Synthesis, structure, and one- and two-photon absorption properties of N-substituted 3,5-bisarylidenepropenpiperidin-4-ones

Article abstract of DOI:10.1016/j.molstruc.2012.12.034

A series of 3,5-bisarylidenepropenpiperidin-4-one compounds with a D-π-A-π-D structure, containing donors (R¹ = NEt₂, NMe₂) and terminal groups at the central nitrogen ring atom (R ² = H, Me, Et, P(O)(OEt)₂) was synthesized with the goal of improving one- and two-photon absorption properties of the earlier designed compounds, which potential activity as photosensitizers was demonstrated with appeal of biological and spectroscopic data. Several of the compounds studied have a two photon absorption cross section approximately six times larger than previously measured for 3,5-bisarylidenemethylenpiperidin-4-ones with short alkene chains. Spectral data are discussed in connection with structural characteristics of studied materials.

Full text of DOI:10.1016/j.molstruc.2012.12.034

Journal of Molecular Structure 1037 (2013) 288–293
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, structure, and one- and two-photon absorption properties
of N-substituted 3,5-bisarylidenepropenpiperidin-4-ones
Evgeniya S. Leonova a, Nikolay S. Makarov b, Alexandr Fonari a, Rachael Lucero a, Joseph W. Perry b,
David M. Sammeth a, Tatiana V. Timofeeva a,
⇑
a New Mexico Highlands University, Las Vegas, NM 87701, USA
b School of Chemistry and Biochemistry and Center for Organic Photonics and Electronics, Georgia Institute of Technology, Atlanta, GA 30332, USA
h i g h l i g h t s
"
"
"
"
A series of 3,5-bisarylidenepropenpiperidin-4-one compounds was synthesized as possible sensitizers for photodynamic therapy.
Their potential applicability as photosensitizers was proved by measurements of their one- and two-photon absorption spectra.
For two compounds TPA cross sections is at least six times larger than for earlier synthesized 3,5-bis(arylidene)piperidin-4-ones.
Spectral data are discussed in connection with structural characteristics of studied materials.
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3,5-bisarylidenepropenpiperidin-4-one compounds with a D–p–A–p–D structure, containing
donors (R1 = NEt2, NMe2) and terminal groups at the central nitrogen ring atom (R2 = H, Me, Et,
P(O)(OEt)2) was synthesized with the goal of improving one- and two-photon absorption properties of
the earlier designed compounds, which potential activity as photosensitizers was demonstrated with
appeal of biological and spectroscopic data. Several of the compounds studied have a two photon absorp-
tion cross section approximately six times larger than previously measured for 3,5-bisarylidenemethy-
lenpiperidin-4-ones with short alkene chains. Spectral data are discussed in connection with structural
characteristics of studied materials.
Received 2 November 2012
Received in revised form 17 December 2012
Accepted 17 December 2012
Available online 5 January 2013
Keywords:
3,5-Bis(arylidene)piperidin-4-one
One-photon absorption
Two-photon absorption
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
the strong electron donors in the 1,5-diaryl-3-oxo-1,4-pentadienyl
pharmacophore converts 3,5-bis(arylidene)piperidinones into the
For
a
,b-unsaturated ketones, the key position is occupied by
compounds with considerable one- and two-photon absorptions
and therefore possible sensitizers [15] for photodynamic therapy
(PDT). In addition to appropriate light absorption characteristics,
potential photosensitizers should exhibit high stability, absorption
in the near IR region, high extinction coefficients and negligible
photobleaching. Compounds which can be used for PDT currently
include push–pull olefins [16], various porphyrin derivatives [17],
conjugated polymers [18] and dendrimers [19]. 3,5-Bis(arylid-
ene)piperidinones present a unique class of compounds to further
investigations in the development of PDT sensitizers.
Based on quantum-chemical computations [20], it was sug-
gested that molecules with elongated methylene chains between
donor and acceptor group should manifest higher one-photon
absorption (OPA) and two-photon absorption (TPA) properties
and consequently higher phototoxic activity. Several such com-
pounds were previously synthesized [15] and studied. These com-
pounds demonstrated low fluorescence quantum yields and short
fluorescence lifetime, suggesting that there might be significant
3,5-bis(arylidene)piperidinones [1,2]. There is significant interest
in these molecules due to their noticeable affinity toward thiols
in cells. This is observed both in vitro and in vivo with little or
no affinity toward the hydroxyl and amino groups found in nucleic
acids [3–5]. Previously these compounds have been shown to be
Mannich bases due to the structure of the 1,5-diaryl-3-oxo-1,4-
pentadienyl pharmacophore (Fig. 1, 1blue line), which interacts
with cellular constituents [6–8] and allows them to display selective
toxicity to neoplasms but not to corresponding normal cells [9].
Initial studies of these compounds show their antitumor
[10,11], antiviral [12], anti-tuberculosis [13] and anti-inflamma-
tory activities [14]. In addition, it was found, that the presence of
⇑
Corresponding author.
E-mail address: tvtimofeeva@nmhu.edu (T. V. Timofeeva).
For interpretation of color in Fig. 1, the reader is referred to the web version of
1
this article.
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.12.034

E.S. Leonova et al. / Journal of Molecular Structure 1037 (2013) 288–293
289
The NHA derivative of 3,5-bis(arylidene)piperidin-4-one
(Me2NPh)2prPH was phosphorylated by diethyl chloridophos-
phate under basic conditions. Chloroform was chosen as solvent,
providing good solubility of both starting material and product.
As it turned out, the strength of triethylamine as a base was opti-
mal for the transformation and resulted in a yield of 65%. The
chemical structures of synthesized products were confirmed by
NMR, mass-spectroscopy, IR and single crystal X-ray analysis.
O
R1
R1
n
n
N
R2
(R1Ph)2 prPR2
Fig. 1. General structure of the 3,5-bis(arylidene)piperidinones.
2.2. Molecular and structural properties of 3,5-
bisarylidenepropenpiperidin-4-ones
excited triplet state formation. Both dark cytotoxicity and photo-
toxicity toward A549 (lung), HepG2 (liver), Cal27 (tongue), MCF-
7 (breast) and C4–2 (prostate) cancer cell lines were measured.
The highest phototoxicity/cytotoxicity ratio was found for a com-
pound with elongated methylene chain. These preliminary studies
provided the direction and motivation for improving the photosen-
sitive properties 3,5-bis(arylidene)piperidinones. As a continuation
of the previous work here we present synthesis and characteriza-
tion of substituted 3,5-bisarylidenepropenpiperidin-4-ones with
general formula (R1Ph)2prPR2, where R1 – donor groups attached
to phenyl ring (R1 = NEt2, NMe2), R2 – substituents at the N atom
of the central acceptor piperidone core (R2 = H, Me, Et, P(O)(OEt)2),
P – peperidone and pr – propene (n = 1), linker between donor and
acceptor fragments (Fig. 1). This formula gives the foundational
molecular structure and will be referenced in the discussions be-
low. The spectroscopic and structural characteristics of all new
materials are presented and discussed within the context of future
applications.
Of the series of synthesized compounds we were able to crystal-
lize one of them (Me2NPh)2prPEt using methylene chloride and
diethyl ether (slow diffusion). Structural characterization of
(Me2NPh)2prPMe and (Et2NPh)2prPMe were presented in
previous publications [23,24]. The compound (Me2NPh)2prPNEt
crystallizes in monoclinic space group C2/c. To characterize planar-
ity of this type of molecules, three almost planar fragments A, B
and C (see Supplementary materials) can be considered (Figs. 2,
3). The piperidone ring adopts flattened boat conformation with
dihedral angle of C2–N–C6 with plane A (C2 ? C6) equal to 57.07°.
The bond-length distributions in the conjugated bridges defi-
nitely show an alternation of single and double bond lengths. In
the aromatic rings we observe bond lengths distribution which
indicates its qunoid character (Table S1). The dihedral angle be-
tween fragments A and B is 12.82° and between fragments A and
C is 19.47°. This deviation from planarity is significantly larger than
in case of relative piperidone molecules, presented in Table S3 (see
Supplementary .aterials), including two with short alkene chain
(Et2NPh)2PMe and (Me2NPh)2PEt [23]. It is possible to see, that
the deviation from planarity in the molecules with ethyl substi-
tutes in the phenyl rings is less significant.
2. Results and discussion
2.1. Chemistry
The synthesis of substituted 3,5-bisarylidenepropenpiperidin-4-
ones (R1Ph)2prPR2 was carried out by earlier developed procedure
utilizing aldol condensation between aldehydes 3a,b and N-deriv-
atives of piperidin-4-ones 1, 2a,b [21] (Scheme 1). For a catalyst we
used strong Lewis acid (BF3ꢀEt2O) in acetonitrile, which resulted in
the products as BF4 salts, facilitate the separation of desired prod-
ucts as clear solid material due to differences in solubility of the
starting materials and the products. The salts were neutralized
without further characterization. Derivatives of 3,5-bisarylid-
enepropenpiperidin-4-ones, (R1Ph)2prPR2, were obtained with
high yields presented in Scheme 1.
2.3. One- and two-photon absorption and fluorescence spectra
OPA, TPA and emission spectra of (Me2NPh)2prPR2 were measured
in toluene (Figs. 4a, 5a), while DMF was used for (Et2NPh)2prPR2
compounds for better solubility (Figs. 4b, 5b). Table 1 summarizes
photophysical properties of the compounds. TPA cross sections
were also measured in chloroform for both (Me2NPh)2prPR2 and
(Et2NPh)2prPR2 series, though poor sample stability in chloroform
restrain us from quantitative comparison. Nevertheless, (Me2NPh)2
prPR2 samples dissolved in chloroform show larger cross sections
compared to samples in toluene, which suggests that the cross sec-
tions are influenced by solvent polarity (see Fig. 5).
It is well known that the phosphorylation is used to improve
drug delivery, as well as cytotoxicity [22]. The compound
(Me2NPh)2prPP(O)(OEt)2 was synthesized (Scheme 2) to estimate
phosphorus’s influence on the properties of the these materials.
All compounds have the absorption maxima near 500 nm. The
maxima of dimethylamino-derivatives, (Me2NPh)2prPR2, are in
the range of 465–475 nm, while the diethylamino-derivatives,
O
O
O
.
BF3 Et2O
CH3CN
N
R'
N
R
R'
R'
R
(Me2NPh)2 pr PMe, 93%
(Et2NPh)2 pr PMe, 92%
(Me2NPh)2 pr PEt, 86%
(Et2NPh)2 pr PEt, 90%
(Me2NPh)2 prPH, 88%
(Et2NPh)2 pr PH, 91%
1, 2a,b
3a,b
R = Me (1), Et (2a), H.HCl.H2O (2b)
R' = NMe2 (3a), NEt2 (3b)
Scheme 1.

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E.S. Leonova et al. / Journal of Molecular Structure 1037 (2013) 288–293
O
O
ClP(O)(OEt)2
NEt3
Me
N
P
Me
Me
N
Me
Me
O
O
O
(Me2NPh)2prPP(O)(OEt)2
Scheme 2.
O
N
the change of the substituents at the central ring. Their cross sec-
tions are larger than that for the (Me2NPh)2prPR2 compounds. This
observation can be linked with structural characteristic of these
molecules, which shows that molecules with ethyl substituents
(Et2NPh)2prPR2 have greater planarity. The only exception is
(Et2NPh)2prPH, which has lower cross sections due to lower
extinction coefficient value. This lower extinction is most likely
an artifact of our measurements as the sample begins to decom-
pose in the solution right away, which results in a reduced value.
This decomposition is thought to be due to either sensitivity
toward light and polar solvents or possibly free-radical induced
oxidation and reduction [25].
11
11'
9'
9
7
7'
10
4
10'
12'
12
5
3
8
8'
2
6
15'
15
N 13'
N
13
14
14'
B
A
C
Fig. 2. Planar fragments in 3,5-bisarylidenepropenpiperidin-4-one (Me2NPh)2prPNEt
molecule.
As it was stated earlier, our goal was to optimize TPA properties
of the previously studied 3,5-bis(arylidene)piperidin-4-ones [20]
so as to make them possible candidates for two photon photody-
namic therapy. TPA activity of 3,5-bis(arylidene)piperidin-4-ones
was measured in between 740 and 860 nm, and the maximum
cross-section was found to be ꢁ300 GM [15]. All the (R1NPh)2prPR2
compounds showed larger cross sections, and the greatest value,
ꢁ1900 GM for (Et2NPh)2prPEt, is six times greater than the
published values. This cross section value is comparable with
porphyrin derivatives used as two-photon sensitizers for TPA laser
treatment of mice tumors located on depth of 2 cm [26,27].
Emission spectra of the compounds are shown in Fig. 5. For the
(Me2NPh)2prPR2 compounds, the emission peak is around 540 nm,
except for the phosphorus-containing sample, which is 15 nm red-
shifted relative to the other samples, similar to its red-shift in OPA.
The (Et2NPh)2prPR2 compounds show similar spectra with the peaks
at 670 nm. The fluorescence quantum yields are rather low, ranging
from 0.05 for (Et2NPh)2prPH to 0.12 for (Me2NPh)2prPP(O)(OEt)2.
The quantum yields are the smallest for the H-substitutients at
the central ring and slightly larger for the other substituents.
Fig. 3. ORTEP plot of (Me2NPh)2prPEt with the numbering scheme in projection on
the best plane. Thermal ellipsoids are shown with 50% probability level. Hydrogen
atoms are drawn as circles of arbitrary small radii for clarity.
(Et2NPh)2prPR2, have a slightly red-shifted absorption maxima
near 460–500 nm. This slight red-shift is expected because of high-
er electron donating properties of diethylamino group. Notably the
substituent at the piperidone nitrogen atom almost do not affect
absorption spectra and extinctions, except for a small red-shift in
maximum of the (Me2NPh)2prPP(O)(OEt)2 compound. The maxi-
mum
extinction
coefficients
are
all
approximately
ꢁ6 ꢂ 105 Mꢃ1 cmꢃ1
.
TPA spectra of the (Me2NPh)2prPR2 compounds show similar
line shapes, independent on the substituents at nitrogen central
core atom. The peak cross sections, however, vary in the series,
monotonically decreasing as R2 goes from H to Me and Et. For
the phosphorus-containing sample, though, the peak cross section
is almost the same as for the (Me2NPh)2prPH. In case of the
(Et2NPh)2prPR2 samples, the TPA spectra also do not vary with
3. Experimental details
3.1. Materials and general methods
NMR spectra were measured with a Bruker AMX-300 spectrom-
eter using residual proton signals of deuterated solvent as an inter-
nal standard (1H, 13C) and H3PO4 31P) as an external standard.
(
Table 1
Photophysical properties of the synthesized compounds.
Compound
kmax*, nm
emax*, Mꢃ1cmꢃ1
kFL
u
kTPA,max
r2, GM
(Me2NPh)2prPH
(Me2NPh)2prPMe
(Me2NPh)2prPEt
(Me2NPh)2prPP(O)(OEt)2
(Et2NPh)2prPH
482
484
491
496
472
508
503
5.60 ꢂ 105
7.65 ꢂ 105
5.39 ꢂ 105
6.54 ꢂ 105
3 ꢂ 105**
550
540
540
555
675
675
675
0.09
0.11
0.10
0.12
0.05
0.07
0.07
810
820
820
820
890
890
890
490
450
380
520
850**
1640
1880
(Et2NPh)2prPMe
(Et2NPh)2prPEt
5.55 ꢂ 105
6.36 ꢂ 105
*
kmax (peak OPA wavelength) and emax (peak extinction coefficient) are shown in DMF for all compounds.
(Et2NPh)2prPH tend to decompose in solution, therefore, even when its extinction is measured right after synthesis, it still shows lower value compared to the other
**
compounds.

E.S. Leonova et al. / Journal of Molecular Structure 1037 (2013) 288–293
291
1PA transition wavelength, nm
300 325 350 375 400 425 450 475 500 525 550 575 600
1PA transition wavelength, nm
7x104
6x104
5x104
4x104
3x104
2x104
300 325 350 375 400 425 450 475 500 525 550 575 600
2000
1800
1600
1400
1200
1000
800
8x104
7x104
6x104
5x104
4x104
3x104
2x104
600
500
400
300
200
100
0
(Et NPh) pr PH
(Et22NPh)22pr PMe
(Et2NPh)2pr PEt
2PA;
2PA;
2PA;
1PA
1PA
1PA
(Me NPh)2 pr PH
2PA;
2PA;
2PA;
2PA;
1PA
1PA
1PA
1PA
b
(Me2NPh) pr PMe
(Me2NPh)2 pr PEt
a
(Me22NPh)22 pr PP(O)(OEt)2
600
400
1x104
1x104
200
0
0
0
600 650 700 750 800 850 900 950 1000 1050 1100 1150 1200
2PA laser wavelength, nm
600 650 700 750 800 850 900 950 1000 1050 1100 1150 1200
2PA laser wavelength, nm
Fig. 4. One-photon (lines) and two-photon absorption spectra of the compounds studied (a) (Me2NPh)2prPR2, in toluene, (b) (Et2NPh)2prPR2, in DMF.
1.2x10-3
1.0x10-3
8.0x10-4
6.0x10-4
4.0x10-4
6.0x10-4
5.0x10-4
4.0x10-4
3.0x10-4
2.0x10-4
1.0x10-4
0.0
a
b
(Me2NPh)2prPH
2.0x10-4
0.0
(Me NPh) prPMe
(Et NPh) pr PH
(Et2NPh)22 pr PMe
(Et22NPh)2 pr PEt
(Me2NPh)22prPEt
(Me22NPh)2prPP(O)(OEt)2
500
550
600
650
700
550
600
650
700
750
800
Wavelength, nm
Wavelength, nm
Fig. 5. Emission spectra of the studied compounds: (a) (Me2NPh)2prPR2; (b) (Et2NPh)2prPR2. Relative to the fluorescence standard Rhodamine 6G, in methanol.
Analytical TLCs were performed with Sorbent Technologies Silica G
TLC plates w/UV254. IR spectra were recorded with KBr pellets on a
‘‘Magna-IR™00 (Nicolet), resolution 6 cmꢃ1, 17 scans. UV spectra
were recorded with UV–visible spectrophotometer HP 8452. Fluo-
rescence spectra were recorded with RF-5301PC spectrofluoropho-
tometer Shimadzu. Fluorescence spectra were collected with the
excitation wavelength set to 490 nm, and the fluorescence quan-
tum yields were measured relative to Rhodamine 6G.
Commercial available initial aldehydes 3 a,b and substituted
piperidin-4-ones 1,
2
a,b were used without additional
purification.
3.2. (3E,5E)-3,5-bis[(2E)-3-(arylidene)prop-2-en-1-ylidene]-1-
methylpiperidin-4-one (General procedure)
Boron trifluoride etherate (4 mmol) was added to a solution of
the corresponding aldehyde 3 a,b (2 mmol) and 4-piperidone 1, 2
a,b (1 mmol) in 1 mL of CH3CN. The mixture was keep overnight.
After chilling the mixture to ambient temperature, the precipitate
was filtered off and recrystallized from MeOH to give the final 3,5-
bisarylidenepropenpiperidin-4-ones as a tetrafluoroborate salts.
The salts were neutralized with 5% water solution of NaHCO3 by
addition of solid material to the above mentioned solution. The ob-
tained precipitates were dried under pressure.
The TPA spectra of (Me2NPh)2prPR2 in toluene solution and
(Et2NPh)2prPR2 in DMF solution were measured over a broad
spectral region using a double-arm two-photon-excited fluores-
cence (2PEF) method [28] relative to Rhodamine 6G in methanol
[29]. The 2PA spectra were also measured in chloroform, however,
photochemical stability of the samples in this solvent was poor.
Freshly prepared samples were excited using vertically polarized
light from a tunable femtosecond (fs) optical parametric amplifier
(TOPAS-C, Spectra-Physics). The relative 2PEF signal of the sample
versus the standard was recorded as a function of excitation wave-
length, using 90° detection geometry and an imaging spectrometer
(Acton SpectraPro-150). The spectra were scaled to the TPA cross
section measured at the selected wavelength of 820 nm, using
Rhodamine 6G in methanol as a Ref. [15] for (Me2NPh)2prPR2,
and 950 nm using LDS-698 in chloroform as a Ref. [21] for
(Et2NPh)2prPR2.
3.3. (3E,5E)-3,5-bis{(2E)-3-[4-(dimethylamino)phenyl]prop-2-en-1-
ylidene}-1-methylpiperidin-4-one ((Me2NPh)2prPMe)
Purple crystalline solid, Mp 194–196 °C. Yield 93%. IR (KBr, n
cmꢃ1): 2929, 2896, 2798 (dimethylamino group vibration), 1650
(C@O), 1593 (C@C), 1572, 1519, 1446, 1364, 1327, 1295, 1229,
1189, 1156, 1119, 1086, 1062, 972, 943, 809. 1H NMR (CDCl3), d,

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E.S. Leonova et al. / Journal of Molecular Structure 1037 (2013) 288–293
ppm: 2.56 (s, 3H, Me), 3.02 (s, 12H, 2NMe2), 3.63 (s, 4H,
1475, 1442, 1360, 1324, 1299, 1287, 1229, 1187, 1156, 1123,
cyclicN(CH2)2), 6.68 (d, 4H, 3JHH = 9.1 Hz), 6.73 (d, 1H, 3JHH = 11.9 Hz,
1058, 968, 944, 841, 809. 1H NMR (CDCl3), d, ppm: 3.02 (s, 12H,
3
3
3
CH), 6.78 (d, 1H, JHH = 11.9 Hz, CH), 6.93 (d, 2H, JHH = 15.3 Hz,
2NMe2), 4.01 (s, 4H, cyclicN(CH2)2), 6.68 (d, 4H, JHH = 9.1 Hz), 6.75
3
3
3
3
CH), 7.41 (d, 4H, JHH = 8.9 Hz), 7.48 (d, 2H, JHH = 11.5 Hz, CH).
High resolution mass spectr, m/z calc. for C28H33N3O 428.2702.
Found, 428.2707.
(d, 1H, JHH = 11.7 Hz, CH), 6.80 (d, 1H, JHH = 11.7 Hz, CH), 6.93
3
3
(d, 2H, JHH = 15.1 Hz, CH), 7.41 (d, 4H, JHH = 8.9 Hz), 7.47 (d, 2H,
3JHH = 11.5 Hz, CH). 13C NMR (CDCl3), d, ppm: 40.40 (2NMe2),
46.67 (C2, C6), 112.20 (C12, C14, C12’, C14’), 118.56 (C8, C8’), 124.89
(C9, C9’), 128.99 (C11, C15, C11’, C15’), 131.59 (C10, C10’), 136.05 (C7,
C7’), 142.63 (C3, C5), 151.14 (C13, C13’), 186.69 (C4). High resolution
mass spectr, m/z calc. for C27H31N3O 414.2545. Found, 414.2548.
3.4. (3E,5E)-3,5-bis{(2E)-3-[4-(diethylamino)phenyl]prop-2-en-1-
ylidene}-1-methylpiperidin-4-one ((Et2NPh)2prPMe)
Purple crystalline solid, Mp 218–220 °C. Yield 92%. IR (KBr, n
cmꢃ1): 2970, 2925, 2896 (diethylamino group vibration), 1659
(C@O), 1593 (C@C), 1565, 1524, 1467, 1409, 1373, 1352, 1299,
1266, 1225, 1197, 1156, 1078, 1004, 976, 952, 812. 1H NMR
(CDCl3), d, ppm: 1.16 (m, 12H, 2 N(CH2CH3)2), 3.14 (s, 3H, Me),
3.25–4.48 (m, 8H, 2 N(CH2CH3)2), 4.30 (s, 4H, cyclicN(CH2)2), 6.47
3.8. (3E,5E)-3,5-bis{(2E)-3-[4-(diethylamino)phenyl]prop-2-en-1-
ylidene}piperidin-4-one ((Et2NPh)2prPH)
Brown crystalline solid, Mp 174–176 °C. Yield 91%. After separa-
tion additional purification was used, particularly column chroma-
tography in spectrophotometric grade acetonitrile. Yield (after
column) 34%. IR (KBr, n cmꢃ1): 2970, 2929, 2893 (diethylamino
group vibration), 1659 (C@O), 1610 (C@C), 1597, 1565, 1520,
1446, 1397, 1372, 1352, 1299, 1266, 1189, 1152, 1082, 1009,
3
(d, 4H, JHH = 9.1 Hz), 6.56–6.69 (m, 2H, CH), 6.98 (d, 2H,
3
3JHH = 14.7 Hz, CH), 7.29 (d, 4H, JHH = 9.4 Hz), 7.62 (d, 2H,
3JHH = 12.1 Hz, CH). High resolution mass spectr, m/z calc. for
C32H41N3O 484.3328. Found, 484.3338.
3
964, 841, 805. 1H NMR (DMSO-d6), d, ppm: 1.10 (t, 3H, JHH = 9.0 -
3.5. (3E,5E)-3,5-bis{(2E)-3-[4-(dimethylamino)phenyl]prop-2-en-1-
ylidene}-1-ethylpiperidin-4-one ((Me2NPh)2prPEt)
Hz, NCH2CH3), 3.33–3.44 (m, 2H, NCH2CH3), 4.23 (s, 4H,
cyclicN(CH2)2), 6.68 (d, 4H, 3JHH = 8.9 Hz), 6.90 (d, 1H, 3JHH = 11.9 Hz,
3
3
CH), 6.95 (d, 1H, JHH = 11.9 Hz, CH), 7.08 (d, 2H, JHH = 14.9 Hz,
3
3
Red crystalline solid, Mp 186–188 °C. Yield 86%. IR (KBr, n
cmꢃ1): 2897, 2856, 2803 (dimethylamino group vibration), 1655
(C@O), 1593 (C@C), 1564, 1524, 1478, 1442, 1364, 1328, 1291,
1234, 1185, 1156, 1123, 1087, 1066, 948, 813. 1H NMR (CDCl3),
CH), 7.38 (d, 2H, JHH = 12.0 Hz, CH), 7.42 (d, 4H, JHH = 9.0 Hz).
High resolution mass spectr, m/z calc. for C31H39N3O 470.3171.
Found, 470.3186.
3
d, ppm: 1.27 (t, 3H, JHH = 7.2 Hz, NCH2CH3), 2.75–2.85 (m, 2H,
3.9. Diethyl ((3E,5E)-3,5-bis{(2E)-3-[4-(dimethylamino)phenyl]prop-
2-en-1-ylidene}-4-oxopiperidin-4-one ((Me2NPh)2prPP(O)(OEt)2)
NCH2CH3), 3.03 (s, 12H, 2NMe2), 3.86 (s, 4H, cyclicN(CH2)2), 6.68
3
3
(d, 4H, JHH = 8.9 Hz), 6.73 (d, 1H, JHH = 11.9 Hz, CH), 6.78 (d, 1H,
3JHH = 11.9 Hz, CH), 6.97 (d, 2H, JHH = 14.9 Hz, CH), 7.42 (d, 4H,
To a mixture of the corresponding 3,5-bis{(2E)-3-[4-(dimethyl-
amino)phenyl]prop-2-en-1-ylidene}piperidin-4-one (Me2NPh)2prPH
(0.9 mmol) and triethylamine (2.2 mmol) in dry tetrahydrofuran
(7 ml) a solution of corresponding chlorophosphate (1.8 mmol) in
dry tetrahydrofuran (3 ml) was added. The reaction mixture was stir-
red at room temperature for over 5 h. The course of reaction was mon-
itored by TLC or NMR as appropriate. After completion of the reaction,
the mixture was evaporated at reduced pressure, dissolved in CH2Cl2
and washed with water. The organic layer was separated, evaporated
at reduced pressure and purified by column chromatography on SiO2
(THF as an eluent). The appropriate fractions were evaporated under
reduced pressure to give the final product. Brown crystalline solid
was obtained, Mp > 350 °C (decomposition). Yield 65%. IR (KBr, n
cmꢃ1): 2382, 2341, 2292 (diethylamino group vibration), 1740,
1732, 1699 (C@O), 1687 (C@C), 1655, 1622, 1597, 1573, 1544, 1519,
1393, 1364, 1287, 1225, 1176, 1152, 1103, 968, 944, 833, 801. 1H
3
3JHH = 8.9 Hz), 7.55 (d, 2H, JHH = 11.7 Hz, CH). 13C NMR (DMSO-
3
d6), d, ppm: 10.69 (NCH2CH3), 40.35 (2NMe2), 51.10 (C2, C6),
51.64 (NCH2CH3), 112.18 (C12, C14, C12’, C14’), 118.26 (C8, C8’),
124.16 (C9, C9’), 129.84 (C11, C15, C11’, C15’), 131.00 (C10, C10’),
144.89 (C3, C5), 151.53 (C7, C7’), 154.67 (C13, C13’), 193.91 (C4). High
resolution mass spectr, m/z calc. for C29H35N3O 442.2858. Found,
442.2858.
3.6. (3E,5E)-3,5-bis{(2E)-3-[4-(diethylamino)phenyl]prop-2-en-1-
ylidene}-1-ethylpiperidin-4-one ((Et2NPh)2prPEt)
Purple crystalline solid, Mp > 300 °C (decomposition). Yield
90%. IR (KBr, n cmꢃ1): 2962, 2929 (diethylamino group vibration),
1650 (C@O), 1626 (C@C), 1597, 1569, 1524, 1401, 1356, 1303,
1262, 1193, 1152, 1115, 980, 956, 813. 1H NMR (DMSO-d6), d,
3
3
4
ppm: 1.09 (t, 12H, JHH = 7.2 Hz, 2 N(CH2CH3)2), 1.15 (t, 3H,
NMR (CDCl3), d, ppm: 1.17 (t, 6H, JHH = 7.0 Hz, JHP = 0.8 Hz,
P(O)(OCH2CH3)2), 2.96 (s, 12H, 2NMe2), 3.78–3.96 (m, 4H, P(O)(OCH2-
CH3)2), 4.26 (d, 3JHP = 9.3 Hz, 4H, cyclicN(CH2)2), 6.70 (d, 4H, 3JHH = 9.1 -
3JHH = 6.0 Hz, NCH2CH3), 3.34–3.45 (m, 2H, NCH2CH3, NCH2CH3),
3
4.02 (s, 4H, cyclicN(CH2)2), 6.64 (d, 4H, JHH = 9.0 Hz), 6.84–7.01
(m, 4H, 2CH), 7.22 (d, 4H, 3JHH = 12.0 Hz), 7.45 (d, 4H, 3JHH = 9.0 Hz).
13C NMR (DMSO-d6), d, ppm: 13.11 (N(CH2CH3)2, NCH2CH3), 44.36
Hz), 6.88 (d, 1H, JHH = 11.7 Hz, CH), 6.93 (d, 1H, JHH = 11.5 Hz, CH),
3
3
3
3
7.04 (d, 2H, JHH = 15.1 Hz, CH), 7.27 (d, 2H, JHH = 11.7 Hz, CH), 7.51
(N(CH2CH3)2), 51.65 (NCH2CH3), 53.37 (C2, C6), 111.82 (C12, C14
,
(d, 4H, JHH = 9.1 Hz). 31P NMR (CDCl3), d, ppm: 8.11. High resolution
3
C12’, C14’), 118.56 (C8, C8’), 123.94 (C9, C9’), 130.03 (C11, C15, C11’,
C15’), 130.59 (C7, C7’), 135.98 (C10, C10’), 142.91 (C3, C5), 148.80
(C13, C13’), 185.43 (C4). High resolution mass spectr, m/z calc. for
mass spectr, m/z calc. for C31H40N3O4P 550.2835. Found, 550.2826.
3.10. Crystallographic determination
C33H43N3O 498.3484. Found, 498.3485.
The X-ray diffraction experiment was performed using a Bruker
3.7. (3E,5E)-3,5-bis{(2E)-3-[4-(dimethylamino)phenyl]prop-2-en-1-
ylidene}piperidin-4-one ((Me2NPh)2prPH)
SMART APEX II CCD diffractometer; Mo
K
a
radiation
(k = 0.71073 Å) at 100 K. The raw data frames were integrated with
the SAINT + program using narrow-frame algorithm [30]. Absorp-
tion corrections were applied using the semiempirical method of
the SADABS program [31]. The structure was solved by direct
methods and refined using the Bruker SHELXTL programs suite
[32] by full-matrix least-squares methods on F2 with SHELXL-97
in anisotropic approximation for all non-hydrogen atoms. All H
Red crystalline solid, Mp > 198 °C (decomposition). Yield 88%.
After separation additional purification was used, particularly col-
umn chromatography in spectrophotometric grade acetonitrile.
Yield (after column) 28%. IR (KBr, n cmꢃ1): 2901, 2807 (dimethyl-
amino group vibration), 1646 (C@O), 1593 (C@C), 1565, 1524,

E.S. Leonova et al. / Journal of Molecular Structure 1037 (2013) 288–293
293
Table 2
Crystallographic data for (Me2NPh)2prPEt.
References
[1] C.A. Mosley, D.C. Liotta, J.P. Snyder, Highly active anticancer curcumin
analogues, in: Bharat B. Aggarwal, Young-Joon Surh, Shishir Shishodia (Eds.),
The Molecular Targets and Therapeutic uses of Curcumin in Health and
Disease, Springer, New York, NY, 2007, pp. 77–105.
[2] J.R. Dimmock, N.M. Kandepu, M. Hetherington, J.W. Quail, U. Pugazhenthi, A.M.
Sudom, M. Chamankhah, P. Rose, E. Pass, T.M. Allen, S. Halleran, J. Szydlowski,
B. Mutus, M. Tannous, E.K. Manavathu, T.G. Myers, E. De Clercq, J. Balzarini, J.
Med. Chem. 41 (1998) 1014.
[3] D.A. Koechel, E.J. Cafruny, J. Med. Chem. 16 (1973) 1147.
[4] J.R. Fry, J.H. Fentem, A. Salim, S.P.A. Tang, M.J. Garle, D.A. Whiting, J. Pharm.
Pharmacol. 45 (1993) 166.
[5] J. Traber, M. Suter, P. Walter, C. Richter, Biochem. Pharmacol. 43 (1992) 961.
[6] U. Das, J. Alcorn, A. Shrivastav, R.K. Sharma, E. De Clercq, J. Balzarini, J.R.
Dimmock, J. Med. Chem. 42 (2007) 71.
Empirical formula
Formula weight
Crystal system
Space group
a, Å
C29H35N3O
441.60
Monoclinic
C2/c
16.858(4)
9.888(2)
30.483(10)
90
100.551(6)
90
4995(2)
8
1.174
1013
0.0553, 0.1175
0.1177, 0.1474
b, Å
c, Å
a
, deg.
b, deg.
c
, deg.
V, Å3
Z
q
calc, g/cm3
GOF on F2
[7] J.R. Dimmock, P. Kumar, A.J. Nazarali, N.L. Motaganahalli, T.P. Kowalchuk, M.A.
Beazely, J.W. Quail, E.O. Oloo, T.M. Allen, J. Szydowski, E. De Clercq, J. Balzarini,
Eur. J. Med. Chem. 35 (2000) 967–977.
[8] J.R. Dimmock, U. Das, H.I. Gul, M. Kawase, H. Sakagami, Z. Baráth, I. Ocsovsky, J.
Molnár, Bioorg. Med. Chem. Lett. 15 (2005) 1633.
R1,
R1,
x
R2 (I > 2
r
(I))
xR2 (all data)
[9] J.L. Wike-Hooley, A.P. van den Berg, J. van der Zee, H.S. Reinhold, Eur. J. Cancer
Clin. Oncol. 21 (1985) 785.
[10] J.R. Dimmock, V.K. Arora, M.J. Duffy, R.S. Reid, T.M. Allen, G.Y. Kao, Drug Des.
Discov. 8 (1992) 291.
[11] H.I. El-Subbagh, S.M. Abu-Zaid, M.A. Mahran, F.A. Badria, A.M. Al-Obaid, J. Med.
Chem. 43 (2000) 2915.
[12] C. Jobin, C.A. Bradham, M.P. Russi, B. Juma, A.S. Narula, D.A. Brenner, R.B.
Sartor, J. Immunol. 163 (1999) 3474.
[13] S. Kumar, U. Narain, K. Misra, Bioconjugate Chem. 12 (2001) 464.
[14] N. Ahmad, S.K. Katiyar, H. Mukhtar, in: J. Thiele, P. Elsner (Eds.), Oxidants and
Antioxidants in Cutaneous Biology, KARGER, Jena, 2001, pp. 128–139.
[15] K.W. Short, T.L. Kinnibrugh, D.M. Sammeth, T.V. Timofeeva, Kessel 7164 (2009)
716411.
atoms were placed in idealized positions and refined with con-
strained CAH distances and Uiso(H) values set to be 1.2Ueq or
1.5Ueq (for methyl group) of the attached C atom. Crystallographic
data have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication No. CCDC 902708. Cop-
ies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk). Details of X-ray exper-
iment and structure solution are presented in Table 2.
[16] G. Kodis, V. Gulbinas, L. Valkunas, S. Jursenas, Adv. Mater. Opt. Electron. 6
(1996) 391.
4. Conclusions
[17] X. Zhou, A.-M. Ren, J.-K. Feng, X.-J. Liu, J. Mol. Struct. 679 (2004) 157.
[18] V.A. Shakin, Sh. Abe, Phys. Rev. B50 (1994) 4306.
[19] M. Drobizhev, A. Karotki, Yu. Dzenis, A. Rebane, J. Phys. Chem. B 107 (2003)
7540.
[20] E.A. Badaeva, T.V. Timofeeva, A.S. Musanov, S. Treriak, J. Phys. Chem. A 109
(2005) 7276.
[21] E.S. Leonova, M.V. Makarov, E.Yu. Rybalkina, T.V. Timofeeva, I.L. Odinets, Eur. J.
Med. Chem. 45 (2010) 992.
[22] M.V. Makarov, E.Yu. Rybalkina, G.-V. Röschenthaler, K.W. Short, T.V.
Timofeeva, I.L. Odinets, Eur. J. Med. Chem. 44 (2009) 2135.
[23] V.N. Nesterov, L.N. Zakharov, S.S. Sarkisov, M.J. Curleyd, A. Urbase, Acta Cryst.
C64 (2008) o73.
A series of 3,5-bisarylidenepropenpiperidin-4-one compounds,
with general formula – (R1Ph)2prPR2 – with different substitutes
at the central nitrogen atom and at the aryl rings was synthesized.
According to obtained spectroscopic data two compounds,
(Et2NPh)2prPMe, and (Et2NPh)2prPEt demonstrated the best
two-photon absorption properties in the studied range. Practical
applications of investigated TPA materials require additional
studies which we plan to conduct in future.
[24] V.N. Nesterov, T.V. Timofeeva, S.S. Sarkisov, A. Leyderman, Ch.Y.-C. Leed, M.Yu.
Antipin, Acta Cryst. C59 (2003) o605.
[25] S.Z. Vatsadze, M.A. Manaenkova, N.V. Sviridenkova, N.V. Zyk, D.P. Krut’ko, A.V.
Churakov, M.Yu. Antipin, J.A.K. Howard, H. Lang, Russ. Chem. Bull. 55 (2006)
1184.
[26] J.R. Starkey, A.K. Rebane, M.A. Drobizhev, F. Meng, A. Gong, A. Elliott, K.
McInnerney, Ch.W. Spangler, Clin. Cancer Res. 14 (2008) 6564.
[27] M. Drobizhev, F. Meng, A. Rebane, Y. Stepanenko, E. Nickel, Ch.W. Spangler, J.
Phys. Chem. B 110 (2006) 9802.
Acknowledgments
This work was supported by the NSF DMR-0934121 and CHE-
0820852. The authors are grateful for this support. We thank Dr.
Michail Makarov and Prof. Dr. Irina L. Odinets for valuable
discussion.
[28] N.S. Makarov, J. Campo, J.M. Hales, J.W. Perry, Opt. Mater. Exp. 1 (2011) 551.
[29] N.S. Makarov, M. Drobizhev, A. Rebane, Opt. Exp. 16 (2008) 4029.
[30] SAINT+, Version 6.2a; Bruker Analytical X-ray System, Inc., Madison, WI, 2001.
[31] SADABS; Bruker Analytical X-ray System, Inc.: Madison, WI (1999).
[32] SHELXTL, Version 6.10; Bruker Analytical X-ray System, Inc., Madison, WI,
1997.
Appendix A. Supplementary material
1H, 13C NMR spectra for (R1Ph)2prPR2 (R1 = NEt2, NMe2; R2 = H,
Me, Et, P(O)(OEt)2), Tables 1S–3S, summarizing the geometrical
parameters obtained from the X-ray data. Supplementary data
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.molstruc.2012.12.034.