (1:1, 1.5:1.5 and
2/2 equiv) were also optimized, which produced 6aa in 28,
36 and 21% yield, respectively. Thus, the optimum condi-
tions of the 5CR were 1a/2a/3a/4a/5/urea/AcOH
1:1:3.5:3.5:1.4:0.2:4. Then, the adding orders of reactants
were investigated. No or less target product 6aa was ob-
tained with changes of the adding orders, which indicates
that the adding order is crucial for the synthesis of 6aa. The
adding orders of urea were also studied, but the yield of 6aa
was not improved.
9
3
1.2 1.5 0.2
10
11
12
13
14
15
16
17
18
19
20
1.6 1.2 1.2 0.2
1.6 1.2 1.8 0.2
24
8
3
3
3
1.2 2.5 0.2
24 32
24 24
24 43
24 54
24 52
24 45
24 48
48 49
1.2
1.2
2
3
0.2
0.2
3.5 1.4 3.5 0.2
1.4 3.5 0.2
4
3.5 1.4
1.4
4
4
0.2
0.2
4
3.5 1.4 3.5 0.2
3.5 1.4 3.5 0.2
6
43
[a] Reaction mixture A (0.2 mmol of 1a and 0.2 mmol of 2a in 0.2 mL of
MeOH kept for 10 min), 3a and urea were added to reaction mixture B
(4a, 38% 5 and AcOH in 1 mL of MeOH kept for 10 min) in sequence,
followed with stirring for desired time. [b] Isolated yields.
5CRs. The yields of 6 correlate with the structures of 2 and
4 in a decrease order: aromatic 2 and 4 > aromatic 2 and
aliphatic 4 > aliphatic 2 and 4 > aliphatic 2 and aromatic 4
(the yield of entry 1 > 10 > 2 > 11 in Table 3). The activity
and the yield would be higher using aromatic aldehyde with
electron-donating substituent as reactant 3 (entry 21) than
using one with electron-withdrawing substituent (entry 19).
The 5CRs would produce complex products when nitroben-
zaldehyde or aliphatic aldehydes such as acetaldehyde and
2-phenylacetaldehyde were used as reactants 3.
Scope of the 5CRs for the synthesis of C-6 unsubstituted
tetrahydropyrimidine-4,5-dicarboxylate (6): In the above op-
timal conditions, a new series of 6 were successfully synthe-
sized via the 5CR (Table 3). Reactants 2 could be aliphatic
(entries 2, 11, 17 and 22) and aromatic (all except entries 2,
11, 17 and 22) primary amines; 4 could also be aliphatic (en-
tries 2, 10, 17 and 22) and aromatic (all except entries 2, 10,
17 and 22) primary amines; and 3 could be electron-donat-
ing (entries 9 and 21) and electron-withdrawing (entry 19)
substituted aromatic aldehydes. Reactants 2 and 4 could be
the same (entries 1–9, 16–22) or different (entries 10–15).
Four target products 6 could be obtained when just two dif-
ferent aromatic primary amines (entries 1, 3, 12 and 13) or
one aromatic primary amine and one aliphatic primary
amine (entries 1, 2, 10 and 11) were used as reactants 2 and
4, respectively. The addition of CH2Cl2 in reaction mixture
B was needed to increase the intermediate solubility and the
5CR yield if the 5CR intermediate would precipitate (en-
tries 9, 16 and 18). Moreover, the 5CR needed to take place
at ꢀ158C when aliphatic and aromatic primary amines were
used as reactants 2 and 4, respectively (entry 11), otherwise
only by-products 7 (main by-product) and 8 could be gener-
ated.
Replacement of ethyl in 1a with methyl did not signifi-
cantly affect the yields of 6 (comparing entries 1 and 16 or 2
and 17 in Table 3).
1H NMR spectral characteristics of 6: All compounds 6
1
show the H NMR spectral characteristics of C2-H (s, 5.6–
6.2 ppm), C6-H2 (d, 3.3–4.4 ppm, J=16.8–18.0 Hz) and
2CH3CH2O (q, 4.0–4.5 ppm; t, 1.0–1.5 ppm, J=7.2 Hz) or
2CH3O (s, 3.5–4.0 ppm), which are closely consistent with
the single crystal structure of 6ba (Figure 1). The relation-
1
ship between H NMR spectra characteristics of 6 and struc-
tures of R2 and R4 are shown in Table S1.
Possible reaction mechanism: According to our previous
studies,[9,28] and the experiment results mentioned above, we
proposed a possible mechanism for the 5CR, which contains
four elementary steps: hydroamination/aza-ene-type reac-
Depending on their structures, reactants 2, 3 and 4 affect
the activities and yields of the 5CRs to different extents. In
general, aromatic 2 and 4 are favorable reactants for the
tion/nucleophilic
addition/intramolecular
cyclization
(Scheme 1). As reported in our previous work,[9] the hydro-
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C-6 Unsubstituted Tetrahydropyrimidines
FULL PAPER
Table 3. Scope of the 5CR for the synthesis of 6.[a]
Entry
R1
R2NH2 2
R4 NH2 4
R3CHO 3
t [d]
6
Yield [%][b]
1
Et 1a
PhNH2 2a
4a
PhCHO 3a
1
54
2
Et 1a
PhCH2NH2 2b
4b
PhCHO 3a
5
29
3
Et 1a
4-Me-PhNH2 2c
4c
PhCHO 3a
1
51
4
Et 1a
4-Cl-PhNH2 2d
4d
PhCHO 3a
1
50
5
Et 1a
4-Br-PhNH2 2e
4e
PhCHO 3a
1
52
6
Et 1a
3-CF3-PhNH2 2 f
4 f
PhCHO 3a
2
50
7
Et 1a
3-Me-PhNH2 2g
4g
PhCHO 3a
1
46
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Q. Zhu, H. Jiang, S. Liu et al.
Table 3. (Continued)
Entry
R1
R2NH2 2
R4 NH2 4
R3CHO 3
t [d]
6
Yield [%][b]
8
Et 1a
PhNH2 2a
4a
4-Br-PhCHO 3b
1
31
9[c]
Et 1a
PhNH2 2a
4a
3-MeO-4-OH-PhCHO 3c
1
53
10
Et 1a
PhNH2 2a
PhCH2NH2 4b
PhCHO 3a
5
37
11[d]
Et 1a
PhCH2NH2 2b
PhNH2 4a
PhCHO 3a
3
21
12
Et 1a
4-Me-PhNH2 2c
PhNH2 4a
PhCHO 3a
1
37
13
Et 1a
PhNH2 2a
4-Me-PhNH2 4c
PhCHO 3a
1
36
14
Me 1b
PhNH2 2a
PhCH2NH2 4b
3-Br-PhCHO 3d
5
35
15
Me 1b
3-CF3-PhNH2 2 f
4-Br-PhNH2 4e
PhCHO 3a
2
61
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C-6 Unsubstituted Tetrahydropyrimidines
Table 3. (Continued)
FULL PAPER
Entry
R1
R2NH2 2
R4 NH2 4
R3CHO 3
t [d]
6
Yield [%][b]
16[c]
Me 1b
PhNH2 2a
4a
PhCHO 3a
1
61
17
Me 1b
PhCH2NH2 2b
4b
PhCHO 3a
1
28
18[c]
Me 1b
Me 1b
Me 1b
4-Me-PhNH2 2c
4c
4a
4a
PhCHO 3a
1
5
1
63
25
51
19
PhNH2 2a
4-CF3-PhCHO 3e
20
PhNH2 2a
4-Br-PhCHO 3b
21
Me 1b
PhNH2 2a
4a
3-MeO-4-OH-PhCHO 3c
1
52
22
Me 1b
n-C4H9NH2 2i
4i
PhCHO 3a
1
41
[a] Reaction mixture A (1 mmol of 1 and 1 mmol of 2 in 0.5 mL of MeOH kept for 10–30 min), 3 (3.5 mmol) and urea (0.2 mmol) were added to reaction
mixture B (3.5 mmol of 4, 1.4 mmol of 38% 5 and 4 mmol of AcOH in 3 mL of MeOH kept for 10 min) in sequence, followed with stirring for desired
time. [b] Isolated yields. [c] 0.5 mL of CH2Cl2 was added in the reaction mixture B. [d] The reaction temperature was ꢀ158C. [e] The structure of 6ba
was confirmed by single-crystal X-ray diffraction analysis (Figure 1).
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Q. Zhu, H. Jiang, S. Liu et al.
Figure 1. Single-crystal structure of 6ba (CCDC-811811).[29]
ACHTUNGTRENNUNGamination of 1 and 2 could complete in 10–30 min and give
Z- and E-isomers 10 in greater than 98% yield. Because of
electron-donating effect and steric hindrance of R2, the elec-
trophilic activity of the imine carbon in 9’ is lower than that
in 9, which was supported by the experimental results in our
previous work.[28] Therefore, the electron-rich double-bond
carbon in 10 chemoselectively attacks the electron-poor
imine carbon in 9 rather than 9’. Z- and E-isomers 10 with 9
proceed an aza-ene-type reaction and form the same C-6
unsubstituted intermediate 11.[9] Intermediate 11 proved not
to be isolated at RT because it could be converted to by-
product 8 via intramolecular cyclization,[9,28] which means
that target product could be obtained only when the reac-
tion activity of 11 and 3 is higher than that of the intramo-
lecular cyclization of 11. Reactant 3 is activated by AcOH
and urea, through which 3 was converted to an active form
3’.[10a–c] The nucleophilic addition reaction of 11 to 3’ shows
very high reaction activity and could occur even at ꢀ158C
(entry 11 in Table 3), which leads to the formation of active
intermediate 12 that could not be insolate at RT, and hence
target products 6 are obtained through the intramolecular
cyclization of 12.
Scheme 1. Possible mechanism of the chemoselective 5CR for the direct
and mild synthesis of 6.
Figure 2. Typical AIEE properties of 6. a) Any of 6 in ethanol solution
(1ꢁ10ꢀ3 ꢀ1ꢁ10ꢀ5 m). b) 6af (left) and 6be (right) crystallized in round
bottom flask (viewed from the flask bottom). c) 6af (left) and 6be (right)
in ethanol/water 1:9 (1ꢁ10ꢀ4 m). Photos were taken under UV light at
365 nm.
tum yield in ethanol solutions (FF,s) and in ethanol/water
(1:9) suspensions (FF,a) of 6 were determined. The FF,s
values of 6 in ethanol solution are near zero because the 50-
fold enlarged emission spectra are noisy signal lines. The
lab,max, lem,max and FF,a values of 6 are shown in Table S2. All
of 6 show high optical absorption with molar absorption co-
efficient (e) higher than 104. Four of 6 with aryl R2 and R4
show strong effect of AIEE with FF,a > 50% and the quan-
tum yield of 6bb is up to 93% (Table 4). On the contrary,
all 6 with alkyl R2 and/or R4 show very weak emission (en-
tries 2, 10, 14, 17 and 22 in Table S2). Therefore, it can be
As shown in Scheme 1, by-products 7,[7,9] and 8[28] could
be generated by the reaction of 11 and 5 as well as the intra-
molecular cyclization of 11, respectively. Except entry 11 in
Table 3, 7 was the main by-product for all of the 5CRs be-
cause 5 could not be completely converted into 9 in the
equilibrium reaction [Reaction (2), shown in Scheme 1] as
well as the reaction of 11 and 5 could easily occur at room
temperature in the presence of AcOH.[9] As reported in our
previous work,[28] aliphatic amines 2 and aromatic amines 4
are the most favorable reactants for the formation of 8,
which well explains why 8 was the main by-product for the
synthesis of 6ak (entry 11 in Table 3).
Table 4. Optical properties of 6 with FF,a higher than 0.5.
Absorption
lab,max
Fluorescence
lem,max
[a]
[c]
[d]
6
e[b]
FF,a
6aa
6ae
6ah
6bb
318
320
316
318
11676
39112
38448
11950
484
477
476
459
0.53
0.58
0.70
0.93
Typical AIEE properties of 6: The most striking result is
that all of 6 possess typical AIEE properties because they
show no emission in solutions (Figure 2a), but emit blue or
green fluorescence in solids (Figure 2b are two typical rep-
resentations, and other ones are shown in Figures S1 and
S2) and in suspensions (Figure 2c).
[a] Maximum absorption wavelengths of 6 in ethanol solution (5.0ꢁ
10ꢀ5 m). [b] Molar absorption coefficient of 6. [c] Maximum emission
wavelengths of 6 in ethanol-water (1:9) suspensions (5.0ꢁ10ꢀ5 m) excited
at 350 nm. [d] Quantum yields of 6 (5.0 ꢁ10ꢀ5 m) in ethanol-water (1:9)
suspensions (FF,a) using the ethanol solution of 9,10-diphenylanthracene
(DPA) (3.0 ꢁ10ꢀ5 m) as a standard reference excited at 350 nm.[30]
The maximum absorption wavelengths (lab,max), maximum
emission wavelengths (lem,max) as well as fluorescence quan-
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C-6 Unsubstituted Tetrahydropyrimidines
FULL PAPER
deduced that aromatic substituents R2 and R4 are needed
for strong emission in aggregates.
trast, a faster rate (at lower temperatures or higher concen-
trations) favored the formation of gf-crystals (condition b).
For example, under the same concentration (10ꢀ2 m), bf-crys-
tals are formed at temperatures equal to or higher than
288C, while gf-crystals are formed at temperatures equal to
or lower than 88C. In contrast, under the same temperature
(88C), bf-crystals are formed at concentrations equal to or
lower than 10ꢀ3 m, and gf-crystals at concentrations equal to
or higher than 10ꢀ2 m. The addition of one of the crystals to
the saturated solution of 6aa could lead to the formation of
the corresponding crystals. In addition, the bf- and gf-crystal
mixtures could be also obtained under certain conditions
(condition c). However, only gf-film was obtained under dif-
ferent conditions (condition d).
The influence of temperatures and concentrations on the
formations of the bf- and gf-particles of 6aa in suspensions
were also investigated. We found that the particles that
formed first under the studied conditions were the gf-forms.
However, they could transform to the bf-forms by increasing
ultrasonic time at higher temperatures. This means that the
gf-particles are the kinetically favored form and the bf-parti-
cles are the thermodynamically favored form. As shown in
Figure 4, the gf-particles of 6aa in suspension (1.0ꢁ10ꢀ5 m)
transformed completely to the bf-forms in 30 min at 408C
under ultrasonic stirring.
Identification of the blue- and green-fluorescence crystals of
6aa: Another interesting phenomenon is that 6aa was found
to have two different kinds of crystals: white crystal emitting
blue fluorescence (bf-crystal) (Figure 3a) and light-green
Figure 3. Two types of crystals of 6aa. a) White crystal emitting blue fluo-
rescence (bf-crystals) and b) light-green crystal emitting green fluores-
cence (gf-crystals) under the daylight and UV light (365 nm), respective-
ly.
crystal emitting green fluorescence (gf-crystal) (Figure 3b).
The parts precipitated out directly from the reaction solu-
tion are the bf-crystals, but the rest isolated from the reac-
tion solution mostly are the gf-crystals. The different crystals
could be separated easily under UV light (l=365 nm) ac-
cording to their different fluorescence. Both of them proved
1
to be racemate 6aa by H and 13C NMR analysis (the spec-
tra for both are the same) as well as optical rotation deter-
mination (a=0). The bf-crystals and gf-crystals of 6aa have
different melt points (130 and 1208C, respectively).
Influences of various conditions on the formation of 6aa in
bf- and gf-aggregates and their preparation: In order to pre-
pare the pure fluorescent isomers of 6aa in different aggre-
gate sizes and to understand the origin of the different fluo-
rescence, the influences of solvent, temperature and concen-
tration on the formations of bf- and gf-crystals were first in-
vestigated. We found that a slower crystallization rate (at
higher temperatures or lower concentrations) favored the
formation of bf-crystals (condition a in Scheme 2). In con-
Figure 4. Transformation of the gf-particles to the bf-particles of 6aa.
a) Emission spectra 6aa in suspension (1.0ꢁ10ꢀ5 m) at 408C for different
ultrasonic stirring times, excited at 350 nm. b) Maximum emission wave-
length depending on ultrasonic stirring time.
To rule out the influence of time, the suspensions of 6aa
prepared at different temperatures and concentrations were
kept in ultrasonic bath for the same time 30 min. The data
indicate that the influences of temperature and concentra-
tion on the formation of the bf- and gf-particles of 6aa in
suspension are similar to that of the bf- and gf-crystals, re-
spectively (Figure 5). The bf- and gf-suspensions of 6aa
(1.0ꢁ10ꢀ5 m) could be prepared at 40 and 08C, respectively
(Figure 5a).
Scheme 2. Preparation conditions of the bf-crystals, gf-crystals and gf-film
of 6aa. a) for bf-crystals: 10ꢀ2 m, ꢁ 288C; 88C, ꢂ 10ꢀ3 m; or adding bf-
crystals in 6aa solutions (10ꢀ1–10ꢀ3 m, ꢀ20 to 288C); b) for gf-crystals:
10ꢀ2 m, ꢂ 88C; 88C, ꢁ 10ꢀ2 m; or adding the gf-crystals in 6aa solutions
(10ꢀ1–10ꢀ3 m, ꢀ20 to 288C); c) for the mixture of bf- and gf-crystals: 5ꢁ
10ꢀ2 m, 88C in dichloromethane/n-hexane (1:20) solutions; d) for gf-film:
spin-coating 6aa (10 mgmLꢀ1 toluene/ethanol) on quartz plate at 1000/
2000/3000 rms. The images of crystals and film are under UV light
(365 nm) and fluorescence microscope (multiplied by 25-fold), respective-
ly.
AIEE and SIE properties of 6aa in bf-aggregates: Red-shift-
ed band and a level-off tail at long wavelengths in the
UV/Vis spectrum of 6aa were observed when the volume
fraction of water (fw) in ethanol increased to 80% (Fig-
ure 6a), and, at the same time, the emission intensity was
enhanced dramatically (Figure 6b and 6c). This indicates the
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Q. Zhu, H. Jiang, S. Liu et al.
ously, 6aa in gf-aggregates also shows SIE characteristics be-
cause all gf-aggregates with different sizes (from several
hundreds of nanometers to several millimeters, Figure 8) ex-
hibit the same lem,max value (484 nm) (comparing Figure 7b
and d).
Figure 5. Emission spectra of 6aa in ethanol-water (5:95) suspensions
(kept in an ultrasonic bath for 30 min) a) with 1.0ꢁ10ꢀ5 m and at different
temperatures (40, 35, 30 and 08C) and b) at 308C and with different con-
centrations (1.0ꢁ10ꢀ6, 1.0, 2.0, 4.0 and 5.0ꢁ10ꢀ5 m), excited at 350 nm.
formation of J-aggregate.[15–16,20,17] Compound 6aa in ethanol
is practically no emissive because the 50-fold enlarged emis-
sion spectrum of 6aa in ethanol is a noisy signal line (Fig-
ure 6b). However, the FF value of 6aa increases to 0.52
(Figure 6c) as the fw value is up to 95%. The emission spec-
tra of 6aa in crystals and in powder (gently ground crystals)
possess the same lem,max value as that in suspensions (com-
paring Figure 6b and d), which indicates that 6aa in bf-ag-
gregates shows SIE characteristics.
Figure 7. AIEE and SIE properties of 6aa in gf-aggregates. a) Absorption
spectra, b) emission spectra and c) relative quantum yields (FF) (with
DPA as standard, excited at 350 nm) of 6aa (1.0ꢁ10ꢀ5 m) in different fw
values of ethanol/water solutions and gf-suspensions (prepared at 08C
with ultrasonic stirring for 30 min); d) emission spectra of 6aa in gf-crys-
tals, gf-powder (ground gf-crystals) and gf-film spin-coating on quartz
plate. Insets in c are 6aa (1.0ꢁ10ꢀ5 m) in ethanol and gf-suspension (fw =
95%) under UV (350 nm), respectively. Insets in d (from top to bottom)
are 6aa in gf-crystals, gf-powder and gf-film under fluorescence micro-
scope (multiplied by 25-fold), respectively.
AIEE and SIE properties of 6aa in gf-aggregates: The opti-
cal properties of 6aa in gf-aggregates are similar to those in
bf-aggregates, except that lem,max is 484 nm (Figure 7). Obvi-
Figure 8. gf-aggregates of 6aa under scanning electron microscope. Parti-
cles in suspension with concentration a) 1.0ꢁ10ꢀ5 and b) 1.0ꢁ10ꢀ4 m, c)
film and d) crystals.
MSM of 6aa in bf-crystals: The MSM of 6aa in bf-crystals
(CCDC-818027[29]) is shown in Figure 9. The R- and S-enan-
tiomers of 6aa line along a axis as R-L and S-L, respectively,
and are paired with each other on bc plane with the H
atoms on the chiral carbon before/behind or behind/before
the central ring tetrahydropyrimidine forming R/S-S/R
stacking mode (Figure 9a). Compound 6aa in bf-crystals
shows a stereoconformation with three adjacent phenyls per-
pendicular from each other (Figure 9b). There are four in-
teractions between the adjacent molecules on bc plane (two
Figure 6. AIEE and SIE properties of 6aa in bf-aggregates. a) Absorp-
tion spectra, b) emission spectra and c) relative quantum yields (FF)
(with 1.0ꢁ10ꢀ5 m 9,10-diphenylanthracence, DPA, in ethanol FF =0.95 as
standard,[30] excited at 350 nm) of 6aa (1.0ꢁ10ꢀ5 m) in different water
fractions (fw) of ethanol/water solutions and bf-suspensions (prepared at
408C with ultrasonic stirring for 30 min); d) emission spectra of 6aa in
bf-crystals and bf-powder (gently ground bf-crystals). Insets in c are 6aa
(1.0ꢁ10ꢀ5 m) in ethanol and bf-suspension (fw =95%) under UV
(350 nm), respectively. Insets in d are 6aa in bf-crystals and bf-powder
under fluorescence microscope (multiplied by 25-fold), respectively.
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C-6 Unsubstituted Tetrahydropyrimidines
FULL PAPER
C-H···p 2.971 ꢂ, 1468, and two aryl C-H···p 2.837 ꢂ, 1488,
Figure 9c), and four interactions between the adjacent mole-
cules along the a axis (two aryl C-H···p 2.930 ꢂ, 1468 and
two aryl C-H···O 2.487 ꢂ, 1778, Figure 9d). The molecules
in R-L and S-L are arranged in head-to-tail direction via the
intermolecular interactions and form two parallel lines
(Schematically represented by two lines of arrows. Arrow
orientation: electron donor to acceptor.) (Figure 9d).
ure 10b). There are six interactions (two aryl C-H···O
2.579 ꢂ, 1368; two C-H···O 2.434 ꢂ, 1438 and two C-H···p
2.634 ꢂ, 1448, Figure 10c) between the adjacent molecules
in gf-crystals. The molecules in R-L and R-L (or S-L and S-
L) are arranged in head-to-tail J-aggregate via the intermo-
lecular interactions and form a zigzag line (Figure 10c).
MSM of 6aa in gf-crystals: The MSM of 6aa in gf-crystals
(CCDC-818026[29]) is different from that in bf-crystals. The
R- and R- (or S- and S-) enantiomers of 6aa line along the b
axis as R-L and R-L (or S-L and S-L), respectively, and
partly overlap with each other on ac plane forming R/R-S/S
stacking mode (Figure 10a). The molecular conformation of
6aa in gf-crystals is similar to that in bf-crystals (Fig-
Figure 10. gf-single-crystal of 6aa (CCDC-818026).[29] a) MSM viewed
down crystallographic b-axis. b) Molecular conformation. c) Interactions
between the adjacent molecules. (Schematically represented by a zigzag
line of arrows. Arrow orientation: electron donor to acceptor.)
Origin of blue and green fluorescent emission of 6aa in bf-
and gf-aggregates: The analysis of single-crystal X-ray dif-
fraction data indicates that the blue and green light-emitting
properties of 6aa result from different MSMs: R/S-S/R
mode for blue light emission (Figure 9a) and R/R-S/S modes
for green light emission (Figure 10a). Therefore, the proc-
esses of preparing the pure bf-aggregates, pure gf-aggregates
as well as bf- and gf-aggregate mixtures of 6aa under differ-
ent aggregation conditions (Scheme 2, Figures 4 and 5) are
practically the processes that alter the ratio of R/S-S/R and
R/R-S/S stacking modes. In other words, the MSMs of 6aa
in crystals and suspensions could be tuned by changing the
aggregation conditions. According to the exciton band
energy diagrams for molecular dimmers with in-line and ob-
lique transition dipoles,[31] respectively, the same molecular
aggregates with in-line transition dipoles should show red-
shift in emission spectrum with respect to that with zigzag
transition dipoles. However, the R/S-S/R stacking mode
(stacking in two parallel lines) shows blue-shift with respect
to R/R-S/S one (stacking in a zigzag line), which may be at-
Figure 9. bf-single-crystal of 6aa (CCDC-818027).[29] a) MSM viewed
down crystallographic a axis. b) Molecular conformation. c) Interactions
between the adjacent molecules on the bc plane. d) Molecular interac-
tions in R-L or S-L lining along the a axis (dotted bonds c and d) and
ones between R-L and S-L in c (dotted bonds a).
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Q. Zhu, H. Jiang, S. Liu et al.
tributed to the intermolecular interactions between the two
parallel lines (2.837 ꢂ bonds in Figure 9c and d) and ones
between adjacent lines (2.971 ꢂ bonds in Figure 9c).
Possible mechanism of thermodynamic and kinetic condi-
tions favoring the formation of the bf- and gf-aggregates of
6aa, respectively: There are eight interactions between adja-
cent molecules in the bf-aggregates (Figure 9c and d) but
six in the gf-aggregates (Figure 10c). This means that the bf-
aggregates might be more stable but formed more slowly in
the equilibrium of dissolution and precipitation than the gf-
aggregates. This means that the bf-aggregates are thermody-
namically favored while the gf-aggregates are kinetically fa-
vored.
Conclusion
We have developed efficient and simple five component re-
actions (5CRs) for the synthesis of C-6 unsubstituted tetra-
hydropyrimidine-4,5-dicarboxylates 6 that would be diffi-
cultly prepared through conventional methods owing to
steric hindrance and regioselectivity. Based on our previous
work and the experiment results reported here, we proposed
a possible mechanism for the 5CR, that is, hydroamination/
aza-ene-type reaction/nucleophilic addition/intramolecular
cyclization.
Moreover, we found that 6 exhibit important AIEE prop-
erties because they show practically no emission in solution
(FF,s !0) but strong emission in aggregates with FF,a up to
93% (6bb). To the best of our knowledge, only AIEE fluo-
rophore 4,4’-bis(1,2,2-triphenylvinyl)biphenyl (BTPE),[26a]
whose FF values in solution and in crystalline fibers (the FF
value of BTPE in suspension has not been reported in refer-
ence 26) are near zero and 100%, show higher AIEE effect
than 6bb does. Products 6 with aryl R2 and R4 show much
higher fluorescence efficiency than those with alkyl R2 and/
or R4. Since the 5CR yields for most of 6 with aryl R2 and
R4 range 47 to 63% that are higher than the overall yield
(41%) of a 4-step reaction with 80% per step, a library of 6
with high fluorescence efficiency could be built fast and effi-
ciently by taking the 5CR advantages of mild reaction con-
ditions, readily available reactants, operational simplicity
and potential ability in building structure diversity products.
One of the 5CR products, 6aa, was found to exhibit two
kinds of fluorescent aggregates, bf- and gf-aggregates. The
bf- and gf-aggregates of 6aa can be prepared under different
conditions (higher temperature and lower concentration for
the bf-aggregates but lower temperature and higher concen-
tration for the gf-aggregates). They belong to different J-ag-
gregates (two parallel lines with R/S-S/R MSM for bf-aggre-
gates and a zigzag line with R/R-S/S MSM for gf-aggre-
gates). The bf-aggregates are thermodynamically favored
but the gf-aggregates are kinetically favored. The particles
initially formed in suspension are the gf-particles that are
stable at 08C but would completely be converted to the bf-
aggregates at 408C in 30 min.
In addition, 6aa exhibits unusual SIE characteristics be-
cause the lem,max values of 6aa in different sizes (from sever-
al hundreds of nanometers to several millimeters) of bf- and
gf-aggregates, from suspension particles, powder, film (only
gf-one obtained) to crystals, are the same, 434 and 484 nm,
respectively. With the convenient 5CR synthetic method,
two easily condition-tuned J-aggregates, as well as the un-
usual AIEE and SIE properties, 6aa is expected to be very
useful in practical application and theoretical research on
the influence of aggregate size on emission.
The AIEE of 6 and the SIE characteristics of 6aa may be
attributed to i) the high flexible structures (the three phenyls
of 6 are not conjugated with each other and connected to
the non-aromatic tetrahydropyrimidine ring via single
bonds); ii) the asymmetric stereostructure (the three phenyls
adjacently are connected to the chiral tetrahydropyrimidine
AIEE mechanism of 6: According to the experimental re-
sults mentioned above, the AIEE property of 6 may result
from their special structure and J-aggregation. Since the
three phenyls of 6 are not conjugated with each other and
ꢀ
ꢀ
connected to a non-aromatic central ring via C C or C N
single bonds, they could rotate freely in monomer (in solu-
tion), which deactivates the corresponding excited states.
This makes 6 non-emissive in solution. The strong fluores-
cence emission of 6 in aggregates should be attributed to its
asymmetric stereo molecule structure (Figure 9b and 10b)
efficiently preventing p–p stacking as well as J-aggregation
(Figure 9d and 10c) restricting intramolecular rotation[32,26b]
and forming intermolecular charge transfer states.[15–16,25,17]
Possible SIE mechanism of 6aa: Yaoꢃs et al. has shown that
the first excited singlet state (S1) and extended charge-trans-
fer states of 1-phenyl-3-((dimethylamino)styryl)-5-((dime-
thylamino)phenyl)-2-pyrazoline (PDDP) in monomer and in
aggregate, respectively, are in equilibrium in particles. They
proposed that the fluorescence from S1 increased with de-
creasing particle size.[25] According to their deduction, the
emission spectrum of an AIEE fluorophore should show in-
dependence of aggregate size because its monomer is none-
missive, similar to 6aa. However, many AIEE fluorophores
show a size-dependent emission feature.[19a,20,26] If one con-
siders that the molecular conformations correlate with emis-
sion wavelengths[33] and that the conformations of molecules
in monomer, crystalline aggregate surface and inner region
should differ from each other, then the emission spectrum
of an organic fluorophore should be the mixture of the
three types of molecules. Since the ratios of the surface and
inner molecules in crystalline aggregates correlate with ag-
gregate sizes, organic fluorophores often show size-depend-
ent emission properties. If an AIEE fluorophore shows the
SIE feature, as for 6aa, the surface molecules in crystalline
aggregates are expected to be nonemissive; if one shows
size-dependent emission properties, the surface molecules
might be expected to be emissive. The non-emission of the
surface molecules in the bf- and gf-crystalline aggregates
may result from the high flexible and asymmetric stereo
structure of 6aa.
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C-6 Unsubstituted Tetrahydropyrimidines
FULL PAPER
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gregation.
Further investigations into the mechanism leading to the
SIE characteristic, the influences of molecular structure on
MSM and the practical applications of the new 5CR prod-
ucts are under way in our laboratory.
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Experimental Section
General: All melting points were taken on a XT-4 micro melting point
apparatus and are uncorrected. 1H NMR (400 MHz) and 13C NMR
(100.6 MHz) spectra were recorded using a Bruker Avance 400 MHz
NMR spectrometer and referenced to 7.24 and 77.0 ppm for CDCl3 with
TMS as internal standard, respectively. Mass spectra were recorded on
an API 4000QTRAP. IR spectra were obtained as potassium bromide
pellets or as liquid films on potassium bromide pellets with a Bruker
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fected at 254 and 365 nm. Photos were taken by Canon PC1356 under
UV 365 nm, by fluorescence microscope (LEICA, DMIRB, Germany) or
by scanning electron microscope (S-3000N, Germany). UV-visible ab-
sorption spectra were recorded on a TU-901. Emission spectra were re-
corded on a Shimadzu RF5301PC spectrofluorophotometer (slit widths
for crystals and suspensions: 3 and 3 nm; for spin-coated film: 5 and
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General procedure for the synthesis of 6: Reaction mixture A (1 mmol of
1 and 1 mmol of 2 in 0.5 mL of MeOH kept for 10–30 min), 3 (3.5 mmol)
and urea (0.2 mmol) were added into reaction mixture B (3.5 mmol of 4,
1.4 mmol of 38% 5 and 4 mmol of AcOH in 3 mL of MeOH kept for
10 min) in sequence, followed with stirring for desired time (monitored
by TLC). The addition of CH2Cl2 (0.5 mL) in reaction mixture B was
needed to increase the intermediate solubility and the 5CR yield if the
5CR intermediate would precipitate. After the completion of the 5CR,
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ethyl acetate (10:1–1:1) as eluent to afford the desired products 6 in 21–
63% yield.
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Preparation of 6aa in bf- and gf-crystals: The bf- and gf-crystal of 6aa
were obtained via the crystallization of 6aa in dichloromethane/n-hexane
(1:20) solutions under different conditions. Conditions for bf-crystals:
10ꢀ2 m, ꢁ 288C; 88C, ꢂ 10ꢀ3 m; or adding bf-crystals in 6aa solutions (10ꢀ1
to 10ꢀ3 m, ꢀ20 to 288C). Conditions for gf-crystals: 10ꢀ2 m, ꢂ88C; 88C,
ꢁ10ꢀ2 m; or adding gf-crystals in 6aa solutions (10ꢀ1 to 10ꢀ3 m, ꢀ20 to
288C).
Preparation of 6aa in ethanol/water suspensions: Distilled water was
slowly injected into a 10 mL of volumetric flask containing 0.1 mL of 6aa
stock ethanol solution (1.0ꢁ10ꢀ3 m), certain volume of ethanol and
0.5 mL of distilled water at certain temperature (408C for bf-suspensions
and 08C for gf-suspensions) under ultrasonic stirring, filling the flask to
point the mark with distilled water, and followed with ultrasonic stirring
for certain time.
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Received: August 24, 2012
Published online: November 29, 2012
1280
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