Characterization and stereochemistry of alkyl 2-chloro-3-formylacrylates: Experimental NMR and theoretical DFT studies

Article abstract of DOI:10.1007/s10947-010-0039-6

The synthesis of alkyl 2-chloro-3-formylacrylates 1 from alkyl pyruvates was carried out using Vilsmeier reaction. The reaction is highly stereoselective and leads to a 95:5 mixture of Z and E stereoisomers. Both stereoisomers were characterized by ¹H and ¹³C NMR. In CDCl₃ solution, the NMR data, particularly the NOEDIFF experiments, show that the major species formed is the Z stereoisomer. Heating compound 1 in THF at reflux afforded the cyclic product 2 in 90 % yield. The interpretation of the experimental data were further supported by DFT/B3LYP calculations.

Full text of DOI:10.1007/s10947-010-0039-6

Journal of Structural Chemistry. Vol. 51, No. 2, pp. 251-257, 2010
Original Russian Text Copyright © 2010 by T. M. Barhoumi-Slimi, M. T. Ben Dhia, M. Nsangou, M. M. El Gaied, and M. R. Khaddar
CHARACTERIZATION AND STEREOCHEMISTRY
OF ALKYL 2-CHLORO-3-FORMYLACRYLATES:
EXPERIMENTAL NMR AND THEORETICAL DFT STUDIES
T. M. Barhoumi-Slimi,1 M. T. Ben Dhia,1 M. Nsangou,2
M. M. El Gaied,1 and M. R. Khaddar1
UDC 547-32;544.122;544.176;539.19
The synthesis of alkyl 2-chloro-3-formylacrylates 1 from alkyl pyruvates was carried out using Vilsmeier
reaction. The reaction is highly stereoselective and leads to a 95:5 mixture of Z and E stereoisomers. Both
1
stereoisomers were characterized by H and 13C NMR. In CDCl3 solution, the NMR data, particularly the
NOEDIFF experiments, show that the major species formed is the Z stereoisomer. Heating compound 1 in
THF at reflux afforded the cyclic product 2 in 90 % yield. The interpretation of the experimental data were
further supported by DFT/B3LYP calculations.
Keywords: synthesis, Vilsmeier reaction, stereoisomerism, stereoselectivity, cyclization, NMR, NOEDIFF,
B3LYP.
INTRODUCTION
ꢀ,ꢁ-Unsaturated carbonyl systems form part of the most interesting synthons in organic synthesis [1]. When other
functions are present together with these systems, a large variety of supplementary reactions may take place leading to
interesting molecules. For instance, the ethyl 3-formylprop-2-enoate is a useful precursor for the synthesis of natural products
such as fruity flavours [2] used in food industry, natural insecticides [3] and hypoglycins [4].
The Vilsmeier reaction is widely used for the synthesis of many heterocyclic compounds [5, 6], particularly for the
synthesis of substituted ꢁ-chloroacrylaldehydes [6-8] which are much less reported in the literature. Surprisingly, very few
authors have reported the synthesis of the chlorinated derivative of ethyl 3-formylbut-2-enoate, the alkyl 2-chloro-3-
formylacrylate 1 [9] which could be used as a precursor for the synthesis of heterocyclic molecules and biomolecules. Fariña
et al. [9a] have reported the synthesis of methyl 2-chloro-3-formylacrylate starting from pseudoesters in several steps.
In this paper, we describe the synthesis of compound 1 through a one-pot Vilsmeier reaction on alkyl pyruvates and
investigate its stereochemistry using both experimental NMR technique and theoretical DFT calculations.
1Laboratory of Structural Organic Chemistry: Organic Synthesis, Faculty of Sciences of Tunis, 1060 Tunis, Tunisia;
2
b.sthouraya@yahoo.com. Department of Physics, Faculty of Science, University of Ngaoundere, Cameroon. The text was
submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 51, No. 2, pp. 266-271, March-April, 2010. Original
article submitted April 14, 2008.
0022-4766/10/5102-0251 © 2010 Springer Science+Business Media, Inc.
251

EXPERIMENTAL
General experimental procedure
DMF and alkyl pyruvates were distilled and DMF was kept over molecular sieves (Union Carbide Type 3 Å). POCl3
1
was used as purchased. IR spectra were recorded in CHCl3 on a Perkin-Elmer Spectrometer Pargon 1000 PC. H and 13C
NMR spectra were recorded on Bruker AC 300.130 (MHz) spectrometer. Chemical shifts are reported in ppm relative to
tetramethysilane in CDCl3. Coupling constants (J values) are given in Hz. Mass spectra were obtained with a Hewlett-
Packard 5890 II instrument.
Preparations
Alkyl 2-chloro-3-formylacrylate (1): Anhydrous N,N-dimethylformamide (6.3 g; 86.25 mmol, 2.5 eq.) was
cautiously added to phosphorus oxychloride (13.22 g; 86.25 mmol, 2.5 eq.) maintained in a nitrogen atmosphere at 0 ꢂC. The
reaction mixture was then stirred at room temperature for 30 min after which time a solution of alkyl pyruvate (4 g; 1 eq.)
was added dropwise. Stirring at room temperature was continued for 24 h and then a solution of sodium hydrocarbonate in
water (20 ml) was added cautiously. The mixture thus obtained was stirred at room temperature for an additional 1 h and the
product was extracted into diethyl ether, dried over magnesium sulfate and concentrated. The crude product was purified by
chromatography on silica gel using diethyl ether — petroleum ether (2:98) as the eluent.
1a: Methyl 2-chloro-3-formylacrylate: Yield 30%, IR: 1738, 1690, 1610 cm–1. Anal. Calcd. for C5H5Cl3: C 40.4, H
3.4, Cl 23.9. Found: C 40.9, H 3.7, Cl 24.2.
Z-1a: NMR 1H: ꢃ 3.94 (s, 3H, He), 7.05 (d, 1H, Hb, J = 6.8 Hz), 10.20 (d, 1H, Ha, J = 6.8 Hz). 13C NMR: ꢃ 54.0 (Ce),
132.1 (Cb), 139.6 (Cc), 161.9 (Cd), 190.5 (Ca).
E-1a: 1H NMR: ꢃ 3.96 (s, 3H, He), 6.61 (d, 1H, Hb, J = 6.6 Hz), 10.14 (d, 1H, Ha, J = 6.6 Hz). 13C NMR: ꢃ 54.0 (Ce),
132.5 (Cb), 137.0 (Cc), 161.9 (Cd), 189.0 (Ca).
1b: Ethyl 2-chloro-3-formylacrylate: Yield 50%; IR: 1740, 1685, 1605 cm–1. M.S. m/Z: (165,163) (M+3, M+1) (9,
25%), (135, 133) (100, 34%), 127 (53%), (119, 117) (23, 70%), 71 (40%), 61 (96%), 53 (84%).
1
Z-1b: H NMR: ꢃ 1.3 (t, 3H, J = 7.2 Hz), 4.23 (q, 2H, J = 7.2 Hz), 7.03 (d, 1H, J = 6.8 Hz), 10.15 (d, 1H,
J = 6.8 Hz). 13C NMR: ꢃ 13.9 (CH3), 63.6 (OCH2), 131.9 (CCl), 140.2 (CH=), 161.5 (COO), 190.7 (CHO).
1
E-1b: H NMR: ꢃ 1.27 (t, 3H, J = 7.2 Hz), 4.17 (q, 2H, J = 7.2 Hz), 6.81 (d, 1H, J = 6.8 Hz), 10.14 (d, 1H, J = 6.8
H). 13C NMR: ꢃ 15.6 (CH3), 62.0 (OCH2), 137.2(CCl), 141.3 (CH=), 161;5 (COO) , 189.3 (CHO).
2: 3-chloro-5-alkoxy-2(5H)-dihydrofuran-2-one: A solution of the aldehyde 1a,b (Z) (100 mg) in anhydrous THF
(5 ml) was introduced in a heating tube (ꢄ100 cm3). The latter was sealed and heated in an oil bath at 80ꢂC for 24 h. Then the
sealed tube was cooled and opened, and the reaction mixture was concentrated in vacuo to remove solvent. The crude product
was purified by chromatography on silica gel to afford 90 mg of the expected compound 2a,b.
2a: 3-chloro-5-methoxy-2(5H)-dihydrofuran-2-one: Yield 90%; IR: 625, 1790 cm–1. 1H NMR: ꢃ 3.61 (s, 3H, He),
5.86 (d, 1H, Ha, J = 1.4 Hz), 7.10 (d, 1H, Hb, J = 1.4 Hz). 13C NMR: ꢃ 52.4 (Ce), 103.2 (Ca), 128.5 (Cc), 138.5 (Cb), 166.8
(Cd). Anal. Calcd. for C5H5ClO3: C, 40.4; H, 3.4; Cl, 23.9. Found: C, 40.7; H, 3.5; Cl, 24.1.
2b: 3-chloro-5-ethoxy-2(5H)-dihydrofuran-2-one: Yield 90%; IR: 1625, 1790 cm–1. 1H NMR: ꢃ 1.27 (t, 3H, CH3,
JCH –H = 7.1 Hz), 3.76 (qd, 1H, Ha, JHa–H = 9.4 Hz, JHa–CH = 7.1 Hz), 3.93 (qd, 1H, HB, JHb–H = 9.4 Hz, JHb–CH3 = 7.1 Hz),
3
a
b
3
a
5.91 (d, 1H, Ha, J = 1.4 Hz), 7.08 (d, 1H, Hb, J = 1.4 Hz). 13C NMR: 14.5 (CH3), 66.5 (OCH2), 101.5 (Ca), 130.5 (Cc), 142.5
(Cb), 166.0 (Cd). M.S. m/Z: M+ 162 (0.03), 147 (0.18), [133(36), 135(12)], [117(100), 119(34)], 118(20), 120(7)], [89(27),
91(9)], 83(84).
252

Computations
Density functional theory (DFT) calculations were carried out on compounds 1 (in both E and Z forms) and 2 using
the suite of programs Gaussian 03W [10], with the non-local hybrid functional denoted as B3LYP [11, 12]. The basis set used
was of three Zêta 6-311++G** type of McLean and Chandler [13] doubly polarized with diffuse functions on all the atoms.
The geometries were optimized using analytical gradient. The harmonic vibrational frequencies of the different stationary
points of the potential energy surfaces (PES) have been calculated at the same level of theory in order to identify the local
minima as well as to estimate the corresponding zero-point vibrational energy (ZPE).
RESULTS AND DISCUSSION
Synthesis
The subjection of ketones bearing methyl or methylene groups in ꢀ position to a Vilsmeier reaction leads generally
to a mixture of Z/E stereoisomers with variable ratios and yields depending on the stability of the obtained products [5, 14].
In our case, the reaction of the Vilsmeier reagent (POCl3/DMF) with the methyl or ethyl pyruvates at room temperature for
24 hours is highly stereoselective and affords a 95/5 mixture of the Z/E stereoisomers in 30% yield for 1a and 50% yield for
1b (Scheme 1).
Scheme 1
On the other hand, it is observed that aldehyde 1 (Z+E: 95/5) may be entirely converted into the furanone 2 when
standing for few months. In the experimental conditions, the furanone 2 is obtained by heating aldehyde 1 at reflux in THF
during 24 h (Scheme 2).
Scheme 2
The formation of the furanone 2 results manifestly from cyclization of the E-stereoisomer. To explain the high
stereoselectivity of the Vilsmeier reaction and the formation of furanone 2, therefore, NMR studies and DFT calculations
were performed.
NMR studies
1
The H NMR spectra of compounds 1 in CDCl3 at 25ꢂC show the doubling of all signals with markedly different
intensities. The aldehyde proton appears as two doublets: the major doublet is at 10.18 ppm and low intensity one is at
10.14 ppm. On the basis of the chemical shift range known for the proton of unsaturated aldehydes, the major lower field
253

TABLE 1. 1H and 13C NMR Chemical Shifts for Compounds 1a and 2a in CDCl3
Compound
ꢃHa
ꢃHb
ꢃHe
ꢃCa
ꢃCb
ꢃCc
ꢃCd
ꢃCe
Z-1a
E-1a
2a
10.18
10.14
5.86
7.05
6.61
7.10
3.94
3.96
3.61
190.5
189.0
103.2
132.1
132.5
138.5
139.6
137.0
128.5
161.9
161.9
166.8
54.0
53.8
52.4
TABLE 2. Calculated Electronic Energy E, ZPE, Corrected Electronic Energy Including the Energy of Level
Zero E1 (in au) and Dipole Moment ꢅ (in Debye) of the Studied Molecules
Compound
Parameter
E-1a
Z-1a
2a
E-1b
Z-1b
2b
E
–879.5294
0.0950
–879.4344
2.6974
–879.5335
0.0951
–879.4384
4.2228
–879.5331
0.0974
–879.4358
4.6941
–918.8593
0.1232
–918.7361
3.0327
–918.8635
0.1232
–918.7403
4.6185
–918.8632
0.1255
–918.7377
4.8754
ZPE
E1 = E + ZPE
ꢅ
doublet (i.e. the predominant species) is assigned to the Z isomer. Furthermore, the vicinal H–H coupling between aldehyde
and vinylic protons, 3J, is in line with this assignment, showing values of 6.60 Hz and 6.80 Hz for the E and Z stereoisomers,
respectively. Interestingly, the NOE difference experiments performed on the major species observed show that the
predominant isomer does exist in the Z configuration (see Table 1). The irradiation of the ester proton (methyl protons)
signals of the major species showed in the 1H NMR spectra an enhancement of 9% and 7% for the peaks related to the vinylic
and aldehydic protons, respectively. This indicates that the interaction of the ester group with the vinylic proton is more
important than that with the aldehydic proton, suggesting that the major species present is in the Z form. Unfortunately, the
very small amount of the E stereisomer (5%) did not allow the measurement of the NOEDIFF.
1
When the H and 13C NMR spectra were measured after heating product 1 in THF at reflux, an interesting spectral
feature was observed. The 1H NMR spectra showed the absence of signals in the region of aldehydic protons and significant
changes in the 13C chemical shifts, in particular of the Ca atom (Table 1).
These interesting observations in the NMR spectra can be rationalized by considering the equilibrium of 1, at high
temperature, between the major E and minor Z forms. It can be proposed that the structure of 1 in the E form would allow full
1
and spontaneous cyclization to the furanone 2 (see Table 1 H and 13C NMR chemical shifts for compounds 1a and 2a in
CDCl3 Scheme 3), while in the Z form the unfavorable position of the aldehyde group prevents such a cyclization. This may
explain the stability of 2 as compared to the E form of 1.
Scheme 3
Theoretical calculations
In order to confirm the NMR data obtained for the studied compounds, the molecular geometries of 1 in the Z and E
forms and 2 were fully optimized at the DFT/B3LYP level of theory using 6-311++G** basis set. The structures have been
identified as local minima on the singlet potential energy surfaces (PES) (Fig. 1). Optimized values of selected geometrical
parameters are listed in Tables 3 and 4. Calculations show that the geometries of the E-isomer of 1a and 1b are the least
254

Fig. 1. DFT(B3LYP)/6-311++G** optimized geometries of
1 and 2.
TABLE 3. Selected Bond Lengths (Å) and Angles (deg.) for Compound 1
Stereoisomer 1a
Stereoisomer 1b
Stereoisomer 1a
Stereoisomer 1b
Parameter
Parameter
Z
E
Z
E
Z
E
Z
E
Bonds lengths
1.512
Bond angles
118.2
C1–C2
C2–C3
C3–C4
C4–O10
C4–Ha
C3–Hb
C2–Cl
C1–O5
C1–O6
O5–C11
1.508
1.341
1.475
1.212
1.103
1.085
1.745
1.334
1.207
1.444
1.510
1.341
1.474
1.212
1.103
1.085
1.746
1.332
1.208
1.456
1.514
1.344
1.479
1.210
1.108
1.085
1.728
1.331
1.209
1.455
C1–C2–C3
C2–C3–C4
C3–C4–O10
C3–C4–Ha
C1–C2–Cl
C2–C3–Hb
C2–C1–O5
C2–C1–O6
C1–O5–C11
119.4
126.2
122.0
116.9
117.6
117.3
112.9
122.3
115.9
119.4
126.2
122.1
116.8
117.6
117.2
112.9
122.0
116.3
118.3
128.6
126.4
113.3
117.7
115.3
112.9
122.3
116.5
1.344
1.479
1.210
1.108
1.085
1.728
1.333
1.208
128.5
126.3
113.3
117.8
115.4
112.9
122.5
115.9
1.443
Dihedral Angle
180.0 0.0
Ha–C4–C3–Hb
180.0
0.0
stable among all the compounds. As can be seen from Table 2, the Z-isomer of 1a is the most stable. The potential energy
difference between the two isomers of 1a is 2.57 kcal/mol (see Table 3). This difference is in good agreement with the
experimental NMR data (95% for Z and 5% for E).
As for the structure of 2, 2a is 2.32 kcal/mol more stable than E-1a. The same trend is observed for the ethylated
compounds 1b and 2b. The Compound 2b is 0.18 kcal/mol less stable than compound Z-1b. In the same way, compound E-
1b is 2.63 kcal/mol less stable than compound Z-1b (see Table 2).
As shown in Tables 3 and 4, the shortest C–C bond lengths calculated at the DFT/B3LYP level of theory are those
of C(2)–C(3) (1.342 Å) in 1 and C(3)–C(4) (1.328 Å) in 2 which correspond to a C–C double bond. In addition, the angle
255

TABLE 4. Selected Bond Lengths and Angles for Compound 2
Parameter
2a
2b
Parameter
2a
2b
Bonds lengths
1.368
Bond angles
106.6
O1–C2
C2–C3
C3–C4
C4–C5
C5–O1
C5–O6
O6–C7
C2–O8
C3–Cl
1.367
1.499
1.328
1.504
1.453
1.380
1.442
1.193
1.718
1.080
O1–C2–C3
C2–C3–C4
C3–C4–C5
C4–C5–O1
O1–C2–O8
C2–C3–Cl
O1–C5–O6
106.7
109.8
108.5
104.8
124.0
121.2
111.7
1.499
1.328
1.503
1.452
1.318
1.432
1.193
1.717
109.8
108.5
104.9
124.0
121.2
111.6
Dihedral angle
119.3
C2–O1–C5–O6
119.3
C4–H10
1.080
C(3)–C(4)–H(9) is smaller in the E-isomer as compared to the Z form, indicating possible existence of some hydrogen bond
interactions which would be more favoured in the E than in Z isomers (see Fig. 1).
The analysis of all the possible space structures of the Z and E isomers shows that the distance between the methylic
protons of the ester group and the vinylic proton is shorter in the Z forms as compared to the E ones [(dC11H8)Z = 4.23 Å vs.
(dC11H8)E = 6.02 Å]. On the other hand, the distance between the methylic protons of the ester group and the aldehydic proton
is larger for Z than that for E stereoisomers: [(dC11H9)Z = 6.61 Å, (dC11H9)E = 4.98 Å] (Tables 3 and 4). Interestingly, in the Z
form of 1a, the distance between H(8) and C(11) carrying the methyl protons is 4.88 Å while that between H(9) and C(11) is
6.44 Å. This is consistent with the results obtained with NOE difference experiments giving an enhancement of 9% and 7%,
respectively.
It is worth noting that the cyclization proposed in Scheme 3 is in good agreement with the theoretical calculations
which show that, on the one hand, the structure of 2a is more favoured than that of the stereoisomer E-1a and, on the other
hand, it is very close in energy to that of Z-1a. The E isomer can thus be considered as an intermediate in the conversion from
Z-1a to 2a when the former is heated. The aldehydic group of E-1a is considerably twisted with the C(1)–C(2)–C(3)–C(4)
dihedral angle of 0.56° (see Table 3).
Despite the fact that we did not calculate the transition states in these systems, it can be considered that the
difference in energy between the two isomers of 1a represents a major part of the activation enthalpy ꢆH* for the conversion
which is at least 2.57 kcal/mol.
CONCLUSIONS
We have reported a new method for synthesizing substituted ꢁ-chloroacrylaldehydes. In addition to its great
reactivity, this precursor is obtained in a high stereoselectivity (Z/E = 95/5). The results of the various investigations by NMR
and those of the theoretical study are in favor of assigning Z-stereochemistry to the major isomer present under the conditions
used. On the basis of the experimental and theoretical data, we have also shown that the predominant stereoisomer, Z-1, is
converted at high temperature to E-1 which in turn is readily cyclized to furanone 2. This may be used as a one-pot
preparation of furanone 2 from ꢁ-chloroacrylaldehydes 1.
The authors would like to thank Dr. M. A. M. K. Sanhoury, MRSC of the Department of Chemistry, Faculty of
Sciences of Tunis, for helpful discussions and assistance in the preparation of this manuscript.
256

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