Synthesis and photoisomerization of 3-cyano-6,6-dimethyl-4-(4-nitro- phenylvinyl)-5,6-dihydropyran-2-one

Article abstract of DOI:10.1023/B:COHC.0000018335.49120.af

The condensation of 4-nitrobenzaldehyde with 3-cyano-4,6,6-trimethyl-5,6- dihydropyran-2-one leads to the formation of a crotonization product and a compound of the Michael adduct type. The main product of the photochemical conversion of (E)-3-cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-dihydropyran- 2-one is the Z-isomer. Investigation of the photoisomerization of 3-cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-dihydropyran-2-one by the semiempirical AM1 method showed that in the ground state the E-isomer was thermodynamically more stable than the Z-isomer. E-Z-photoisomerization is effected most probably through the lowest excited singlet state S₁.

Full text of DOI:10.1023/B:COHC.0000018335.49120.af

Chemistry of Heterocyclic Compounds, Vol. 39, No. 12, 2003
SYNTHESIS AND PHOTOISOMERIZATION
OF 3-CYANO-6,6-DIMETHYL-4-(4-NITRO-
PHENYLVINYL)-5,6-DIHYDROPYRAN-2-ONE
D. Jansone, M. Fleisher, G. Andreeva, L. Leite, J. Popelis, and E. Lukevics
The condensation of 4-nitrobenzaldehyde with 3-cyano-4,6,6-trimethyl-5,6-dihydropyran-2-one leads to
the formation of a crotonization product and a compound of the Michael adduct type. The main product
of the photochemical conversion of (E)-3-cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-dihydropyran-
2-one is the Z-isomer. Investigation of the photoisomerization of 3-cyano-6,6-dimethyl-4-(4-
nitrophenylvinyl)-5,6-dihydropyran-2-one by the semiempirical AM1 method showed that in the ground
state the E-isomer was thermodynamically more stable than the Z-isomer. E-Z-photoisomerization is
effected most probably through the lowest excited singlet state S1.
Keywords: 3-cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-dihydropyran-2-one, 4-nitrobenzaldehyde,
3-cyano-4,6,6-trimethyl-5,6-dihydropyran-2-one, aldol condensation, AM1 semiempirical method,
E-Z-photoisomerization.
The biological activity of γ- and δ-lactones is known [1]. With the aim of searching for new
pharmacologically active compounds of this class, 3-cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-
dihydropyran-2-one (3) was synthesized by the condensation of 3-cyano-4,6,6-trimethyl-5,6-dihydropyran-2-one
(1) with 4-nitrobenzaldehyde (2) in EtOH in the presence of NaOH. It was discovered that, like the condensation
of pyranone 1 with pyridine aldehydes [1], in the reaction with aldehyde 2 a crotonization product 3 was formed
and also a compound of the Michael adduct type, viz. bis(3-cyano-6,6-dimethyl-2-oxo-5,6-dihydro-4-pyranyl-
methyl)-4-nitrophenylmethane (4).
In the case of benzaldehydes the reaction also proceeds in a manner uncharacteristic for an aldol
condensation. The yields of pyranones 3 and 4 at molar ratios of aldehyde 2–pyranone 1–NaOH of 1:2:0.06 were
23 and 75% respectively. However, unlike the reaction of pyridine aldehydes with pyranone 1, when aldehyde
predominates in the reaction medium (ratio of aldehyde 2 to pyranone 1 is 1.5:1) only the crotonization product
is formed in 60% yield. The yield of reaction products was assessed quantitatively by HPLC without isolating
them. Reaction dynamics were studied using TLC. Judging by the TLC results product 4 is formed initially, but
pyranone 3 appears in the reaction mixture later. It follows from this that the mechanism proposed by the authors
of [2,3] providing for the formation of a compound of the Michael adduct type 4 by addition of a second
molecule of pyranone 1 to compound 3 is scarcely probable.
_______
* Dedicated to the Greatly Respected Academician Janis Stradins on the occasion of his Jubilee.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: misha@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 12, pp. 1800-1807, December, 2003. Original article submitted May 26,
2003.
1584
0009-3122/03/3912-1584$25.00©2003 Plenum Publishing Corporation

Me
NO2
NC
O
+
Me
Me
OHC
O
2
1
NaOH
CH2
HC
CH=CH
NC
O
NC
NO2
NO2
Me
Me
O
O
O
Me
Me
2
4
3
The coupling constant (16.2 Hz) of the vinyl group protons in the 1H NMR spectrum of vinylpyranone 3
shows the E-configuration of the obtained compound (Table 1).
The biological activity of organic compounds, including lactones, usually depends on their geometric
configuration [4]. The photoisomerization of pyranone 3 was studied experimentally and theoretically to obtain
further information on the isomerism of the synthesized compounds. One intense absorption band was present at
344 nm in the UV spectrum of a 0.026 mM solution of pyranone 3 in ethanol (Fig. 1). Effects, which were
characteristic of E→Z-isomerism, were observed in the absorption spectrum on irradiating a solution of this
compound with sunlight. These effects were a reduction in the intensity of the characteristic band accompanied
by a small hypsochromic shift (from 344 to 325 nm), and a some increase in the intensity of the absorption in the
high frequency, the so-called "cissoid", region of the spectrum [5,6]. After exposing compound 3 solution to
sunlight for 3 h, the content of the Z- and E-isomers was 80 and 20% respectively, and remained unchanged on
1
further irradiation. In the H NMR spectrum of the products obtained after irradiation new signals appeared at
low field at 6.83 and 7.23 ppm. The coupling constants of the vinylic protons at 11.6 Hz is characteristic of a
Z-isomer. Isolation of pure Z-isomer from the mixture by column chromatography on silica gel 0.06-0.2 mm
(Acros) was unsuccessful.
TABLE 1. 1H NMR Spectrum of the Synthesized Compounds 3 and 4
Compound
1H NMR spectrum, δ, ppm (J, Hz)*
1.55 (6H, s, pyranone CH3); 2.88 (2H, s, pyranone CH2);
7.31 and 7.54 (2Н, d, J = 16.2, CH=CH); 7.76 (2Н, m, J = 9.0, phenyl H(2), H(6));
8.3 (2H, m, phenyl H(3), H(5))
3
E-3 + Z-3
1.37 (6H, s, CH3 Z-isomer); 1.55 (6H, s, CH3 E-isomer); 2.39 (2H, s, CH2 Z-isomer);
2.88 (2H, s, CH2 E-isomer); 6.83 and 7.23 (1H and 1H, d and d, J = 11.6, CH=CH
Z-isomer); 7.31 and 7.52 (1H and 1H, d and d, J = 16.2, CH=CH E-isomer);
7.41 and 8.27 (2H and 2H A2M2 m, J = 9.2, C6H4 Z-isomer);
7.31 and 7.52 (2H and 2H, A2M2 m, J = 9.0, C6H4 E-isomer)
1.22 and 1.35 (12H, s, CH3); 2.84 (4H, m, pyranone CH2);
3.11 and 3.71 (5H, m, CH(CH2)2); 7.68 (2H, d, J = 9.6, phenyl H(2), H(6));
8.18 (2H, d, phenyl H(3), H(5))
4
_______
* The 1H NMR spectra were taken in CDCl3 (compound 3) and in DMSO-d6
(compound 4).
1585

Wavelength, nm
Fig. 1. 1) Absorption spectrum of pyranone 3 in ethanol at 20°C (E-isomer) and
2) after irradiation with sunlight for 3 h (20% E-isomer + 80% Z-isomer).
Quantum-chemical calculations by the AM1 method [7] were carried out by us with the aim of clarifying
the mechanism of photoisomerization. Structural and energy characteristics calculated for the ground state as
well as mainly for the two lower excited states (Figs. 2-4, Table 2). Taking into consideration the data on the
heat of formation, the E-isomer is the more stable structure. The photoisomerization process observed by us
resulting in the predominance of the thermodynamically less stable Z-form is called as an optical pump [8].
Comparison of the calculated values of the C(2)–C(3) bond order indicates that the double bond of the Z-isomer
is more strong than that one for the E-configuration.
hν
⇒
E
Z
Fig. 2. Geometry of the E- and Z-isomers of pyranone 3 in the electronic S0 ground state
calculated by the AM1 method.
1586

According to the calculations, on going from the ground S0 state to the excited S1 state the cis isomer
becomes the more stable structure (Table 3, Fig. 3). Comparison of the data of Table 2 shows that the change in
dihedral angle H(1)–C(2)–C(3)–H(4) of the E-isomer is insignificant while this angle for the Z-isomer is
changed by approximately 90°. An increase in C(2)–C(3) bond length in relation to the S0 state is specific for
E
Z
Fig. 3. Geometry of the E- and Z-isomers of pyranone 3 in the S1 state calculated by the AM1 method.
E
Z
Fig. 4. Geometry of the E- and Z-isomers of pyranone 3 in the T1 state.
1587

TABLE 2. Characteristics of the Z- and E-Isomers of Compound 3 in the S0,
S1, and T1 States Calculated by the AM1 Method
Isomer
Calculated characteristics
Heat of formation, kcal/mol
Figure
State
Е
Z
2
3
4
S0
S1
T1
3.74
98.16
38.3
6.87
89.40
38.3
Dihedral angle
Н(1)–С(2)–С(3)–Н(4), deg.
2
3
4
S0
S1
T1
177.6
166.0
95.35
-1.96
-89.33
-95.35
Bond order C(2)–C(3)
2
3
4
S0
S1
T1
1.829
1.140
1.043
1.880
1.093
1.043
Bond length С(2)–C(3), Å
2
3
S0
S1
1.344
1.390
1.339
1.378
4
T1
1.440
1.440
the S1 state. A significant reduction of bond order occurs (from 1.829 to 1.140 for the E-form and from 1.880 to
1.093 for the Z-configuration), which indicates conversion of the multiple bond practically into a single bond,
and consequently rotation about this bond is possible. The height of the rotational barrier, found from the
reaction coordinates, is 0.21 kcal/mol for the E-isomer and 8.97 kcal/mol for the Z-isomer. This denotes that the
photoexcitation of the E-isomer with subsequent transition into the Z-isomer is an energetically more favorable
process than the reverse conversion and must lead to a predominance of the Z-isomer in the photostationary
state. The difference in the values of the activation energy is displayed spectroscopically in the hypsochromic
shift of the absorption maximum. Calculations show that on deactivation of the S1 state the E- and Z-isomers are
converted respectively into the E- and Z-isomers in the S0 state of the molecule of 3.
It has been established for many chemical compounds that E–Z isomerization occurs with the
participation of triplet states [9-12]. As the calculations showed, on transfer to this state the structure of the
E-isomer is changed most significantly. The dihedral angle H(1)–C(2)–C(3)–H(4) is reduced from 166.0 to
95.35°. The change in angle for the Z-isomer is only ~6°. The characteristics obtained (Table 2) and also the
visualization of the molecular structures (Fig. 4) indicate that in the triplet state the E- and Z-configurations of
pyranone 3 are mirror antipodes. The further reduction of the order of the C(2)–C(3) bond and the low barrier to
rotation about this bond (2.46 kcal/mole) provide an easy interconversion of one isomeric form into the other.
Deactivation of the T1 state, unlike the singlet S1 state, leads for both the E- and the Z-isomer only to one S0
ground state, just to the E-isomer.
TABLE 3. Calculated Spectral Characteristics of E- and Z-Pyranones 3
E-Isomer
Oscillator strength
Z-Isomer
Oscillator strength
Energy, nm
Energy, nm
487.2
413.5
341.0
332.2
296.7
281.2
240.3
239.2
226.6
218.6
0.0
486.4
413.2
334.8
309.1
292.7
276.1
247.5
238.2
228.2
219.6
0.0
0.0
0.0
0.006
1.327
0.011
0.149
0.022
0.050
0.052
0.029
0.006
0.711
0.023
0.189
0.091
0.045
0.140
0.171
1588

The obtained results therefore point in favor of a singlet mechanism for carrying out the E–Z
photoisomerization of pyranone 3.
Using the equilibrium geometry of the ground state of the E- and Z-isomers of compound 3,
spectroscopic parameters, viz. transition energies and oscillator strengths (Table 3), were calculated for the
isomers by the INDO/S-SCF-CI method [13]. Analysis showed that transitions caused by excitation of an
electron from the highest occupied molecular orbital to the lowest vacant molecular orbital (π→π*) were
characterized by the greatest intensity.
Based on the data of Table 3 theoretical UV absorption spectra were constructed for the E- and
Z-isomers of pyranone 3 and also for mixtures of them (Fig. 5). Since the absorption spectra of heterocyclic
compounds are as a rule unsymmetrical [14,15], a bi-Gaussian function was used to describe the shape [16].
Comparison of the spectra given in Figs. 1 and 5 indicate the good correlation between the experimental data and
the theoretical calculations. In particular, the hypsochromic deviation of the position of the absorption maximum
of the E-isomer of compound 3 in the calculated spectrum from experimental was 12 nm and of its mixture with
the Z-conformation was 15 nm. The absorption maximum of the Z-isomer of pyranone 3 in the calculated
spectrum was at 302 nm.
EXPERIMENTAL
The UV spectra were obtained on a SF 46 spectrophotometer (LOMO) in ethanol. For E-pyranone 3
1
log ε was 4.57. The H NMR spectra were recorded on a Varian Mercury 200 (200 MHz) instrument, internal
standard was TMS. HPLC was carried out on a Gilson 303 instrument on a Waters column (3.9 × 150 mm)
packed with Nova-Pak silica sorbent. Eluent (ethyl acetate–hexane, 1:1) flow rate was 1 ml/min with a
spectrophotometric detector (λ = 254 nm). Analysis by TLC was carried out on Silufol UV 254 plates, eluent
was ethyl acetate–hexane, 1:1).
Quantum-chemical calculations were carried out by the semiempirical AM1 method with full
optimization of the geometric parameters of both the ground and the two lowest excited states of the E- and
Z-isomers of pyranone 3. Calculations for the excited states were carried out taking into account for interaction
of configurations [keyword of program OPEN (2,2)]. The spectroscopic parameters of the E- and Z-isomers of
pyranone 3, enabling comparison and prediction of the electronic absorption spectra to be carried out, were
calculated by the INDO/S-CI method [13] with the ArgusLab program 3.0 [17]. The theoretical absorption
spectra were constructed using program written by us in FORTRAN 77 language. A normalized bi-Gaussian
function was used for the shape of the individual spectral peaks [16]. In the case of the E-isomer spectrum a
mean-square width of 30 nm was chosen for the forepart edge of the peak and 24 nm for the backpart edge. For
the Z-isomer spectrum the corresponding values were 30 and 26 nm.
Figs. 1-5 were obtained using the programs JPlot [18] and JMol [19].
Condensation of 3-Cyano-4,6,6-trimethyl-5,6-dihydropyran-2-one with Benzaldehyde 2. A mixture
of pyranone 1, benzaldehyde 2, NaOH (molar ratio aldehyde–pyranone–NaOH, 1:2:0.06) in ethanol was stirred
vigorously, heated to boiling, and boiled for 4 h. The Michael adduct type product 4 began to precipitate in the
course of the reaction, and was filtered off from the hot solution. The crotonization product 3 was precipitated
after cooling the reaction mixture to room temperature. Both products were recrystallized from ethanol.
Pyranone 3. Mp 224-226°C. Found, %: C 64.40; H 4.67; N 9.35. C16H14N2O4. Calculated, %: C 64.42;
H 4.73; N 9.39.
Pyranone 4. Mp 204-207°C (decomp.). Found, %: C 64.65; H 4.42; N 9.03. C25H25N3O6. Calculated, %:
C 64.79; H 5.44; N 9.07.
The 1H NMR spectra of compounds 3 and 4 are given in Table 1.
1589

REFERENCES
1.
D. Jansone, L. Leite, M. Fleisher, J. Popelis, I. Mazheika, E. Lukevics, G. Melikyan, and A. Avetisyan,
Khim. Geterotsikl. Soedin., 298 (1998).
2.
3.
4.
C. S. Marvel, L. E. Coleman, and G. P. Scott, J. Org. Chem., 20, 1785 (1955).
N. Wachter-Jurcsak, C. Radu, and K. Redin, Tetrahedron Lett., 39, 3903 (1998).
S. Nishikawa, M. Sato, H. Kojima. C. Suzuki, N. Yamada, M. Inagaki, N. Kashimura, and H. Mizuno,
J. Agr. Food Chem., 44, 1337 (1996).
5.
E. S. Stern and C. J. Timmons, Gillam & Stern's Introduction to Electronic Absorption Spectroscopy in
Organic Chemistry, 3rd Edit., Arnold, London (1970), 277 pp.
6.
7.
8.
C. N. R. Rao, Electronic Spectra in Chemistry [Russian translation], Mir, Moscow (1964), p. 123.
M. J. S. Dewar, E. G. Zoebish, E. F. Healy, and J. J. P. Stewart, J. Am. Chem. Soc., 107, 3902 (1985).
G. O. Bekker (editor), Introduction to the Photochemistry of Organic Compounds [Russian translation],
Khimiya, Leningrad Otd. (1976), p. 273.
9.
10.
11.
J. A. Barltrop and J. D. Coyle, Excited States in Organic Chemistry, Wiley, New York (1975), 376 pp.
N. J. Turro, Molecular Photochemistry [Russian translation], Mir, Moscow (1967), p. 208.
J. Michl and V. Bonacic-Koutecky, Electronic Aspects of Organic Photochemistry, John Wiley, New
York (1990), 475 pp.
12.
13.
W. M. Horspool, in A. Gilbert (editor), Photochemistry, Specialist Periodical Reports, Vol. 28, Royal
Society of Chemistry, Cambridge (1977), p. 124.
M. C. Zerner, G. H. Loew, R. F. Kirchner, and U. T. Mueller-Westerhoff, J. Am. Chem. Soc., 102, 589
(1980).
14.
15.
16.
B. Klabuhn, D. Spindler, and H. Goetz, Spectrochim. Acta A, 29, 1283 (1973).
L. Antonov and D. Nedeltcheva, Chem. Soc. Rev., 29, 217 (2000).
E. A. Kyullik, M. R. Kal'yurand, and M. N. Koel', Application of Computers in Gas Chromatography [in
Russian], Nauka, Moscow (1978), p. 127.
17.
18.
19.
ArgusLab 3.0 Program. http://www.planaria-software.com.
JPlot 1-2: http://www.cig.ensmp.fr/~vanderlee.
JMol: http://www.openscience.org/~gezelter.
1590