Why is the reaction of ethyl (2-cyanoacetyl)carbamate with ethyl orthoformate highly stereoselective?

Article abstract of DOI:10.1002/poc.979

The reaction of ethyl (2-cyanoacetyl)carbamate (1) with ethyl orthoformate in the presence of acetic anhydride is highly stereoselective and only E-ethyl (2-cyano-3-ethoxyacryloyl)carbamate (E-2) is isolated. The reaction is thermodynamically controlled and the product distribution depends on the relative stability between E-2 and Z-2. Both the resonance stabilization of 1.47 kcal mol^-1 and the steric hindrance of 2.28 kcal mol^-1 in favour of E-2 contribute to the relative stability (3.75 kcal mol^-1) between Z-2 and E-2, which is calculated from four isodesmic reactions, and this is the reason why the reaction of compound 1 with ethyl orthoformate is highly stereoselective. The electron-withdrawing ability of some substituents was evaluated. The sequence of π-accepting ability is C(O)NHC(O)OEt > C(O)NH₂ > CN and the sequence of σ-accepting ability is CN > C(O)NHC(O)OEt > C(O)NH₂. Copyright

Full text of DOI:10.1002/poc.979

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2005; 18: 1183–1189
Published online 15 September 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.979
Why is the reaction of ethyl (2-cyanoacetyl)carbamate
with ethyl orthoformate highly stereoselective?
y
Kuangsen Sung,* Ming-Chi Lin, Pin-Mei Huang, Bo-Ren Zhuang, Robert Sung and Ru-Rong Wu
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan, Republic of China
Received 25 January 2005; revised 14 June 2005; accepted 14 June 2005
ABSTRACT: The reaction of ethyl (2-cyanoacetyl)carbamate (1) with ethyl orthoformate in the presence of acetic
anhydride is highly stereoselective and only E-ethyl (2-cyano-3-ethoxyacryloyl)carbamate (E-2) is isolated. The
reaction is thermodynamically controlled and the product distribution depends on the relative stability between E-2
ꢀ
1
ꢀ1
and Z-2. Both the resonance stabilization of 1.47 kcal mol and the steric hindrance of 2.28 kcal mol in favour of
ꢀ1
E-2 contribute to the relative stability (3.75 kcal mol ) between Z-2 and E-2, which is calculated from four isodesmic
reactions, and this is the reason why the reaction of compound 1 with ethyl orthoformate is highly stereoselective.
The electron-withdrawing ability of some substituents was evaluated. The sequence of ꢀ-accepting ability is
C(O)NHC(O)OEt > C(O)NH > CN and the sequence of ꢁ-accepting ability is CN > C(O)NHC(O)OEt > C(O)NH .
2
2
Copyright # 2005 John Wiley & Sons, Ltd.
KEYWORDS: isomerization; electron delocalization; stereoselective
INTRODUCTION
good model to study why this type of reaction is highly
stereoselective.
One of the popular methods of preparing vinyl ethers is to
treat active methylene compounds with ethyl orthofor-
O
O
1
mate [Eqn (1)]. Some of the reactions of this type are
N
acetic anhydride
+
HC(OC H )
2 5 3
highly stereoselective but it was not until 1973 that Ceder
and Stenhede figured out the configuration of the highly
stereoselective product by NMR studies using a chemi-
N
H
O
1
2
cal-shift reagent Eu(fod) -d . However, none of the
3
27
literature reports on why this type of reaction is highly
stereoselective.
N
N
C(O)NHC(O)OEt
C(O)NHC(O)OEt
hν
O
H
H
O
X
X
E-2
Z-2
2 C2H5OH
CH2
+
HC(OC H )
2
CHOC2H5
+
5 3
ð2Þ
Y
Y
ð1Þ
COMPUTATION
To prepare an intermediate to uracil derivatives, ethyl
2-cyanoacetyl)carbamate (1) was treated with ethyl
orthoformate in the presence of acetic anhydride in our
laboratory and only E-ethyl (2-cyano-3-ethoxyacryloyl)-
carbamate (E-2) was found [Eqn (2)]. This reaction is a
All the calculations reported here were performed with
3
the Gaussian 98 program. Geometry optimizations of
(
compounds Z-2, Z-2a, E-2, E-2a, Z-3, E-3, Z-4, E-4, Z-5,
E-5, Z-6, E-6, E-7, 8, 9 and 10 at the B3LYP/6-31þG*
level and geometry optimizations of compounds 11a–11d
and 12a–12d at the HF/6-31þG* level were carried out
without any symmetry restriction. Optimized structures
of compounds Z-2, Z-2a, E-2, E-2a, Z-3, E-3, Z-4, E-4,
Z-5, E-5, Z-6, E-6, E-7, 8, 9 and 10 at the B3LYP/
*Correspondence to: K. Sung, Department of Chemistry, National
Cheng Kung University, Tainan, Taiwan, Republic of China
E-mail: kssung@mail.ncku.edu.tw
y
Coquitlan, B.C., Canada V3C6K8.
Current address: Riverside Secondary School, 2215 Reeve Street, Port
6
-31þG* level are shown in Figs 1 and 2. After all the
Contract/grant sponsor: National Science Council of Taiwan;
Contract/grant number: NSC 92-2113-M-006-010.
geometry optimizations had been performed, analytical
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1183–1189

1
184
K. SUNG ET AL.
lFe i vg eul re. 1. Optimized structures of compounds Z-3, E-3, Z-4, E-4, Z-5, E-5, Z-6, E-6, E-7, 8, 9 and 10 at the B3LYP/6-31þG*
3
vibration frequencies were calculated at the same level to
determine the nature of the located stationary points.
Thus, all the stationary points found were characterized
properly by evaluation of the harmonic frequencies.
The single-point energies of the optimized structures of
Z-2 and E-2 were calculated at the B3LYP/6-31þG*,
HF/6-311þþG(3df,3pd) or B3LYP/6-311þþG(3df,3pd)
level with scale zero-point vibration energies included.
The single-point energies of the optimized structures of
yield. No trace of Z-2 has been found. In E-2, the J
coupling constant between the vinyl proton and the nitrile
carbon is 11 Hz whereas that between the vinyl proton
and amide carbon is 2 Hz, indicating that the vinyl proton
5
is trans to the nitrile group. The configuration assign-
ment for E-2 is consistent with that made by Ceder and
2
Stenhede.
After 2 h of ultraviolet irradiation at ꢂ ¼ 254 nm, 40%
of E-2 was isomerized to Z-2. Two days after stopping the
irradiation, most of the Z-2 was isomerized back to E-2
at room temperature. The E-2 cannot be isomerized to
Z-2 thermally but it can photochemically whereas Z-2 can
be isomerized back to E-2 thermally. This implies that the
reaction of compound 1 with ethyl orthoformate in the
presence of acetic anhydride is very likely to be under
thermodynamic control.
1
1a–11d and 12a–12d were calculated at the MP2/6-
3
included. The scale factor of 0.9804 for zero-point
1þG* level with scale zero-point vibration energies
4
vibration energies is used according to the literature.
Calculated energies of all the above structures are shown
in Table 1.
Whether the ꢃ-ketoester part of E-2 stays as the keto or
enol form is important for the configuration assignment.
RESULTS AND DISCUSSION
1
15
On applying NMR of H– N HSQC an off-diagonal
cross-peak shows a correlation between hydrogen at ꢄ
9.20 and urethane nitrogen at ꢄ 138.6 by means of their
spin–spin coupling, indicating that E-2 stays as the keto
Reaction of compound 1 with ethyl orthoformate in the
presence of acetic anhydride in chloroform was carried
out under reflux for 2 h and only E-2 was isolated in 75%
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1183–1189

STEREOSELECTIVE REACTION OF ETHYL (2-CYANOACETYL)CARBAMATE WITH ETHYL ORTHOFORMATE
1185
Figure 2. Optimized structures of compounds Z-2, Z-2a, E-2 and E-2a at the B3LYP/6-31þG* level
form. The results have been found with solvents such as
acetone-d , acetonitrile-d and CDCl . Based on the
NMR results, Z/E-isomers of 2 were optimized at the
B3LYP/6-31þG* level and at least two interesting con-
formers were located for each of the geometric isomers
more stable than E-2a. The backbones of Z-2, Z-2a and
E-2 stay in the same plane whereas the C(O)NHC(O)OEt
group is twisted away from the plane of the rest of
the structure in E-2a. The major structure difference
6
3
3
—
—
of the conformers is the dihedral angle of C—C—C—O.
The more stable conformers (Z-2 and E-2) have the s-cis
(
Fig. 2). Conformers Z-2 and Z-2a were located for the Z-
ꢀ
1
—
—
isomer of 2, and Z-2 is 0.60 kcal mol (1 kcal ¼ 4.184 kJ)
conformation of C—C—C—O, so they can pull the
bulky C(O)NHC(O)OEt group away from the vinyl
hydrogen or ethoxy group to avoid steric hindrance.
more stable than Z-2a. Conformers E-2 and E-2a were
located for the E-isomer of 2, and E-2 is 7.36 kcal mol
ꢀ
1
Table 1. Calculated energies E (hartrees) of compounds Z-2, Z-2a, E-2, E-2a, Z-3, E-3, Z-4, E-4, Z-5, E-5, Z-6, E-6, E-7, 8, 9, 10,
1a–11d and 12a–12d
1
Compound
E
Compound
E
Compound
E
Compound
E
a
a
a
a
a
a
Z-2
ꢀ760.39510
Z-2a
ꢀ760.39415
E-2
ꢀ760.40220
E-2a
760.39047
a
a
(
ꢅ ¼ 3.61 D)
(ꢅ ¼ 11.46 D)
(ꢅ ¼ 3.11 D)
(ꢅ ¼ 10.32 D)
b
b
ꢀ
756.20947
ꢀ756.21758
(ꢅ ¼ 3.50 D)
b
b
(
ꢅ ¼ 4.05 D)
c
c
c
c
ꢀ
760.64792
ꢀ760.65472
(
ꢅ ¼ 3.52 D)
(ꢅ ¼ 3.12 D)
a
a
a
a
a
a
a
a
Z-3
Z-5
E-7
ꢀ324.58158
ꢀ288.65880
ꢀ401.02284
E-3
E-5
8
11b
12b
ꢀ324.58279a
Z-4
Z-6
9
11c
12c
ꢀ668.14732
ꢀ632.22523
ꢀ669.35125
Eꢀ4
E-6
10
11d
12d
ꢀ668.15450
ꢀ632.22920
ꢀ402.22028
a
ꢀ288.65914
a
a
ꢀ325.78183
d
d
d
d
d
d
d
1
1
1a
2a
ꢀ327.96330
ꢀ419.98200
ꢀ496.19390
ꢀ762.54350
ꢀ762.90122
d
ꢀ328.32998
ꢀ420.32998
ꢀ496.55515
a
ꢀ1
B3LYP/6-31þG*//B3LYP/6-31þG*. At this level, E(Z-2) ꢀ E(E-2) ¼ 4.5 kcal mol (1 kcal ¼ 4.184 KJ).
b
c
d
ꢀ1
HF/6-311þþG(3df,3pd)//B3LYP/6-31þG*. At this level, E(Z-2) ꢀ E(E-2) ¼ 5.1 kcal mol
.
ꢀ1
B3LYP/6-311þþG(3df,3pd)//B3LYP/6-31þG*. At this level, E(Z-2) ꢀ E(E-2) ¼ 4.3 kcal mol
MP2/6-31þG*//HF/6-31þG*.
.
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1183–1189

1
186
K. SUNG ET AL.
The less stable conformers (Z-2a and E-2a) have the s-
reaction of 1 with ethyl orthoformate is highly stereo-
selective, one needs to look further into the relative
stability between Z-2 and E-2.
—
—
trans conformation of C—C—C—O, causing significant
steric hindrance between the bulky C(O)NHC(O)OEt
group and the vinyl hydrogen or ethoxy group. To reduce
the steric hindrance, E-2a twists C(O)NHC(O)OEt away
Single point energies of B3LYP/6-31þG*-optimized
structures of Z-2 and E-2 at three different levels are
ꢀ1
—
—
—
from the C—C plane (dihedral angle of C—C—C—
ꢁ
shown in Table 1. Why is E-2 4.3–5.1 kcal mol more
stable than Z-2?. The relative stability of geometric
isomers may be controlled by several factors such as
intramolecular hydrogen bonding, dipole moment, steric
hindrance, and electron delocalization, which will be
discussed in order to explain the relative stability between
Z-2 and E-2.
O ¼ 145.4 ) but loses resonance stabilization along the
—
ethoxy, C—C and C(O)NHC(O)OEt groups, which
makes it 2.31, 2.91 and 7.36 kcal mol less stable than
ꢀ
Z-2a, Z-2 and E-2, respectively, implying that there is
intramolecular hydrogen bonding between the N—H
group and the oxygen of the ethoxy group in Z-2a. In
Z-2a, the C(O)NHC(O)OEt group stays in the same plane
as the moiety of ethyl vinyl ether in spite of steric hind-
rance between the C(O)NHC(O)OEt and ethoxy groups,
and the distance between the hydrogen of the N—H
Based on the optimized structure of Z-2, it is unlikely
that Z-2 has intramolecular hydrogen bonding. On the
other hand, Z-2a does form intramolecular hydrogen
bonding, but this stabilization effect is offset by steric
hindrance between C(O)NHC(O)OEt and ethoxy groups,
˚
group and the oxygen of the ethoxy group is 1.97 A,
indicating that it has intramolecular hydrogen bonding,
ꢀ
1
making Z-2a 0.6 kcal mol less stable than Z-2. In E-2,
the distance between the vinyl hydrogen and the oxygen
ꢀ1
which means that Z-2a is only 0.6 kcal mol less stable
than Z-2.
˚
of the amide moiety is 2.40 A and the electronegativity of
Calculated thermodynamic data of the conformational
isomerization for Z/E isomers of compound 2 are
shown in Table 2. According to the relationship ꢀG ¼
the vinyl carbon is not strong enough, so it is unlikely that
E-2 has intramolecular hydrogen bonding. Thus intramo-
lecular hydrogen bonding is not important in explaining
why E-2 is much more stable than Z-2.
6
ꢀ1
ꢀ
RT(lnK), a ꢀG(298 K) value of ꢀ1.77 kcal mol
indicates that around 95% of the Z-isomer of 2 stays as
Z-2, and around 99.99% of the E-isomer of 2 stays as E-2
As shown in Table 1, the dipole moments of Z-2 and E-
2 are 3.52 and 3.12 D, respectively, at the B3LYP/6-
311þþG(3df,3pd)//B3LYP/6-31þG* level. Dipole mo-
ments of chloroform and acetonitrile are 1.04 and
ꢀ1
due to a ꢀG(298 K) value of ꢀ6.67 kcal mol . Accord-
ing to experimental results, isomerization of 2 from the Z-
isomer to the E-isomer is spontaneous at room tempera-
ture but calculated free energies of Z/E isomerization
from Z-2 to E-2a or from Z-2a to E-2a are 3.24 and
8
3.92 D, and their dielectric constants are 4.81 and 36.6,
8
respectively. Chloroform is a non-polar aprotic solvent
whereas acetonitrile is a dipolar aprotic solvent. Based on
ꢀ1
9
the useful rule of thumb of ‘like dissolves like’, chloro-
1
.47 kcal mol , respectively, indicating that these two
processes are not thermodynamically favourable and E-
a is much less stable than Z-2 and Z-2a. On the other
form may stabilize E-2 better than Z-2 whereas acetoni-
trile may stabilize Z-2 better than E-2. However, the
reaction of 1 with ethyl orthoformate is highly stereo-
selective in both chloroform and acetonitrile, indicating
that the dipole moment is not a major factor in making E-
2 much more stable than Z-2.
2
hand, calculated free energies of Z/E isomerization
from Z-2 to E-2 or from Z-2a to E-2 are ꢀ3.43 and
ꢀ
1
ꢀ
5.19 kcal mol , respectively, which are consistent with
experimental results and much more negative than
ꢀ1
7
ꢀ
0.62 kcal mol
for Z/E isomerization of 2-butene.
To investigate the contribution of resonance effects and
steric hindrance to the stability of both E-2 and Z-2, E-2 is
divided into two systems (Z-3 and E-4) and Z-2 is divided
into another two systems (E-3 and Z-4). The isodesmic
reactions of Eqns (3)–(6) were designed to predict reso-
nance stabilization in Z-3, E-4, E-3 and Z-4, respectively.
The isodesmic reaction in which the total number of each
Because around 95% of the Z-isomer of 2 stays as Z-2,
the process from Z-2 to E-2 is considered. Negative
entropy is not favourable for this isomerization from Z-
2 to E-2 but favourable enthalpy dominates this isomer-
ization. Therefore, to answer the question of why the
4
b
type of bond is identical in the reactants and products
4b
successfully predicts the heat of formation and sub-
ꢀ
1
Table 2. Calculated energies ꢀE (kcal mol ), enthalpies
ꢀ1
ꢀ1 ꢀ1
(
kcal mol ), entropies (cal mol K
) and free energies
kcal mol ) of Z/E and conformational isomerization of
10
stituent effects on the stability of functional groups. To
ꢀ1
(
consider steric hindrance in Z-2, E-2, Z-3 and Z-4, the n-
propyl group replaces the ethoxy substituent and Z-5, E-
5, Z-6 and E-6 were designed for a significant reduction
compound 2 at the B3LYP/6-31þG*//HF/6-31þG* level
ꢀH(298 K) ꢀS(298 K) ꢀG(298 K)
ꢀE
—
in the resonance effect along two substituents across C—
C. Thus, the steric hindrance in Z-3 is close to that in Z-5,
Z-2 ! E-2
Z-2 ! E-2a þ 2.91
Z-2a ! E-2 ꢀ5.05
Z-2a ! E-2a þ 2.31
Z-2a Ð Z-2 ꢀ0.60
E-2a Ð E-2 ꢀ7.36
ꢀ4.46
ꢀ4.29
þ 2.88
ꢀ5.05
þ 2.11
ꢀ0.77
ꢀ7.16
ꢀ2.87
ꢀ1.22
0.49
þ 2.14
þ 3.36
ꢀ1.65
ꢀ3.43
þ 3.24
ꢀ5.19
þ 1.47
ꢀ1.77
ꢀ6.67
ꢀ
1
which is 0.21 kcal mol according to Eqn (7), and the
ꢀ
1
resonance stabilization in Z-3 is ꢂ10.69 kcal mol
( ¼ 10.48 þ 0.21) based on Eqn (3). Similarly, the steric
hindrance in Z-4 is close to that in Z-6, which is equal to
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1183–1189

STEREOSELECTIVE REACTION OF ETHYL (2-CYANOACETYL)CARBAMATE WITH ETHYL ORTHOFORMATE
1187
ꢀ
1
2
.49 kcal mol based on Eqn (8), and the resonance
( ¼ 2.49 þ
ꢀ1
stabilization in Z-4 is ꢂ10.66 kcal mol
8
.17) according to Eqn (6).
ð8Þ
ꢀ
1
Z-6: steric hindrance ꢂ2.49 kcal mol ;
ð3Þ
ꢀ
1
Z-3: steric hindrance ꢂ0.21 kcal mol ; resonance stabi-
lization ꢂ10.69 kcal molꢀ
1
ð9Þ
ꢀ
1
E-7: steric hindrance ꢂ0.0 kcal mol ; resonance stabi-
ꢀ
1
lization ꢂ12.24 kcal mol
To investigate the contribution of resonance effects and
steric hindrance to the stability of E-2 and Z-2, the
isodesmic reactions of Eqns (3)–(8) are considered.
ð4Þ
ꢀ1
E-4: steric hindrance ꢂ0.0 kcal mol ; resonance stabi-
Equations (7) and (8) show a small steric interaction
ꢀ1
lization ꢂ12.68 kcal molꢀ
1
(0.21 kcal mol ) with the cyano group cis to an n-propyl
group, whereas there is a significant steric interaction of
ꢀ
1
2
.49 kcal mol with the C(O)NHC(O)OEt group cis to
ꢀ
1
an n-propyl group. The difference (2.28 kcal mol ) is
taken as the steric contribution to the energy difference
between E-2 and Z-2. The total energy difference be-
tween E-2 and Z-2 may be estimated as the stabilization
ð5Þ
ꢀ1
E-3: steric hindrance ꢂ0.0 kcal mol ; resonance stabi-
energy difference of Eqn (3) þ Eqn (4) ꢀ Eqn (5) ꢀ Eqn
lization ꢂ11.24 kcal molꢀ
1
ꢀ1
(
6) ¼ 3.75 kcal mol , so the resonance stabilization for
E-2 relative to Z-2 is estimated as 3.75ꢀ2.28 ¼
ꢀ1
1
.47 kcal mol .
The trans delocalization energy from the ethoxy to the
ꢀ1
C(O)NHC(O)OEt group in E-4 is 12.68 kcal mol based
on Eqn (4), whereas the trans delocalization energy from
the ethoxy to the nitrile group in E-3 is 11.24 kcal mol
according to Eqn (5), indicating that the C(O)NH-
ꢀ1
ð6Þ
ꢀ
1
C(O)OEt group is a better ꢀ-acceptor than the nitrile
group by 1.44 kcal mol . Based on Eqn (9) the trans
Z-4: steric hindrance ꢂ2.49 kcal mol ; resonance stabi-
ꢀ1
ꢀ
1
lization ꢂ10.66 kcal mol
delocalization energy from the ethoxy to the C(O)NH
ꢀ
2
The contribution of resonance stabilization and steric
hindrance in E-2 can be estimated to be the sum of
stabilization energies in Eqns (3) and (4), which is
23.16 kcal mol . Similarly, the contribution of reso-
nance stabilization and steric hindrance in Z-2 presum-
1
group in E-7 is 12.24 kcal mol , indicating that the
C(O)NH group is a better ꢀ-acceptor than the nitrile
2
ꢀ1
ꢀ1
group by 1.00 kcal mol but a worse ꢀ-acceptor than the
C(O)NHC(O)OEt group by 0.44 kcal mol . However,
ꢀ
1
reported resonance substituent constants R (or ꢁ ) of
R
ably equals the sum of stabilization energies in Eqns (5)
ꢀ
1
1a
1
and (6), which is 19.41 kcal mol . Thus, the energy
nitrile and C(O)NH are 0.15 and 0.10 by Hansch et al.
2
11b
and 0.08 and 0.08 by Charton,
indicating that the
difference between E-2 and Z-2, which is calculated
ꢀ
1
resonance substituent constants vary with different mod-
els or solvents.
from these four isodesmic reactions, is 3.75 kcal mol
ꢀ
1
which is close to the energy difference (4.5 kcal mol ) of
these two molecules calculated at the B3LYP/6-31þG*
level.
ꢀ
ꢁ
-accepting ability: CðOÞNHCðOÞOEt > CðOÞNH > CN
2
-accepting ðinductiveÞ ability: CN > CðOÞNHCðOÞOEt > CðOÞNH2
We successfully obtained field substituent constants
from relative deprotonation Gibbs free energies of 4-
substituted quinuclidinium ions 11 [Eqn (10)] by ab initio
calculations at the CBS-4M level. The relative depro-
tonation Gibbs free energies were rescaled by a factor of
ð7Þ
11
Z-5: steric hindrance ꢂ0.21 kcal molꢀ
1
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1183–1189

1
188
K. SUNG ET AL.
Table 3. Relative deprotonation Gibbs free energies
ꢁ-acceptor than the C(O)NHC(O)OEt group, whereas the
C(O)NHC(O)OEt group is a better ꢀ-acceptor than the
nitrile group.
ꢀ1
[ꢀG(298 K), kcal mol )] of 4-substituted quinuclidinium
ions 11a–11d [Eqn (10)], the calculated field substituent
G
constants (ꢁ ) at the MP2/6-31þG*//HF/6-31þG* and
F
CBS-4M levels in the gas phase and Charton’s inductive
1
1b
substituent constant (ꢁI)
EXPERIMENTAL
G
ꢁF
R
ꢀꢀG(298 K)
ꢁI
General. Unless stated otherwise reagents were obtained
from commercial suppliers and used as received. Ethyl
(2-cyanoacetyl)carbamate (1), was prepared according to
H
CN
0.00 (0.00)
11.61 (11.65)
4.72 (4.21)
6.16
0.00 (0.00)
0.66 (0.66)
0.27 (0.24)
0.35
0.00
0.57
0.28
C(O)NH2
C(O)NHC(O)OEt
13
the literature method.
E-Ethyl (2-cyano-3-ethoxyacryloyl)carbamate (E-2). To a
solution of 1 (0.156 g, 1 mmol) and acetic anhydride
(1 ml) in 2ml of chloroform, ethyl orthoformate (0.296 g,
G 12
ꢀ
1/17.53 to become ꢁ , which is well correlated with
F
11
Taft’s ꢁ and Charton’s ꢁ . Now we obtain the field sub-
F
I
ꢁ
stituent constants of CN, C(O)NH , and C(O)NHC(O)OEt
2
2 mmol) was added. The mixture was refluxed at 80 C
in the same way at the MP2/6-31þG*//HF/6-31þG*
under a nitrogen atmosphere for 2 h. After the reaction
was complete, the reaction mixture was cooled down and
concentrated by rotary evaporator. Ether was poured into
the reaction mixture and the mixture stayed in the fridge
for 12 h. After filtration of the mixture, a white powder
was collected and recrystallized in chloroform–ether.
level. As shown in Table 3, both the CBS-4M and
MP2/6-31þG*//HF/6-31þG* calculation levels give si-
G
milar and coherent results. The ꢁF of CN, C(O)NH and
2
C(O)NHC(O)OEt is 0.66, 0.27, and 0.35, respectively,
indicating that the sequence of the inductive effect is
CN > C(O)NHC(O)OEt > C(O)NH . It was reported that
1
Yield: 75%; H NMR (CD CN), ꢄ 1.23 (3H, t, CH ),
3
2
3
acetonitrile is three orders of magnitude more acidic than
6
N,N-dimethylacetamide, indicating that more of the
1.34 (3H, t, CH ), 4.12 (2H, q, CH ), 4.39 (2H, q, CH ),
3 2 2
13
8.17 (1H, s, CH), 9.12 (1H, s, NH); C NMR (CDCl ), ꢄ
3
acidity of acetonitrile is dominated by the inductive effect
because the amide group is a better ꢀ-acceptor than the
nitrile group.
14.80, 15.87, 63.13, 75.69, 89.30, 114.69, 152.22,
162.01, 175.13; IR (thin film), 2227 (CN), 1774, 1689
ꢀ
1
þ
—
(C—O) cm ; MS (EI) m/z 212 (4, M ), 118 (100), 88
32), 74 (24), 57 (28); HRMS (EI), m/z calc. for
C H N O 212.0797, found 212.0801.
(
9
12 2 4
Acknowledgement
ð10Þ
1
1a,12a: R¼ H; 11b,12b:R ¼ CN; 11c,12c: R¼ C(O)NH ;
Financial support by the National Science Council of
Taiwan (NSC 92-2113-M-006-010) and computer time
from the National Center for High-performance Comput-
ing of Taiwan are gratefully acknowledged.
2
1
1d,12d: R ¼ C(O)NHC(O)OEt
CONCLUSION
The highly stereoselective reaction of 1 with ethyl ortho-
formate in the presence of acetic anhydride produces E-2
only. The E-2 cannot be isomerized to Z-2 thermally but it
can photochemically, whereas Z-2 can be isomerized
back to E-2 thermally, indicating that the reaction of 1
with ethyl orthoformate is thermodynamically controlled.
The calculated free energy of Z/E isomerization from Z-2
to E-2 is ꢀ3.43 kcal mol , which is thermodynamically
favourable and consistent with the experimental results.
Negative entropy is not favourable for this isomerization,
but favourable enthalpy dominates. Both the resonance
REFERENCES
1
. (a) Leeming P, Ray CA, Simpson SJ, Wallace TW, Ward RA.
Tetrahedron. 2003; 59: 341–352; (b) Volle JN, Schlosser M. Eur.
J. Org. Chem. 2002; 9: 1490–1492; (c) Wang JH, Shen YQ, Yu
CX, Si JH. J. Chem. Soc., Perkin Trans. 1 2000: 1455–1460; (d)
Palanki MSS, Erdman PE, Gayo-Fung LM, Shevlin GI, Sullivan
RW, Suto MJ, Goldman ME, Ransone LJ, Bennett BL, Manning
AM. J. Med. Chem. 2000; 43: 3995–4004; (e) Hanack M,
Hackenberg J, Menke O, Subramanian LR, Schlichenmaier R.
Synthesis 1994: 249–251; (f) Phillips JG, Chu D, Seif L, Spanton
S, Henry R, Plattner JJ. Tetrahedron Lett. 1993; 34: 3259–3262;
(g) McFadden HG, Huppatz JL, Aust. J. Chem. 1991; 44: 1263–
1273; (h) Chu DTW, Lico IM, Claiborne AK, Faubl H. Can. J.
Chem. 1991; 25: 1521–1527; (i) Hosmane RS, Bertha CM. J. Org.
Chem. 1990; 55: 5206–5216;(j) Doleschall G, Seres P. J. Chem.
Soc., Perkin Trans. 1 1988: 1875–1879; (k) Moriya O, Urata Y,
Ikeda Y, Ueno Y, Endot T. J. Org. Chem. 1986; 51: 4708–4709;
ꢀ1
ꢀ
1
stabilization of 1.47 kcal mol and the steric hindrance
ꢀ1
of 2.28 kcal mol in favor of E-2 contribute to the energy
ꢀ
1
difference (3.75 kcal mol ) between Z-2 and E-2 calcu-
lated from the four isodesmic reactions of Eqns (3)–(6),
which causes the reaction of 1 with ethyl orthoformate
to be highly stereoselective. The nitrile group is a better
(
1
l) Perez MA, Soto JL, Guzman F, Diaz A. Synthesis 1984: 1045–
047; (m) Arys M, Christensen TB, Eriksen J. Tetrahedron Lett.
1984; 25: 1521–1524.
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1183–1189

STEREOSELECTIVE REACTION OF ETHYL (2-CYANOACETYL)CARBAMATE WITH ETHYL ORTHOFORMATE
1189
2
3
. Ceder O, Stenhede U. Tetrahedron 1973; 29: 1585–1590.
. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Zakrzewski VG, Montgomery JA, Jr., Stratmann
RE, Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN,
Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R,
Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J,
Petersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK,
Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz
JV, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I,
Gomperts R, Martin RL, Fox DJ, Keith T, AlLaham MA, Peng
CY, Nanayakkara A, Gonzalez C, Challacombe M, Gill PMW,
Johnson B, Chen W, Wong M W, Andres JL, Gonzales C, Head-
Gordon M, Replogle ES, Pople JA. Gaussian98, Revision A9.
Gaussian: Pittsburgh, PA, 1998.
5. Silverstein RM, Webster FX. Spectrometric Identification of
Organic Compounds (6th edn). John Wiley: New York, 1998.
6. Carey FA, Sundberg RJ. Advanced Organic Chemistry, Part A: Struc-
ture and Mechanism (2nd edn). Plenum Press: New York, 1984.
7. Isaacs N. Physical Organic Chemistry (2nd edn). Longman
Scientific & Technical: Harlow, Essex, 1995.
8. Lide DR. Handbook of Chemistry and Physics (85th edn). CRC
Press: New York, 2004.
9. Morrison RT, Boyd RN. Organic Chemistry (6th edn). Prentice
Hall International: London, 1992.
10. (a) Sung K. J. Org. Chem. 1999; 64: 8984–8989; (b) Sung, K.
J. Chem. Soc., Perkin Trans. 2 1999: 1169–1173; (c) Sung, K.
J. Chem. Soc., Perkin Trans. 2 2000: 847–852.
11. (a) Hansch C, Leo A, Taft RW. Chem. Rev. 1991; 91: 165–195; (b)
Charton M, Prog. Phys. Org. Chem. 1981; 13: 119–251.
12. Sung, K. J. Chem. Soc., Perkin Trans. 2 2002: 1658–1661.
13. Atkinson MR, Shaw G, Warrener RN. J. Chem. Soc. 1956: 4118–
4123.
4
. (a) Sung K, Wu SH, Wu RR, Sun SY. J. Org. Chem. 2002; 67:
4
298–4303; (b) Foresman JB, Frisch A. Exploring Chemistry with
Electronic Structure Methods (2nd edn). Gaussian: Pittsburgh PA,
996.
1
Copyright # 2005 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2005; 18: 1183–1189