Enols of 2-nitro- and related 2-substituted malonamides

Article abstract of DOI:10.1002/poc.1611

The structures of 2-substituted malonamides, YCH(CONR¹R ²)CONR³R⁴ (Y=Br, SO₂Me, CONH ₂, COMe, and NO₂) were investigated. When Y=Br, R ¹R²=R³R⁴=HEt; Y=SO₂Me, R¹-R⁴=H and for Y=CONH₂ or CONHPh, R ¹-R⁴=Me, the structure in solution is that of the amide tautomer. X-ray crystallography shows solid-state amide structures for Y=SO ₂Me or CONH₂, R¹-R⁴=H. Nitromalonamide displays an enol structure in the solid state with a strong hydrogen bond (O^{. . .}O distance=2.3730 A at 100 K) and d(OH) 6≠d(O^{. . .}H). An apparently symmetric enol was observed in solution, even in appreciable percentages in highly polar solvents such as DMSO-d₆, but K_enol values decrease on increasing the solvent polarity. The N,N′-dimethyl derivative is less enolic. Acetylmalonamides display a mixture of enol on the acetyl group and amide in non-polar solvents, and only the amide in DMSO-d₆. DFT calculations gave the following order of pK_enol values for Y: H > CONH ₂ > COMe ≥ COMe (on acetyl) ≥ MeSO₂>CN> NO₂ in the gas phase, CHCl₃, and DMSO. The enol on the C=O group is preferred to the aci-nitro compound, and theN-O-H^{. . .}O=C is less favored than the C=O-H^{. . .}O=C hydrogen bond. Copyright

Full text of DOI:10.1002/poc.1611

Research Article
Received: 9 June 2009,
Revised: 7 July 2009,
Accepted: 8 July 2009,
Published online in Wiley InterScience: 9 September 2009
(www.interscience.wiley.com) DOI 10.1002/poc.1611
Enols of 2-nitro- and related 2-substituted
malonamides
Ahmad Basheera, Masaaki Mishimab and Zvi Rappoporta
*
The structures of 2-substituted malonamides, YCH(CONR1R2)CONR3R4 (Y ¼ Br, SO2Me, CONH2, COMe, and NO2) were
investigated. When Y ¼ Br, R1R2 ¼ R3R4 ¼ HEt; Y ¼SO2Me, R1–R4 ¼ H and for Y ¼CONH2 or CONHPh, R1–R4 ¼ Me, the
structure in solution is that of the amide tautomer. X-ray crystallography shows solid-state amide structures for
Y ¼SO2Me or CONH2, R1–R4 ¼ H. Nitromalonamide displays an enol structure in the solid state with a strong hydrogen
bond (O. . .O distance ¼ 2.3730 A at 100 K) and d(OH) ¼ d(O. . .H). An apparently symmetric enol was observed in
˚
solution, even in appreciable percentages in highly polar solvents such as DMSO-d6, but Kenol values decrease on
increasing the solvent polarity. The N,N(-dimethyl derivative is less enolic. Acetylmalonamides display a mixture of
enol on the acetyl group and amide in non-polar solvents, and only the amide in DMSO-d6. DFT calculations gave the
following order of pKenol values for Y: H > CONH2 > COMe ‡ COMe (on acetyl) ‡ MeSO2 > CN > NO2 in the gas phase,
. . .
—
—
C is less
—
CHCl , and DMSO. The enol on the C O group is preferred to the aci-nitro compound, and the N—O—H
O
—
3
. . .
—
—
—
favored than the C O—H
O
C hydrogen bond. Copyright ß 2009 John Wiley & Sons, Ltd.
—
Supporting information may be found in the online version of this article.
Keywords: enols; nitromalonamides; solvent effects; substituent effects; calculations
˚
non-bonding distances of 2.4–2.5 A, indicating the existence of
very strong intramolecular hydrogen bonds.
INTRODUCTION
Extensive data on keto/enol equilibria (Eqn (1)) are available for
aldehydes and ketones (2, X ¼ H, alkyl, Ar). The equilibrium
constant Kenol ¼ [1]/[2] depends on the nature of Y and Y0.[1]
In the present work, our aims were the following: (a) to extend
the scope of enolizable 2-substituted malonamides and compare
the effects of Cb-EWGs (Br, NO2, CN, CONH2, SO2Me, COMe,
CO2Me) on the extent of enolization in solution or on the
solid-state structure, with the Cb-CN analogs; (b) to investigate
the enolization regioselectivity when more than one enolization
site is available.
Kenol
Y0YCbHCað¼ OÞX
Y0YCb¼ CaðOHÞX
ꢀꢀꢀꢀꢀ*
)ꢀꢀꢀꢀꢀ
ð1Þ
2
1
Enols (1) of carboxylic acid derivatives (2, X ¼OH, OR, NRR0,
OCOR) are much less stable and their Kenol values are many orders
of magnitude smaller than those of aldehydes and ketones.[2,3]
Recent studies on the preparation of these enols, especially of
amides, involve two approaches. (1) Addition of nucleophiles
(e.g., H2O, RR0NH) to ketenes;[4–14] this mostly gives short-lived
enols,[4–14] although several of them are kinetically stabilized by
bulky aryl groups[15–23] and are sufficiently long-lived to be
detected by 1H and 13C NMR spectroscopies.[15–23] (2) Addition of
organic isocyanates RNCO to CH2YY0 (where Y and Y0 are
electron-withdrawing groups (EWGs)) gives the amides 2, and/or
their enols 1, X ¼ NRR0 or 1/2 mixtures.[24–32] Many of these enols
are thermodynamically stable and many of their solid state
structures were determined by X-ray crystallography. Their
stability is consistent with calculations: e.g., the calculated
pKenol ¼ ꢀlog Kenol value for (NC)2CHCONH2 is ꢀ0.2 (H. Yamataka,
unpublished results), and the enol was indeed isolated.
By using the second approach, more than 150 Y0Y-substituted
enols of amides, 1, X ¼ NRR0, were prepared.[24–32] Recently inves-
tigated systems are the enols of cyanomalonamides R1R2NCOCH(CN)-
CONHR3 3.[33] They display high Kenol values, e.g., when R3 ¼ Ph, Kenol
in CDCl3 ¼ 4.0, 9.0, and ꢁ50 for NR1R2 ¼ NMe2, NHMe, and NH2,
respectively, and the enols are observed even in the highly polar
DMSO-d6. In the solid state, the enols display very short OꢂꢂꢂO
RESULTS
Synthesis
Nine substituted malonamides were prepared. Bromination of
malonamides 4a and 4b in AcOH solution gave the known
bromomalonamides 5a and 5b[34] (Eqn (2)). Reaction of sodium
dimethyl malonate with methanesulfonyl chloride gave the
dimethyl methylsulfonylmalonate 6, which reacted with 25%
ammonia solution to give methylsulfonylmalonamide 7 (Eqn (3)).
The known tricarbomethoxymethane 8[35] was similarly prepared
*
Correspondence to: Z. Rappoport, Institute of Chemistry and the Lise Meitner
Minerva Center for Computational Quantum Chemistry, The Hebrew Univer-
sity, Jerusalem 91904, Israel.
E-mail: zr@vms.huji.ac.il
a
A. Basheer, Z. Rappoport
Institute of Chemistry and the Lise Meitner Minerva Center for Computational
Quantum Chemistry, The Hebrew University, Jerusalem 91904, Israel
b
M. Mishima
Institute for Materials, Chemistry and Engineering, Kyushu University,
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
J. Phys. Org. Chem. 2010, 23 255–265
Copyright ß 2009 John Wiley & Sons, Ltd.

A. BASHEER, M. MISHIMA AND Z. RAPPOPORT
from dimethyl malonate and methyl chloroformate. Its reaction
with concentrated NH3 solution gave the known methanetri-
carboxamide 9[36] (Eqn (3)). An asymmetric triamide 11 was
prepared by reacting the anion of the diamide 10 with phenyl
isocyanate (Eqn (4)).
Bromomalonamides 5 show only CH amide signals but no OH
enol signals at d ¼ 4.60–4.71 in CDCl3 and DMSO-d6 solution. The
MeSO2-substituted malonamide 7, which is highly insoluble in
CDCl3 even to obtain NMR data in a 600 MHz instrument, displays
only an amide structure in the NMR spectra in DMSO-d6 solution.
Methanetricarboxamide 9[36] is insoluble in CDCl3, and in THF-d8
and DMSO-d6 solution it displays only the amide signals. Previous
calculation showed that 9 is more stable than its isomeric enol
with pKenol ¼ 1.3 (H. Yamataka, unpublished results). Its
N,N,N0,N0-tetramethyl, N00-phenyl derivative 11, which is soluble
in CDCl3, shows only amide signals.
CH2ðCONHRÞ2 þ Br2=AcOH
4a: R ¼ H
BrCHðCONHRÞ2
5a: R ¼ H
(2)
4b: R ¼ Et
5a: R ¼ Et
Tautomerism of nitromalonamide 12a was previously studied
in DMSO-d6 solution and isomers 12a, 13a (45:55 ratio), and the
ð3Þ
enol imine HOC( NH)CH(NO )CONH were identified.[38] 12a is
—
—
2
2
insoluble in CDCl3 and is 100, 100, 82, and 51% enolic (13a) in
THF-d8, CD3CN, DMF-d7, and DMSO-d6, respectively (Table 1). In 4,
2, 1, 0.67, and 0.5 ratios of CDCl3:DMSO-d6 mixtures, the spectra
display 99, 96, 89, 83, and 79% of 13a, respectively. We did not
observe the enol imine in DMSO-d6. More negative pKenol values
in solvents of lower polarity were found in all earlier studies of
intramolecularly hydrogen-bonded enols.[24–31] The high enol
percentage contrasts with the small percentage (ꢃ10%) of the
enol of the nitro-activated system, 1a/2a, X ¼ NHPh, Y ¼ NO2,
Y0 ¼CO2Et in CDCl3[25]. In the 1H NMR spectra, the d(OH) is at
18.73–18.93 in THF-d8, CD3CN, DMF-d7, and DMSO-d6. The OH
signals are sharp with the integration of half of the intensity of the
NH2 signals of 13a. In mixtures of DMSO-d6 and CDCl3, traces of
CH2ðCONMe2Þ þPhNCO Et N=DMF PhNHCOCHðCONMe2Þ (4)
3
2
2
10
11
Nitration of malonamides 4a and 4c with 100% fuming nitric
acid at ꢀ10 8C, according to Johnson and Nicolet,[37] gave the
stable enols 13a and 13b of the nitromalonamides 12a and 12b
(Eqn (5)). Attempts to prepare N,N,N0,N0-tetramethylnitromalon-
amide 14 by nitration of N,N,N0,N0-tetramethylmalonamide with
100% fuming nitric acid at ꢀ10 8C (and raising the temperature to
35 8C) or in AcOH with 99% nitric acid at 10–20 8C failed.
100% fuming HNO3
CH2ðCONHRÞ
4a : R ¼ H
O2NCHðCONHRÞ2 or RNHCðOHÞ ¼ CðNO2ÞCONHR
(5)
12a : R ¼ H
13a : R ¼ H
4c : R ¼ Me
12b : R ¼ Me
13b : R ¼ Me
Reaction of the sodium salt of acetoacetanilide 15 with the
isocyanates 16a and 16b yielded both the acetylmalonamides
17a and 17b and their E/Z isomeric enols on the acetyl group 18a
and 18b (Eqn (6)).
sharp H2O signals are observed at 3.2–3.3 ppm[39] (and 2.14 ppm
in CD3CN)[39] with 0.6–3.0-fold higher intensities of the H2O
signal. This excludes a significant exchange of enolic OH with H2O
at the above concentrations. A lack of observed exchange is
common for enols of amides substituted by b,b-EWGs having
high d(OH) values, probably due to the strong intramolecular
hydrogen bonding in the enols (H. Yamataka, unpublished
results).[24–33] The NH2 signals of either 12a or 13a display two 2H
signals of equal intensity for the different NH groups (Table 1). In
CD3CN, there is some broadening of the OH and 13a NH2 signals,
suggesting that these groups are involved in a mutual exchange
process, well below the coalescence temperature. The 13C NMR
spectra display only two low field signals: for Ca at 170.2 and for
Cb at 106.1 ppm in DMSO-d6 and at 171.5 and 107.4 ppm in
DMF-d7, respectively (Table 1). The NMR d values are similar to
those reported.[38] In contrast with the asymmetric solid state
structure (as discussed below), the 1H- and 13C-NMR data in
solution indicate an ‘apparent’ symmetry, reflected in the
identical NHR groups (Fig. 1), in contrast with the calculations
(see below). This is ascribed to the O—H. . .O hydrogen bond in
13a with a low barrier to the enolic H movements between the
oxygens.[33,40]
Structures in solution
All systems were investigated in solution by 1H and 13C NMR
spectroscopy in order to determine if their structure is the amide,
its enol, or their mixture. The data are given in Table 1 and in
Tables S1 and S2 of the Supporting Information. The enols of
acetylmalonamides 18a and 18b display low field OH signals at
15.42–16.04 ppm. The lowest field OH signals are at >18.7 ppm
for the nitromalonamides 13a and 13b (Table 1). The Kenol values
were calculated from the relative integration of appropriate
signals such as CH(amide) or NH (amide) versus OH or NH (enol).
The possibility of enolization on the NO2 group is discussed below.
In DMSO-d6, 13a shows only a negligible concentration effect
on the OH chemical shift (Table 2). Based on the behavior of other
systems[27,29,41] where OH ionization followed by interaction of
the formed proton with H2O, is reflected by large upfield chemical
shifts, this is interpreted as evidence that 13a does not significantly
ionize. Moreover, it strengthens the absence of exchange of the OH
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 255–265

2-NITRO- AND RELATED 2-SUBSTITUTED MALONAMIDES
J. Phys. Org. Chem. 2010, 23 255–265
Copyright ß 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

A. BASHEER, M. MISHIMA AND Z. RAPPOPORT
effects were calculated by using both the Onsager reaction field
model[43–47] and the continuum PCM-SCRF model.[48–51] The best
agreement of the observed pKenol results is with the PCM values
*
at B3LYP/6-31þG as follows: Y, solvent: pKenol(cal.), pKenol(obs.):
H, H2O,10.0, 9.2–9.7;[52] NO2, DMSO, ꢀ2.2, ꢀ0.02; 12b, CHCl3 ꢀ2.3,
ꢄꢀ2.0; THF,ꢀ2.2, ꢀ1.28; MeCN, ꢀ1.7, ꢀ1.06; DMSO, ꢀ1.5, 0.75;
**
17a, CHCl3, 1.2, ꢀ0.14; 17b, CHCl3, 2.2, 0.05. The B3LYP/6-31G
values are several pKenol units more negative, e.g., by ca. 4.0 units
for 12a and 12b in the gas phase. The corresponding
**
6-311þþG values are ca. 1.7 pKenol units lower than at
*
B3LYP/6-31þG . Likewise for the gas phase pKenol values of the
Figure 1. Structures of two conformers of the enol of nitromalonamide.
(a) A formal symmetric structure 13 with an O—H. . .
O
C hydrogen bond.
model PhNHCOCH(CO2Me)CO2R, the available reliable exper-
—
—
(b) A non-symmetric structure 19 with an O—H. . .ONO hydrogen bond
imental data in CCl4 when R ¼ Me, CH2CF3 (both E and Z)[24–26]
**
**
follow the order B3LYP/6-31G < B3LYP/6-311þþG < B3LYP/
with traces of water in the DMSO-d6. This contrasts Sebban et al.[38]
report of d(OH)¼ 3.46 for 13 in DMSO-d6, which was ascribed to OH
exchange with residual water.
6-31þG and are closer to the B3LYP/6-31þG values (Table S5 of
*
*
*
the Supporting Information). Consequently, the B3LYP/6-31þG
values are used in this work.
*
Although a 16-fold dilution decreases the Kenol values, all the values
except for the first value are within the integration error of ꢅ2%.
N,N0-Dimethylnitromalonamide 12b is soluble in CDCl3 where
it is 100% enolic. The percentage of the enol decreases with the
increased solvent polarity, being 95, 92, 49, and 15% in THF-d8,
CD3CN, DMF-d7, and DMSO-d6, respectively. The d(OH) is again at
a very low field: 19.17 (CDCl3), 19.29 (THF-d8), 19.20 (CD3CN), and
19.51 (C6D6). Ca and Cb again display only one signal each, at
168.8–169.0 and 106.6–107.5, respectively (Table 1). The trend of
higher percentage of enol for the less N-substituted systems
resembles that for the cyanomalonamides.[33]
Acetylmalonamides 17/18 display a mixture of amide and enol
on the acetyl group in CDCl3. When the two amide groups are
identical as in 18a, only signals for one enol were observed,
whereas for 18b with two different amide groups, signals for the
two E/Z enol isomers were observed (Eqn (6)). Attempts to
crystallize these compounds for X-ray crystallography have failed,
since malonamides were obtained by decomposition.
A correlation of the B3LYP/6-31þG pKenol values versus the
observed values deviate significantly from linearity (R2 ¼ 0.857)
(Fig. S1 of the Supporting Information). Other features arising
from Table 3 are: (a) all the pKenol PCM values, except two, are
0.2–2.7 units (1.4–8.7 in water) more negative than the
corresponding Onsager values; (b) three minima were found
for acetylmalonamide in the gas phase and CHCl3. The pKenol
*
values (gas phase or CHCl3) at PCM, B3LYP/6-31þG are 0.7(2.1),
0.2(1.8), and ꢀ0.9 (0.7), respectively, for Y ¼COMe-1 which
enolizes on the amide with OH. . .O ¼ CNH2 H-bond, COMe-2
which enolizes on the amide with OH. . .
O
—
CMe H-bond, and
—
COMe-3 which enolizes on the acetyl with a MeCOH. . .
O
—
CNH
—
2
H-bond. (c) The order of pKenol values for
Y
is:
H > CONH2 > COMe ꢁ COMe (on acetyl) ꢁ MeSO2 > CN > NO2
and pKenol(12b) > pKenol (12a) in the gas phase, CHCl3 and
DMSO. The order of pKenol’s for Y ¼ MeCO (on acetyl) and MeSO2
is solvent dependent.
DFT calculations
DFT calculations of DH, DG, DS, and pKenol values for the most
stable conformations of YCH(CONH2)2, 17a/18a, 17b/18b, and
their tautomers (Table 3 and Tables S3 and S4 of the Supporting
*
**
Information) at B3LYP/6-31þG and B3LYP/6-31G were con-
ducted, both for the gas phase, CHCl3 (dielectric constant
e ¼ 4.89)[42] and DMSO (e ¼ 46.45)[42] solutions, and for 12a/13a
and 12b/13b in MeCN and THF, and CH2(CONH2)2 in H2O, for
which experimental pKenol values are available. The solvent
(d) The gas phase pKenol values are more negative than those in
CHCl3 by ꢀ0.2 to ꢀ2.3 units. (e) The solvent effect on pKenol values
follows the polarity of the media: gas phase < CHCl3 < THF <
MeCN < DMSO < <H2O, except that for Y ¼ H, CONH2
pKenol(CHCl3) ¼ pKenol(DMSO).
As the well known nitro fi aci-nitro equilibria can display
significant equilibrium constants,[53] the possibility that for
Y ¼ NO2, the observed ‘enols’ in solution are indeed the aci-nitro
tautomers 19a and 19b cannot be ignored, although exper-
imental evidence for 19a was not previously mentioned in
Table 2. Concentration effect of 12a on Kenol and d (OH)
values in DMSO-d6.
Dilution factor
d(OH)
%Amide
%Enol
Kenol
studies of nitromalonamide.[38,54] This question is related to the
—
1a
2
3
4
8
16
18.71
18.72
18.72
18.72
18.72
18.72
39.5
43.5
45
46
47.5
47.5
60.5
56.5
55
54
52.5
52.5
1.53
1.30
1.22
1.17
1.11
1.11
possibility that an OH. . .ONO rather than an OH. . .
bond exists in the enol (as discussed below).
O
C hydrogen
—
However, gas phase computations at various levels had shown
that in closely related equilibrium between the enol
a
2-hydroxy-1-nitroethylene 20 and the aci-nitro-2-oxo tautomer
21 (Eqn (7)), 20 is 4–5 kcal/mol more stable than 21.[55] We
reported in a preliminary calculation that enolization of 12a to
13a is favored over the formation of the aci-nitro tautomer
a 0.1 M of 12a.
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 255–265

2-NITRO- AND RELATED 2-SUBSTITUTED MALONAMIDES
Table 3. Thermodynamic differences and pKenol values between enol and amide (enol–amide) for amide/enol pairs using the PCM
*
**
and Onsager models at B3LYP/6-31þG or at B3LYP/6-31G for YCH(CONH2)2 in kcal/mol (DS in e.u.) in the gas phase and in several
solventsa
Y
Solvent
DH
DG
DS
pKenol
H
Gas-phase
9.0
5.6
10.9
7.5
ꢀ6.4
S6.3
8.0
5.5
CHCl3
11.0(8.4)
7.3(6.7)
11.2(9.4)
7.4(6.8)
12.8(9.4)
8.6(6.8)
2.2
S0.4
2.6 (1.8)
12.0 (10.2)
8.4 (7.7)
12.0 (10.4)
8.5 (7.7)
13.6 (10.4)
9.7 (7.8)
3.9
1.7
4.3 (3.5)
0.2 (1.2)
4.3 (3.3)
0.2 (1.0)
1.0
S3.7
2.9 (0.9)
S2.4 (S4.0)
3.7 (1.0)
S2.5 (S4.2)
0.5
ꢀ3.3 (ꢀ6.0)
S3.5 (S3.3)
ꢀ2.8 (ꢀ3.2)
S3.6 (S3.1)
ꢀ2.6 (ꢀ3.2)
S3.5 (S3.1)
ꢀ5.8
8.8 (7.5)
6.1 (5.6)
8.8 (7.6)
6.2 (5.7)
10.0 (7.6)
7.1 (5.7)
2.9
DMSO
H2O
CONH2
MeCO-1b
MeCO-2b
MeCO-3c
MeSO2
CN
Gas-phase
CHCl3
S7.1
1.3
ꢀ5.6 (ꢀ5.7)
S3.4 (S7.0)
ꢀ5.1 (ꢀ5.7)
S3.2 (S6.9)
ꢀ5.3
3.1 (2.6)
0.2 (0.9)
3.1 (2.4)
0.1 (0.7)
0.7
S0.8 (S0.9)
2.8 (1.6)
DMSO
S0.8 (S1.1)
ꢀ0.6
Gas-phase
CHCl3
S5.0
S4.3
S2.7
0.4(ꢀ0.7)
S5.5(S5.3)
1.3(ꢀ0.8)
S4.2(S5.5)
ꢀ1.0
ꢀ8.5 (ꢀ5.6)
S10.3 (S4.3)
ꢀ8.0 (ꢀ5.8)
S5.7 (S4.3)
ꢀ5.2
2.1 (0.7)
S1.8 (S3.0)
2.7 (0.7)
S1.8 (S3.1)
0.4
DMSO
Gas-phase
CHCl3
S5.4
S4.0
2.4 (0.3)
S2.9 (S4.3)
3.1(0.2)
S4.5
S3.0
ꢀ0.1(ꢀ1.3)
S5.9(S5.7)
0.8(ꢀ1.5)
S4.6(S5.8)
ꢀ1.8
ꢀ8.4 (ꢀ5.4)
S10.2 (S4.7)
ꢀ7.8(ꢀ5.7)
S5.5(S4.7)
ꢀ4.2
1.8 (0.2)
S2.1 (S3.1)
2.3(0.2)
DMSO
S3.0(S4.4)
ꢀ0.5
S2.2(S3.2)
ꢀ0.4
Gas-phase
CHCl3
S5.4
S4.3
S3.9
S3.1
ꢀ1.2 (2.5)
S6.1 (S6.0)
ꢀ0.4 (ꢀ2.8)
S4.8 (S6.2)
ꢀ2.0
1.0 (ꢀ1.2)
S3.3 (S4.8)
1.7 (ꢀ1.4)
S3.5 (S5.0)
ꢀ0.8
ꢀ7.3 (ꢀ4.4)
S9.4 (S4.0)
ꢀ7.0 (ꢀ4.7)
S4.7 (S4.1)
ꢀ4.0
0.7 (ꢀ0.9)
S2.4 (S3.5)
1.2 (ꢀ1.0)
S2.5 (S3.7)
ꢀ0.6
DMSO
Gas-phase
CHCl3
S5.8
S4.8
S3.2
S3.6
0.2 (ꢀ1.9)
S4.1 (S5.8)
1.3 (ꢀ1.8)
S3.2 (S5.9)
ꢀ4.7
1.4 (ꢀ0.6)
S3.1 (S4.9)
2.6 (ꢀ0.5)
S2.2 (S4.9)
ꢀ4.3
ꢀ3.9 (ꢀ4.1)
S3.2 (S3.2)
ꢀ4.4 (ꢀ4.2)
S3.2 (S3.2)
ꢀ1.2
1.0(ꢀ0.5)
S2.3 (S3.6)
1.9 (ꢀ0.4)
S1.6 (S3.6)
ꢀ3.2
DMSO
Gas-phase
CHCl3
S8.0
S7.8
S0.5
S5.7
ꢀ2.8 (ꢀ3.1)
S6.5 (S6.4)
ꢀ1.8 (ꢀ2.4)
S5.7 (S5.7)
ꢀ8.0
ꢀ2.2 (ꢀ2.9)
S6.2 (S6.5)
ꢀ1.3 (ꢀ2.5)
S5.4 (S6.4)
ꢀ6.2
ꢀ1.8 (ꢀ0.7)
S0.9 (0.3)
ꢀ1.8 (0.1)
S0.8 (2.3)
ꢀ5.9
ꢀ1.6 (ꢀ2.1)
S4.5 (S4.8)
ꢀ0.9 (ꢀ1.8)
S4.0 (S4.7)
ꢀ4.5
DMSO
NO2
Gas-phase
CHCl3
S13.3
S11.5
S5.8
S8.5
ꢀ5.8 (ꢀ6.6)
S11.3 (S12.2)
ꢀ5.4 (ꢀ6.4)
S10.9 (S12.1)
ꢀ4.7 (ꢀ6.1)
S10.3 (S11.8)
ꢀ4.0 (ꢀ5.0)
S9.5 (S10.5)
ꢀ3.7 (ꢀ4.8)
S9.1 (S10.4)
ꢀ2.9 (ꢀ4.4)
S8.5 (S10.1)
ꢀ6.0 (ꢀ5.6)
S6.0 (S5.7)
ꢀ5.8 (ꢀ5.6)
S6.0 (S5.7)
ꢀ5.9 (ꢀ5.5)
S6.1 (S5.7)
ꢀ2.9 (ꢀ3.7)
S7.0 (S7.7)
ꢀ2.7 (ꢀ3.5)
S6.7 (S7.6)
ꢀ2.1 (ꢀ3.3)
S6.3 (S7.4)
THF
MeCN
(Continues)
J. Phys. Org. Chem. 2010, 23 255–265
Copyright ß 2009 John Wiley & Sons, Ltd.
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A. BASHEER, M. MISHIMA AND Z. RAPPOPORT
Table 3. (Continued)
Y
Solvent
DMSO
DH
DG
DS
pKenol
ꢀ4.7 (ꢀ6.1)
S10.4 (S12.2)
2.7 (ꢀ6.0)
ꢀ3.0 (ꢀ4.4)
S8.6 (S10.5)
4.6 (ꢀ4.4)
ꢀ5.8 (ꢀ5.5)
S5.9 (S5.7)
ꢀ6.3 (ꢀ5.5)
S6.1 (S5.7)
ꢀ2.2 (ꢀ3.2)
S6.3 (S7.7)
3.4 (ꢀ3.2)
H2O
S3.6 (S11.8)
S1.8 (S10.1)
S1.3 (S7.4)
YCH(CONHR1)CONHR2
NO2CH(CONHMe)2
d
Gas-phase
CHCl3
ꢀ9.1
S13.3
ꢀ6.3
S10.6
ꢀ9.2
ꢀ4.6
S7.8
S8.9
ꢀ5.6 (ꢀ6.5)
S9.5 (S11.5)
ꢀ5.3 (ꢀ6.2)
S10.7 (S11.4)
ꢀ4.6 (ꢀ5.9)
S10.2 (S11.1)
ꢀ4.5 (ꢀ5.9)
S10.1 (S11.7)
5.8 (ꢀ5.9)
S1.6 (S11.6)
0.2
ꢀ3.2 (ꢀ4.3)
S6.9 (S10.5)
ꢀ3.0 (ꢀ4.1)
S8.9 (S10.4)
ꢀ2.3 (ꢀ3.7)
S8.6 (S10.1)
ꢀ2.1 (ꢀ3.8)
S8.5 (S9.0)
8.3 (ꢀ3.7)
1.2 (S8.9)
1.3
ꢀ8.2 (ꢀ7.2)
S8.9 (S3.4)
ꢀ7.7 (ꢀ7.2)
S6.0 (S3.4)
ꢀ7.5 (ꢀ7.3)
S5.2 (S3.3)
ꢀ8.1 (ꢀ7.3)
S5.3 (S8.9)
ꢀ8.6 (ꢀ7.3)
S9.4 (S8.9)
ꢀ3.7
ꢀ2.3 (ꢀ3.2)
S5.0 (S7.7)
ꢀ2.2 (ꢀ3.0)
S6.5 (S7.6)
ꢀ1.7 (ꢀ2.7)
S6.3 (S7.4)
ꢀ1.5 (ꢀ2.8)
S6.3 (S6.6)
6.1 (ꢀ2.7)
0.9 (S6.6)
1.0
THF
MeCN
DMSO
H2O
MeCOCH-
(CONHPh)2
Gas-phase
CHCl3
e
S2.4
S1.7
1.7(1.0)
S2.5
S1.2
1.2(0.5)
0.7(ꢀ0.2)
ꢀ3.2(ꢀ3.7)
S2.4(ꢀ2.7)
ꢀ2.9(ꢀ3.8)
S2.3(ꢀ2.9)
ꢀ5.2
S2.0(ꢀ2.9)
1.0(ꢀ0.4)
S1.3(ꢀ2.1)
S0.9(ꢀ1.5)
DMSO
Gas-phase
CHCl3
1.9(0.8)
S1.1(ꢀ2.3)
1.0
1.4(0.6)
S0.8(ꢀ1.7)
0.7
S1.8(ꢀ3.1)
ꢀ0.5
MeCOCH-
(CONHPh)CONHPr ꢀ if
3.9
0.6(ꢀ1.1)
S2.7
3.0(0.6)
S1.8(S3.1)
2.6(0.4)
S3.9
S2.0
2.2(0.5)
S1.3(S2.3)
1.9(0.3)
ꢀ7.9(ꢀ5.8)
S4.6(S4.3)
ꢀ4.2(ꢀ6.0)
S5.9(ꢀ4.6)
S3.2(S4.4)
1.3(ꢀ1.4)
DMSO
S3.1(ꢀ4.7)
S1.4(ꢀ3.4)
S1.0(ꢀ2.5)
a
*
Values in roman font with no parentheses were calculated at PCM at B3LYP/6-31þG and values in bold font were calculated by PCM
**
at B3LYP/6-31G . Values in parentheses were calculated by the Onsager method. For values calculated by the SCRF-PCM model, the
molecular cavity used is the united atom topological model applied on radii optimized for the HF/6-31G(d) level of theory.
b For enolization on the CONH2 group (refer to text).
c For enolization on the COMe group (refer to text).
d 12b/13b.
e 17a/18a.
f 17b/18b.
19a.[33] B3LYP/6-31þG calculations now give pKenol values of
6-31G , the pKenol values are ꢀ3.0 and ꢀ6.6 for 19a and ꢀ2.9
*
**
ꢀ2.2 and ꢀ1.7 for the formation of enols 19a
and ꢀ7.2 for 19b, compared with the respective values of ꢀ4.5,
ꢀ8.5 for 13a and ꢀ3.9, ꢀ7.8 for 13b (Table 3). Earlier calculations
indicate that the conformer 21a is 2.6 kcal/mol less stable than
13a.[52]
Structures in the solid state
X-ray diffractions of the MeSO2- and H2NCO-substituted
malonamides 7 and 9 display amide structures. Significant bond
lengths and angles are given in Table 4, and additional data, the
ORTEPs, and the calculated values are given in the CIFs and in Fig.
S2 of the Supporting Information.
and 19b having N—O—H. . .
O
C hydrogen bonds. At higher
**
—
—
**
levels (B3LYP/6-31G and B3LYP/6-311þþG ), the aci-nitro
structures converged to the hydrogen transferred conformations
13a and 13b (Fig. 1). These pKenol values are lower than the values
of ꢀ4.5 and ꢀ3.9, computed for 13a and 13b (Table 3), excluding
aci-nitro formation.
A significantly observable hydrogen bonding to the NO2 group
is also excluded by computations. At B3LYP/6-31þG and B3LYP/
Nitromalonamide was previously found by X-ray crystal-
lography to have the enol structure 13a at room temperature.[56]
The non-bonded O. . .O distance of 2.384 A (Table 4) is one of the
˚
shortest known, indicating a very strong O—H. . .
O
—
C hydrogen
—
bond.[33,57] Despite the chemical symmetry of the compound, the
*
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Copyright ß 2009 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2010, 23 255–265

2-NITRO- AND RELATED 2-SUBSTITUTED MALONAMIDES
˚
Table 4. Selected bond lengths, non-bonding distances (in A), and angles (in 8) for the enol or amide of 2-substituted malonamides
YCH(CONH2)2
a
Y
Species/Bond
NO2, 295 K[56]
Enol
NO2, 100 K
Enol
NO2 , 15 K[58]
Enol
SO2Me, 173 K
Amide
CONH2, 173 K
Amide
C1—C2
C2—C3
C1—O1
C3—O3
C1—N1
C3—N3
C2—N2
N2—O21
N2—O22
O1—H
1.447(5)
1.456(4)
1.302(4)
1.281(4)
1.301(4)
1.322(5)
1.397(4)
1.244(3)
1.249(4)
1.01(5)
1.144(5)
2.384(4)
1.99(5)
1.91(5)
8
1.4429(18)
1.4535(18)
1.2963(16)
1.2780(16)
1.3065(18)
1.3127(18)
1.3838(16)
1.2414(15)
1.2497(15)
1.11(2)
1.466(3)
1.463(2)
1.292(3)
1.285(3)
1.317(2)
1.323(2)
1.394(2)
1.256(2)
1.258(3)
1.140(10)
1.308(11)
2.391(3)
1.897(11)
1.851(10)
1.527(3)
1.531(3)
1.221(2)
1.223(3)
1.312(3)
1.307(3)
1.5291(18)
1.5326(19)
1.2362(17)
1.231(2)
1.3200(19)
1.316(3)
1.3173(17)
O3ꢂꢂꢂH
1.28(2)
O1ꢂꢂꢂO3
2.3730(14)
1.96(2)
1.952(19)
O21ꢂꢂꢂH
O22ꢂꢂꢂH
Angle
C1—C2—C3
C2—C1—O1
C2—C3—O3
C2—N2—O21
C2—N2—O22
O1—H—O3
N1—H—O21
N3—H—O22
119.0(3)
117.9(3)
117.9(3)
119.9(3)
120.2(3)
154(5)
118.73(11)
118.02(12)
117.94(11)
120.38(11)
119.93(11)
166(2)
118.7(2)
117.8(2)
117.7(2)
120.0(2)
119.9(2)
155.1(8)
122.3(7)
125.8(8)
109.46(15)
120.40(17)
121.48(18)
110.72(12)
121.94(12)
119.72(15)
131(4)
125(3)
128.8(17)
129.5(17)
a Neutron diffraction results.
O—H and O. . .H hydrogen bond lengths are 1.01 and 1.44 A,
respectively (Table 4).
from that of the enols of cyanomalonamides, where a closer to
apparent symmetrical O—H. . .O bond was mostly observed at
higher, rather than at lower temperature.[33] The pairs of C—C
˚
As the X-ray data for several enols of cyanomalonamides show
temperature-dependence,[33] we re-measured the X-ray structure
at 100 K. The ORTEP drawing is shown in Fig. 2. Additional data
˚
and C—O bond lengths differ by 0.0048 and 0.01 A, respectively,
values which are slightly lower than in the earlier measurements.
In neutron diffraction (ND) of 12a at 15 K,[58] the O—H bond is
somewhat longer than the X-ray data but the d(OꢂꢂꢂH) - d(O—H)
difference is the same as at 100 K.
are given in Fig. S2 of the Supporting Information. The O. . .
˚
O
non-bonded distance of 2.373 A is slightly shorter than that at
room temperature, and is close to the recently calculated value of
[40]
The O. . .H—O bond is apparently
—
We note that the X-ray C O, C—O, C C, C—C, and C—N
—
—
˚
2.380 A at B3LYP/DZPþþ.
—
‘more symmetric’ with O—H and O. . .H distances of 1.11 and
1.28 A (<O—H. . .O ¼ 1648), respectively. This behavior differs
bond lengths are almost the same at both temperatures. Only the
O—H and O. . .H distances, which are sensitive to errors, are
different. Almost all the ND bond lengths are slightly longer than
those obtained by X-ray diffraction (Table 4).
˚
DISCUSSION
Substituent effects in promoting enolization in the
2-Y-malonamide system
The high Kenol values for R1R2NCOCH(CN)CONHR3 3Ð
1
2
3
[33]
—
R R NCOC(CN) C(OH)NHR equilibria
suggest Y-substituted
—
malonamides as a suitable model for evaluating the effect of Y on
the extent of enolization. However, our experiments offered very
limited information on this question. When Y ¼ Br, MeSO2, and
CONH2, no enol was observed in CDCl3; when Y ¼COMe, the
enolization occurred on Y, MeO2CH(CONH2)CONHPh could not be
prepared, and pKenol values for enolization on the amide carbonyl
are available only when Y ¼CN, NO2.
Figure 2. ORTEP for nitromalonamide enol 13a at 100 K
J. Phys. Org. Chem. 2010, 23 255–265
Copyright ß 2009 John Wiley & Sons, Ltd.
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A. BASHEER, M. MISHIMA AND Z. RAPPOPORT
The lack of enolization when Y ¼ Br reflects its electron-
donation by resonance (spþ ¼ 0.15).[59] In contrast, the reasons for
the exclusive formation of amide in solution and the isolation of
solid amide crystals when Y ¼ MeSO2 and CONH2 are not obvious.
The MeSO2 group is a similar EWG by resonance (sꢀR ¼ 0.30)[60] to
cyano (sꢀR ¼ 0.31; sꢀP ¼ 0.99)[60,61] and is less electron-
withdrawing than NO2 (sꢀR ¼ 0.46; sꢀP ¼ 1.23),[60,61] the Y groups
that gave a higher enol percentage for YCH(CONH2)CONHR.
However, we encountered many cases of formation of 0–2% enol
for RNHCOCHY0Y00, Y0 ¼CO2R, CN and Y00 ¼ RSO2 (R ¼ Me, Ph), and
this is corroborated by calculations (A. Basheer, M. Mishima, Z.
Rappoport, in preparation). The expected 1–2 units higher
experimental pKenol than the calculated pKenol (CHCl3) value
when Y ¼ MeSO2 in Table 3 suggests that a low enol 7 percentage
could have been observed in CDCl3, if it would not be hampered
by the low solubility in CDCl3—a solvent more favorable for
enolization than the other solvents. The absence of enol of the
triamide is at least partially due to steric hindrance to the enol
planarity by mutual interaction of the amide groups of the
relatively crowded system, as shown by calculations (Fig. S3 of the
Supporting Information).
The calculations predict[33] an appreciable percentage of enol
for MeO2CCH(CONH2)2, i.e., 3, Y ¼CO2Me, but it could not be
studied since the reaction product from PhNCO with
CH2(CONH2)CO2Me decomposed before its NMR spectrum could
be measured. Attempted purification by chromatography or
crystallization gave the malonamide derivative.
ꢀ
**
Figure 3. Plot of pKenol for YCH(CONH2)2 at B3LYP/6-31G versus sp
When Y ¼COMe, selective enolization on the acetyl carbonyl to
give enol 18, rather than on the amido carbonyl, prevented
determination of pKenol on the amide. This is consistent with the
calculated pKenol values of CH3COZ, Z ¼ Me, NH2,[62] and with
precedents observed for carbonyl-activated amides,[25] and was
corroborated by the calculations of Table 3. Consequently,
experimental pKenol values are available only when Y ¼CN or NO2
and they are discussed below.
formations with one or two Me group(s) adjacent to Y, DpKenol
¼
pKenol(NO2) ꢀ pKenol(CN) > 0, or >7.5, respectively, i.e., CN is the
better enolization promoter. Moreover, for the YCH(CO2Me)-
CONHPh system, the enol percentage in CDCl3 is smaller for
Y ¼ NO2 than for Y ¼CN,[25] and for YCH(CO2Me)CONHPh, Y¼NO2
and CO2Me promote enolization nearly equally.[24,25]
However, the calculated order of pKenol values for Y groups
(Table 3) is H > CONH2 > COMe ꢁ COMe (on acetyl) ꢁ MeSO2 >
CN > NO2. The calculated pKenol values were correlated with
various substituent cꢀonstants. Correlation of pKenol(CHCl3) at
Solvent effects on pKenol values
Experimental pKenol values for 12a/13a and 12b/13b are
available in the following deuteriated solvents (e values for the
protic solvent in parenthesis): THF-d8 (7.58), CD3CN (35.94),
DMF-d7 (36.70), and DMSO-d6 (46.45),[42] and for 12b/13b also in
CDCl3 (4.89) and C6D6 (2.27)[42] in which 12a/13a are insoluble.
The upper limit for the pKenol values for 12a/13a in THF-d8 and
CD3CN and for 12b/13b in CDCl3 and C6D6 are ꢄꢀ2.0 since only
the enol is observed. The values follow the order C6D6,
CDCl3 < THF-d8 < CD3CN < DMF-d7 < DMSO-d6, resembling the
orders for other enol/amide pairs[24–31] and the solvent polarity
based on e. This is ascribed to the higher polarity, and hence to
higher solvation of the amide in a more polar solvent, since the
polarity of the zwitterionic enol is lowered by charge
neutralization arising from intramolecular hydrogen bonding,
which amounts to internal solvation.
**
*
B3LYP/6-31G with sp is better than at B3LYP/6-31þG and is
reasonably linear with a correlation coefficient of R2 ¼ 0.962
(Fig. 3). The corresponding correlations with the resonance
parameter, DsꢀR , is of lower quality with R2 ¼ 0.899. MeSO2 and
COMe deviate positively and CN deviates negatively from the
plots (Fig. S4 of the Supporting Information). Consequently,
negative charge dispersal by resonance is significant, as expected
for the enol, but the substituent effects on both sides of Eqn (1)
should be considered, as was suggested earlier.[24,25,31]
For Y ¼ NO2 and CN, an exact comparison is impossible, since
pKenol values are known when Y ¼ NO2, R ¼ H, Me, but not for
Y ¼CN, R ¼ H, Me. However, the effect of change from R ¼ Me to
R ¼ i ꢀ Pr on the percentage of enol is small.[33] Hence,
the
K
enol(O2NCH(CONHMe)2)/Kenol(NCCH(CONHMe)CONHPr ꢀ i)
The pKenol values for 12a/13a and 12b/13b were calculated in
six solvents, with e changing from benzene to DMSO, H2O
(e ¼ 78.36)[42] in order to compare the observed and calculated
values in solution and to obtain values beyond the limited
experimental range (Table 5). The calculated solvent effect is
ratios of 8.5, 2.1, 9.4, 1.0, and 0.55 in CDCl3, THF-d8, CD3CN,
DMF-d7, and DMSO-d6, respectively, indicate NO2 as a better
promoter of enol formation than a CN in non-polar and
moderately polar solvents, but that NO2 is a similar or better
promoter of enolization than CN in the more polar solvents.[33]
This conclusion is not general. The calculated Kenol(O2NCH-
(CONR1R2)2)/Kenol(NCCH(CONR1R2)2 ratios for various combi-
nations of R1,R2 ¼ H, Me are strongly dependent on R1 and R2
and the conformation of both the enol and the amide. In con-
*
significant. For 12a/13a, pKenol at B3LYP/6-31þG changes from
ꢀ4.5 in the gas phase to ꢀ2.2 in DMSO, and for 12b/13b, it
changes from ꢀ4.6 to ꢀ1.5. The values for water are much more
positive: 3.4 (12a) and 6.1 (12b). The change follows the solvent
polarity.
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J. Phys. Org. Chem. 2010, 23 255–265

2-NITRO- AND RELATED 2-SUBSTITUTED MALONAMIDES
Bromomalonamides
Table 5. Calculated pKenol values for 12a and 12b at B3LYP/
*
6-31þG in various media based on the CPM model
These compounds were prepared according to Whiteley and
coworkers.[34] 1H NMR for 5a (DMSO-d6, rt) d: 4.66 (1H, s), 7.57 (2H,
s), 7.66 (2H, s) and for 5b (CDCl3, rt) d: 1.17 (6H, t, J ¼ 7.3 Hz), 3.32
(4H, q, J ¼ 7.2 Hz), 4.71 (1H, s), 7.57 (2H, s).
Medium
pKenol 12a
pKenol 12b
Gas phase
C6H6
CHCl3
THF
MeCN
DMSO
H2O
ꢀ4.5
ꢀ2.9
ꢀ2.9
ꢀ2.7
ꢀ2.1
ꢀ2.2
3.4
ꢀ4.6
ꢀ2.9
ꢀ2.3
ꢀ2.2
ꢀ1.7
ꢀ1.5
6.1
Reaction of malonamides with ammonium hydroxide solution
To dimethyl methylsulfonylmalonate 6 (2.10 g, 10 mmol), 25%
aqueous NH4OH solution (10 ml) was added at ice bath
temperature. The mixture was stirred overnight and the formed
white precipitate was filtered, washed with cold water (20 ml),
and dried at rt, giving 1.56 g (87%) of the pure 7, mp 222–223 8C.
Anal. Calcd for C4H8N2O4S: C, 26.67; H, 4.44; N, 15.55. Found: C,
26.94; H, 4.39; N, 15.63%. 1H NMR (DMSO-d6, rt, 400 MHz) d: 3.20
(3H, s), 4.71 (1H, s), 7.68 (2H, s), 7.76 (2H, s).
A similar procedure was used for the synthesis of 9, mp
215–216 8C (lit.[36] 203 8C dec) in 78% yield from tricarbomethox-
ymethane 8 (1.0 g, 5.3 mmol) and 25% aqueous NH4OH solution
(5 ml). Anal. Calcd for C4H7N3O3: C, 33.10; H, 4.83; N, 28.97. Found:
C, 33.33; H, 4.85; N, 28.82%. 1H NMR (DMSO-d6, rt, 100.133 MHz) d:
3.92 (1H, s), 7.33 (3H, s), 7.46 (3H, s). 13C NMR (DMSO-d6, rt,
100.133 MHz) d: 60.8 (d, J ¼ 133 Hz), 167.4 (d, J ¼ 6.4 Hz).
While the qualitative order of the solvent effect resembles that
in the experiment, the computed values for 12b/13b are more
negative (ꢀ2.2 in THF-d8 to ꢀ1.5 in DMSO-d6) than the
experimental values (ꢀ1.28 in THF-d8 to ꢀ0.75 in DMSO-d6) at
**
B3LYP/6-31G
.
The calculated dipole moments of the amides and the enols
(Table S6 of the Supporting Information) follow the polarity order
at all levels of calculations, but, consistently, the change is smaller
for the enols. All the changes mentioned confirm the explanation
given for the solvent effect.
Nitromalonamide 12a
Nitromalonamide, mp 170–171 8C (lit.[37] 172 8C, lit.[38] 177 8C)
was prepared according to Johnson and Nicolet.[37] 1H NMR
(DMSO-d6, rt): amide 12a, d: 5.90 (1H, s), 7.76 (2H, s), 7.92 (2H, s);
enol 13a, d: 8.95 (2H, s), 9.27 (2H, s), 18.73 (1H, s). 13C NMR
(DMSO-d6, rt): amide 12a, d: 90.4 (t of d, Jd ¼ 138 Hz, Jt ¼ 10.6 Hz),
161.4 (s); enol 13a, d: 106.1 (s), 170.2 (s).
CONCLUSIONS
In solution, 2-Y-substituted malonamides Y ¼ Br, SO2Me, CONH2
exist as the amide tautomers. Nitromalonamide exists as an enol
in the solid state with an extremely short O. . .O distance of
˚
2.3730 A, and in solution as an enol/amide mixture with lower but
appreciable Kenol values in the more polar solvents. The N,N0-di-Me
derivative is less enolic than nitromalonamide. Calculated
pKenol(YCH(CONH2)2) values in the gas phase or in CHCl3 follow
the order for Y: H > CONH2 > COMe ꢁ COMe (on acetyl) ꢁ
MeSO2 > CN > NO2 and are approximately linear with sꢀp (Y).
N,N(-Dimethylnitromalonamide 12b
The compound was prepared by a modified procedure of
Johnson and Nicolet.[37] To a solution of stirred fuming nitric acid
(10 ml) at ꢀ15 8C, N,N0-dimethylmalonamide (2 g, 15.4 mmol) was
added in small portions within 5 min at <ꢀ10 8C. The mixture
was poured into ice-cold water (100 ml) and when no precipitate
was formed, it was extracted with ethyl acetate (2 ꢆ 50 ml), the
organic phase was dried (NaSO4) and the solvent was evaporated.
The formed precipitate was dried at rt, giving 1.83 g (10.5 mmol,
68%) of pure N,N0-dimethylnitromalonamide 12b, mp
161–162 8C. Anal. Calcd for C5H9N3O4: C, 34.29; H, 5.14; N,
EXPERIMENTAL
General methods
Melting points are uncorrected. 1H and 13C NMR spectra were recorded
as described previously.[21] Precursors for synthesis, and solvents
and deuteriated solvents for NMR measurements were purchased
from a commercial supplier and used without further purification.
1
24.00. Found: C, 34.52; H, 5.11; N, 23.86%. H NMR (CD3CN, rt):
Amide 12b, d: 2.76 (0.57H, d, J ¼ 5.3 Hz), 5.76 (0.08 H, s), 7.23
(0.18H, s); Enol 13b, d: 2.93 (6H, d, J ¼ 5.0 Hz), 9.93 (2H, s), 19.20
(1H, s). 13C NMR (CD3CN, rt): Amide 12b, d: 26.1 (d, J ¼ 140.1 Hz),
90.1 (d, J ¼ 138 Hz), 160.4 (s); Enol 13b, d: 26.2 (d, J ¼ 140.3 Hz),
107.4 (s), 169.0 (s). Additional spectral data in different solvents
are given in Tables 1, 2, S1, and S2.
Calculations
Conformational searches were carried out using Spartan ’04
program (Wavefunction Inc.) at PM3 and several conformers,
which have the lowest-energy, were further optimized at RHF/
*
3-21G level of theory to search the lowest energy conformer
(global minimum). Finally, the geometries were fully optimized at
2-Acetyl-N,N(-malondianilide 17a/18a
*
**
the B3LYP/6-31þG and B3LYP/6-31G levels of theory with
normal convergence using the Gaussian 03 program.[63]
Vibrational normal mode analyses were performed at the same
level to ensure that each optimized structure was a true minimum
on the potential energy surface, not an imaginary frequency, and
to calculate the thermal correction needed to obtain the Gibbs
free energies.
The procedure is similar to the preparation of both the isopropyl
derivative 17b/18b, R ¼ i ꢀ Pr and the asymmetric triamide 11.
To a stirred suspension of sodium (0.25 g, 11 mmol) in dry THF
(50 ml) acetoacetanilide (1.77 g, 10 mmol) was added. After
overnight stirring, all the Na had reacted and a white solid sodium
salt was precipitated. Phenyl isocyanate (1.08 ml, 10 mmol) was
added dropwise and the solid was dissolved. The mixture was
J. Phys. Org. Chem. 2010, 23 255–265
Copyright ß 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

A. BASHEER, M. MISHIMA AND Z. RAPPOPORT
refluxed for 2 h, giving a yellow precipitate of the sodium salt of
16a [(PhNHCO)2CCOMe]Na. 1H NMR (DMSO-d6, rt) d: 2.40 (3H, s),
6.88 (2H, t, J ¼ 7.2 Hz), 7.22 (4H, t, J ¼ 7.9 Hz), 7.57 (4H, d,
J ¼ 7.8 Hz), 12.67 (1H, s), 13.89 (1H, s).
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1998, 120, 1827–1834.
The salt was dissolved in DMF (12 ml) and the solution was
added dropwise, with stirring and cooling, to a cold 2 N HCl
solution (100 ml). The white oily solid formed was kept overnight
in a refrigerator, filtered, washed with cold water (50 ml), and
dried, giving 1.92 g (5.54 mol, 55%) of the enol/amide mixture
17a/18a, mp 148–149 8C (lit.[64] mp 145–146 8C). The compounds
are unstable and decomposed during purification and recrys-
tallization. Anal. Calcd for C12H19N3O2: C, 62.34; H, 5.63; N, 18.18.
Found: C, 61.97; H, 5.94; N, 18.11%. 1H NMR (CDCl3, 298 K,
400 MHz) displayed signals for a 58:42 enol:amide mixture.
(Amide, 17a) d: 2.42 (3H, s), 4.78 (1H, s), 7.11–7.21 (5.7H, m), 7.32
(8.5H, t, J ¼ 7.7 Hz), 7.39 (2.9H, t, J ¼ 8.3 Hz), 7.50–7.57 (11.2H, m),
9.56 (2H, s); (Enol, 18a) d: 2.35 (4H, s), 7.11–7.57 (m), 7.63 (1.34H, s,
NH), 9.95 (1.38H, s), 15.73 (1.38H, s). 13C NMR (CDCl3, 298 K)
(Amide, 17a) d: 29.7 (q, J ¼ 129.1 Hz), 67.7 (d, J ¼ 132.5 Hz), 120.4
(d, J ¼ 163.8 Hz), 125.3 (d of t, Jd ¼ 162.3 Hz, Jt ¼ 7.5 Hz), 128.9 (d,
J ¼ 161.5 Hz), 136.7 (t, overlaps enol signal), 162.8 (d, J ¼ 6.2 Hz),
199.7 (t, J ¼ 6.0 Hz). (Enol, 18a) d: 22.1 (d of q, Jq ¼ 129.2 Hz,
Jd ¼ 5.9 Hz), 102.5 (s), 120.4 (d, J ¼ 162.3 Hz), 125.3 (d,
Jd ¼ 163.0 Hz), 129.0 (d, J ¼ 161.5 Hz), 136.8 (t, overlaps amide
signal), 167.1 (s), 168.8 (s), 178.7 (t, J ¼ 5.4 Hz).
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The isopropyl derivative 17b/18b, mp 139–140 8C was
prepared in 67% yield by a procedure similar to the preparation
of 17a/18a. Anal. Calcd for C4H7N3O3: C, 33.10; H, 4.83; N, 28.97.
Found: C, 33.33; H, 4.85; N, 28.82%.
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PhNHCOCH(CONMe2)2 11
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Mp 185–186 8C, Anal. Calcd for C14H19N3O3: C, 60.65; H, 6.86; N,
15.16. Found: C, 60.37; H, 6.88; N, 14.84%. 1H NMR (CDCl3, 298 K,
400 MHz) d: 3.03 (6H, s), 3.17 (6H, s), 4.90 (1H, s), 7.10 (1H, t,
J ¼ 7.2 Hz), 7.31 (2H, t, J ¼ 7.5 Hz), 7.59 (2H, d, J ¼ 7.8 Hz), 10.29
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J. Phys. Org. Chem. 2010, 23 255–265
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