Deuterium isotope effects on 13C and 15N chemical shifts of intramolecularly hydrogen-bonded enaminocarbonyl derivatives of Meldrum's and Tetronic acid

Article abstract of DOI:10.1016/j.molstruc.2010.03.059

Secondary deuterium isotope effects on ¹³C and ¹⁵N nuclear shieldings in a series of cyclic enamino-diesters and enamino-esters and acyclic enaminones and enamino-esters have been examined and analysed using NMR and DFT (B3LYP/6-31G(d,p)) methods. One-dimensional and two-dimensional NMR spectra of enaminocarbonyl and their deuterated analogues were recorded in CDCl₃ and CD₂Cl₂ at variable temperatures and assigned. ¹J_NH coupling constants for the derivatives of Meldrum's and tetronic acids reveal that they exist at the NH-form. It was demonstrated that deuterium isotope effects, for the hydrogen bonded compounds, due to the deuterium substitution at the nitrogen nucleus lead to large one-bond isotope effects at nitrogen, ¹Δ¹⁵N(D), and two-bond isotope effects on carbon nuclei, ²ΔC(ND), respectively. A linear correlations exist between ²ΔC(ND) and ¹Δ¹⁵N(D) whereas the correlation with δNH is divided into two. A good agreement between the experimentally observed ²ΔC(ND) and calculated dσ¹³C/dR_NH was obtained. A very good correlation between calculated NH bond lengths and observed NH chemical shifts is found. The observed isotope effects are shown to depend strongly on Resonance Assisted Hydrogen bonding.

Full text of DOI:10.1016/j.molstruc.2010.03.059

Journal of Molecular Structure 976 (2010) 377–391
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Deuterium isotope effects on 13C and 15N chemical shifts of intramolecularly
hydrogen-bonded enaminocarbonyl derivatives of Meldrum’s and Tetronic acid
*
Saif Ullah, Wei Zhang, Poul Erik Hansen
Department of Science, Systems and Models, Roskilde University, P.O. Box 260, DK-4000 Roskilde, Denmark
a r t i c l e i n f o
a b s t r a c t
Secondary deuterium isotope effects on 13C and 15N nuclear shieldings in a series of cyclic enamino-dies-
ters and enamino-esters and acyclic enaminones and enamino-esters have been examined and analysed
using NMR and DFT (B3LYP/6-31G(d,p)) methods. One-dimensional and two-dimensional NMR spectra of
enaminocarbonyl and their deuterated analogues were recorded in CDCl3 and CD2Cl2 at variable temper-
Article history:
Received 10 February 2010
Received in revised form 19 March 2010
Accepted 20 March 2010
Available online 25 March 2010
1
atures and assigned. JNH coupling constants for the derivatives of Meldrum’s and tetronic acids reveal
that they exist at the NH-form.
In honour of Professor Austin Barnes on his
65th birthday.
It was demonstrated that deuterium isotope effects, for the hydrogen bonded compounds, due to the
deuterium substitution at the nitrogen nucleus lead to large one-bond isotope effects at nitrogen,
1D15N(D), and two-bond isotope effects on carbon nuclei, 2DC(ND), respectively. A linear correlations
exist between 2DC(ND) and 1D15N(D) whereas the correlation with dNH is divided into two. A good
Keywords:
Deuterium isotope effects
Enaminocarbonyl
Meldrum’s acid
Tetronic acids
DFT calculations
RAHB
agreement between the experimentally observed 2DC(ND) and calculated d 13C/dRNH was obtained. A
r
very good correlation between calculated NH bond lengths and observed NH chemical shifts is found.
The observed isotope effects are shown to depend strongly on Resonance Assisted Hydrogen bonding.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
ꢁ0.8 ppm (asymmetric). Hydrogen bond can be further subdivided
into those with resonance assisted hydrogen bond (RAHB)
A key feature of molecular structure is hydrogen bonds which
have been studied both theoretically and experimentally over the
years. Characterization of hydrogen-bonded systems is an impor-
tant feature in both organic and biological molecules and it is
therefore of importance to explore the strength and geometry of
hydrogen bonding [1–5]. Looking at deuterium isotope effects on
chemical shifts, intramolecular hydrogen bonded compounds can
be divided into compounds with localized hydrogen bond and
non-localized hydrogen bond (equilibrium cases or part of a tauto-
meric system). A localized hydrogen bond and non-localized
hydrogen bond can be differentiated by measuring deuterium iso-
tope effects on the carbon atom directly attached to the proton do-
nor functional group. For the localized hydrogen bond cases the
2DC(D) is not influenced by the temperature, in contrast to non-
localized hydrogen bond which indicates temperature sensitive
deuterium isotope effect values [8]. The 2DC(D) values reported
for localized hydrogen bond lies only in the positive range
ꢀ0.1 ppm to ꢀ0.5 ppm, while for non-localized hydrogen bond
case high positive values observed, in the range ꢀ0.5 ppm to
ꢀ0.7 ppm (symmetric double-minimum proton potential), high
positive values 0.7–2.3 ppm and negative values ꢁ0.3 to
(Scheme 1) and those with non-resonance assisted (non-RAHB)
hydrogen bonds [1,2,6,7]. RAHB systems can be recognized using
PCA analysis [8]. Non-RAHB systems are found, e.g. in protonated
DMAN’s [9] and in Mannich bases [10] but these show usually
smaller values for deuterium isotope effects [9]. Deuterium isotope
effects on chemical shifts can be primary, p
D D. The
or secondary s
primary deuterium isotope effect is defined as pD1H(D) =
d(H) ꢁ d(D) and the secondary isotope effects on 13C chemical
shifts as follows: nD13C(OD) = d13C (OH) ꢁ d13C(OD), where n is
the number of bonds between the site of deuteration and the ob-
served
d
nuclei,
while
on
15N
it
is
1D15N(D) =
15N(H) ꢁ d15N(D) [7]. Various structural factors such as conjuga-
tion, torsional angle, hybridization, and resonance might affect
the sign and magnitude of isotope effects [8,9]. In order to investi-
gate the strength and geometry of hydrogen bonds, isotopic substi-
tution is potentially very useful. Secondary deuterium isotope
effect (DIE) on 13C chemical shifts, nD13C (OD), have been studied
extensively in intramolecular hydrogen-bonded systems and as-
cribed qualitatively to the hydrogen bond strength [4,8–25]. Deu-
terium isotope effects on 1D15N(D) chemical shifts have not been
studied as frequently, since indirect detection via long-range cou-
plings is often necessary due to the very long relation times of
the deuteriated nitrogen, but one advantage to be considered for
the observation of 15N nucleus is its large chemical shift range
* Corresponding author. Tel.: +45 46 742432; fax: +45 46 743011.
E-mail address: poulerik@ruc.dk (P.E. Hansen).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.03.059

378
S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
‘‘Enaminocarbonyl” are a group of organic compounds bearing
an amino entity linked through a C@C to a keto group or keto-ester
group forming the conjugated system ANAC@CACOA or
ANAC@CACO2A, having the ambident nucleophilicity of enamino-
carbonyl and ambident electrophilicity of enones, belong to a class
of versatile intermediates for the synthesis of various pharmaceu-
tical and bioactive heterocyclic compounds, natural products and
numerous products of medicinal interest [50–52]. Accordingly, a
number of important medicinal agents contain enaminocarbonyl
as common pharmacophores and have demonstrated a wide range
of potential therapeutic utility including anti-inflammatory [53],
anticonvulsant [54,55], antibacterial [53,56] and antitumour
agents [53,57].
Scheme 1. RAHB.
[4,18,22,26–36]. The important parameters which directly tell
about the strength and structure of hydrogen bond are donor–
acceptor distance, bond order, 2DC(ND) or 2DC(OD) and 1D15N(D)
[37].
In spite of their biological importance, the synthesis of enami-
nocarbonyl, especially cyclic ones, (Scheme 2) has gained little
attention so far. In the present work we have synthesized a number
of enaminocarbonyl derived from Meldrum’s acid and Tetronic
acid and they are investigated by means of deuterium isotope ef-
fects on 13C and 15N chemical shifts combined with theoretical
(DFT type) of structures and NMR properties.
The main objective of the present study is to evaluate the sen-
sitivity of the NAHꢄ ꢄ ꢄO@C type of intramolecular hydrogen bond-
ing by measuring deuterium isotope effects on chemical shifts,
With the development of fast, efficient computers and commer-
cial software in recent years, theoretical calculations have shown
great promise to calculate structures of hydrogen-bonded systems
[20,23,38–40], chemical shifts calculations (nuclear shieldings)
[38,41–48] and deuterium isotope effects on nuclear shieldings
[38,45,48]. The two-bond deuterium isotope effects on 13C and
15N chemical shifts at the neighbouring atom can be approximated
using the Jameson formula [49]:
X
r
ꢁ
rꢂ
¼
ðd
r=drXHÞe½h
D
rXHi ꢁ h
DrXDiꢃ where X ¼ C; N
ð1Þ
Scheme 2. Possible tautomers of enaminocarbonyl (derivatives of tetronic acids). Two sets of signals were detected by the ‘external’ equilibrium (a, b to c, d) but no separate
signals were seen by ‘internal’ equilibria (a–b and c–d) because the equilibrium is too fast on the NMR time scale at 298 K or non-existing and structure of six-membered
cyclic enaminocarbonyl (derivatives of Meldrum’s acid).

S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
379
especially for 1D15N(D) which is a sensitive gauge to hydrogen
bonding, as it has been shown that compounds lacking NAH pro-
tons could be deprived of their activity [58]. A further aim is to
investigate deuterium isotope effect on 13C and 15N chemical shifts
and to show how 2DC(ND) and 1D15N(D) relate to structural
parameters. In addition, DFT calculations are used to obtain struc-
Scheme 3. a and b Experimentally observed deuterium isotope effects in CD2Cl2 on 13C chemical shifts. 1H NH chemical shifts are given in italics. Superscript letters: a298 K;
b220 K.

380
S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
Scheme 3 (continued)

S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
381
Scheme 4. General structure for the enaminocarbonyl 13_Z–19_Z taken from Ref.
[4]. Only the Z forms are shown, but compounds 16 and 18 are also found in
solution as E isomers.
tural parameters, to calculate nuclear shieldings and isotope ef-
fects. All compounds are presented in Schemes 3 and 4.
Fig. 2. Chemical structure, atom numbering scheme and long range 1H–13
interactions observed for 2.
C
of compound 8_15N was completed on the basis of J-values, col-
lected in the experimental section and depicted in Fig. 3. The 1H
NMR spectra show two sets of resonance signals including the
NH proton. The 1H chemical shifts of the NH proton were assigned
on the basis of the nature of the acceptor group, as the C@O group
is a stronger acceptor group than COOR [4], the NH proton of tau-
tomer-b having a keto acceptor group will be at a higher frequency.
Therefore, the downfield shifted NH resonance signal at 11.04 ppm
was attributed to tautomer-b and the upfield resonance signal at
10.09 ppm to tautomer-d, both of the NH resonances are rather
broad. The proton NMR spectrum recorded in CDCl3 at 298 K was
analysed by taking into account the maximum number of peak
pairs using the line shape analysis algorithm (Levenberg–Marqu-
ardt fit) available in Mestre-C [59] and the determined average ra-
tio b/d was found to be 1.45.
Again, the main difficulty lies in the assignment of the C-9 and
the two carbonyl groups. The C-6 carbonyl groups can due to their
high chemical shifts be distinguished from C-4 and C-9. C-9 can be
assigned due to the one-bond coupling constant to 15N. C-4 is then
assigned by default. To assign the C-9 pair one can use the 3J(C,N)
coupling to assign the one belonging to the b-tautomer and for the
two C-4 carbons the one belonging to the d-tautomer shows a
3J(C,N) coupling.
2. Results
The 1H, 13C and 15N signal assignments were performed by the
combined use of one-dimensional and two-dimensional heteronu-
clear correlation experiments, chemical shifts and coupling con-
stants to 15N. The 1H, 13C and 15N NMR assignments are collected
in the experimental section.
2.1. NMR assignments
2.1.1. 2,2-Dimethyl-5-(1-methylamino-ethylidene)-1,3-dioxane-4,6-
dione (1_15N)
The main problem is the assignment of C-4, C-6 and C-9 as they
have rather similar 13C chemical shifts (see experimental). C-9 can
be assigned based on the one-bond CAN coupling constant of
14.8 Hz (see Fig. 1). The two carbonyl carbons C-4 and C-6 can
be distinguished based on a three-bond CAN coupling of 1.8 Hz.
This is to C-6 as the coupling geometry in this case is trans.
The main difference between compound 1 and compounds 2–7
is an extra ester functional group in the latter (see Scheme 3). C-4
and C-6 can be assigned in analogy with 1, whereas C-24 is as-
signed based on the HMBC correlation to CH2-16 and CH2-25
(see Fig. 2). The same approach was adopted to assign compounds
9–12 (see Fig. 4).
For derivatives like 11 the situation is like that described above
for 1 and 2.
2.1.2. 3-(1-Methylamino-ethylidene)-furan-2,4-dione (8_15N)
The 1H, 13C and 15N NMR assignments including chemical shifts
and coupling constants for approximately 70% deuteriated sample
2.2. Structural assignments
Compounds like 1 and 2 have previously in a single case been
reported [60]. However, in this case they were described as tauto-
meric systems between an enaminone as seen in Scheme 2 and an
enolimine. This is not the case as demonstrated for 1_15N as the
1J(N,H) coupling constant is 90.6 Hz. This clearly demonstrates
only a single form, the enaminone one.
For compounds 8–12 two tautomers are found (Scheme 3). This
corresponds to the parent tetronic acids [24]. From NMR spectra
the b/d ratios could be determined as: 1.45; 1.33; 1.92; 1.46 and
2.18, respectively.
2.3. Deuterium Isotope Effects
Deuterium isotope effects on 13C chemical shifts were deter-
mined for compounds with deuterium substitution of the NH pro-
ton involved in an intramolecular hydrogen bond. The solvent used
Fig. 1. Chemical structure, atom numbering scheme and long range 1H–15N and
13C–15N interactions observed for 1_15N.

382
S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
Fig. 3. 8_15N Chemical structure, atom numbering scheme and long range 1H–15N and 13C–15N interactions observed for tautomers b and tautomer-d.
Fig. 4. Compound 11. Chemical structure, atom numbering scheme and long range 1H–13C interactions observed for tautomers b and tautomer-d.
is CD2Cl2 and the data at two different temperatures are given in
Scheme 3. The isotope effects for enamino-diesters and enamino-
esters (derivatives of Meldrum’s acid and tetronic acid) could be
observed at ambient temperature. The values of 1D15N(D),
2DC(ND) and dNH for compounds 13_Z to 19_Z are taken from
Ref. [4] and the compounds are presented in Scheme 4.
2.3.1. 2DC-9(ND)
The 2 C(ND) isotope effects on 13C chemical shielding are larger
D
for ketone acceptors (C@O) as compared to esters (COOR). The
graph in Fig. 5 shows a displacement between the two types of
enaminocarbonyl (acyclic and cyclic) is possibly caused by the fact
that the cyclic compounds have two mesomerically electron with-
drawing substituents. There are no clear-cut temperature varia-
tions observed for all the compounds given in Scheme 3 as the
cyclic enamino-diesters 1, 2, 5 and cyclic enamino-esters 9_b to
12_b show a decreasing 2DC-9(ND) isotope effect with decreasing
temperature, whereas compounds 3–4, 6–7, 8_b and 8_d to 12_d
show a slightly increasing tendency.
Fig. 5. Plot of experimentally observed 2
enaminocarbonyl. Cyclic enaminocarbonyl from this work; acyclic from Ref. [4].
DC(ND)Obs vs. dNHObs for acyclic and cyclic
The 4
DC-4(ND) isotope effects at the C@O carbon increases with
decreasing temperature for all the cyclic enamino-diesters except
2.3.2. nDC(ND)
1, whereas the isotope effect for all the cyclic enaminones motif
The 4DC(ND) deuterium isotope effects observed at the car-
bonyl carbon (C@O) in the studied enamino-esters are larger than
enaminones, but vary in an irregular way (Scheme 3).
( DC-4(ND)) decrease with
4DC-6(ND)) and enamino-esters motif (4
decreasing temperature. Deuteriation at the NH position also led to
long range isotope effect at 13C chemical shifts up to six bonds on

S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
383
both side of nitrogen nucleus ranging from 0.005 ppm to
0.019 ppm as also found earlier for Meldrum’s and barbituric acids
[61].
mentally observed 2
carbonyl shows a good correlation (Fig. 8).
D
C(ND)Obs for both acyclic and cyclic enamino-
A steric effect (twist) was found for the structure of 4 containing
tert-butyl moiety leading to different isotope effects.
3.2. Structures
For derivatives of Meldrum’s acid only the NH-form is pre-
dicted. In all but 4 a hydrogen bonded form is found. The NAH
bond lengths are given in Table 1 and so are the Nꢄ ꢄ ꢄO distances.
For 4 a twisted forms are arrived at as seen in Fig. 9a and b. The
twisted form in Fig. 9b is at higher energy (6.96 kcal/mol) as com-
pared to the structure in Fig. 9a.
2.3.3. 1D15N(D)
Deuterium isotope effects on 15N chemical shifts were mea-
sured from a one-tube experiment for 1_15N and 8_15N (both
15N-enriched) in CDCl3 solution at 298 K, and summarized in Figs. 6
and 7. A linear dependence was observed between 1 15N(D)Obs vs.
D
15
dNHObs and d
N
vs.1JNH coupling constants (plot not shown).
Obs
One-bond deuterium isotope effect on 15N chemical shifts can
be measured from the HMBC spectra of partially deuteriation at
the NAH hydrogen site: 1D15N(D) = d15N(H) ꢁ d15N(D). A value of
1.16 ppm for the deuterium isotope effect of 1_15N was measured
from the centre of the NH resonance to the centre of ND resonance
in the F1 dimension, using the correlations between H-16 to NAH
and NAD, respectively or to H-10. It can be seen from Fig. 7 that
2DC(ND) and 1D15N(D) correlate to a reasonable degree.
3.3. Calculated RNAH
The signals of the NHꢄ ꢄ ꢄO protons (dNH) involved in intramolec-
ular hydrogen bond appear in the range 6.33–11.78 ppm. A plot of
calculated RNAH bond lengths in Å vs. experimentally observed
dNH in ppm gives a linear relationship and is shown in Fig. 10. A
plot of 1 15N(D)Obs vs. calculated RNAH bond lengths again shows
D
a split in correlations (Fig. 11) (see also Figs. 5 and 6). In the plots
are included data (acyclic enaminones and enamino-esters) from
Ref. [4].
3. Theoretical work
3.1. Calculated dr
13C/dRNH
3.4. Calculated 1H, 13C and 15N chemical shifts
The two-bond deuterium isotope effects on 13C nuclear shield-
ing, d
13C/dRNH, was calculated using the above mentioned geom-
r
The Density Functional Theory (DFT) calculations of all the com-
pounds in Scheme 3 were performed to determine the 1H, 13C and
15N chemical shifts. Then, a simple averaging is done for equivalent
protons. A linear regression fit of all the predicted 1H and 13C nu-
clear shieldings vs. experimental values are given in the following
plots (Figs. 12–14).
etries simply by shortening the NAH bond 0.01 Å, recalculating the
nuclear shieldings and finally, subtracted the optimized nuclear
shieldings on 13C nucleus from the nuclear shielding of reduced
NAH bond lengths. The plot of calculated dr
13C/dRNH vs. experi-
4. Coupling constants
As already mentioned 1JNH spin–spin coupling constants can be
used to determine the presence of either a single form or a tauto-
meric equilibrium. The values of the NH coupling constant are
known to be dependent on several factors like hybridization,
charge density, hydrogen bonding and polarity of the NAH bond
1
[62,63]. JNH for a hydrogen bonded situation varies from 87 up
to 95 Hz [63,64]. In this work, we have synthesized two 15N-en-
riched model compounds (Figs. 1 and 3), 1_15N (enamino-diester)
and 8_15N (enamino-ester). Other coupling constants obtained
from the 15N enriched derivatives are seen in Fig. 15. Especially
3
the three-bond JCN coupling turned out to be useful as they de-
pend on geometry (see previously).
Fig. 6. Plot of experimentally observed 1D15N(D)Obs vs. dNHObs for cyclic enamino-
carbonyl from this work; acyclic enaminocarbonyl from Ref. [4].
Fig. 8. Plot of experimentally observed two-bond deuterium isotope effect on 13C
chemical shifts vs. calculated change in nuclear shieldings for acyclic and cyclic
enaminocarbonyl.
Fig. 7. Plot of 2DC(ND)Obs vs. 1D15N(D)Obs
.

384
S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
Table 1
13
13
15
Deuterium isotope effects in various enaminocarbonyl (measured at 298 K in CD2Cl2 unless otherwise stated), d
calculated bond lengths (Å), RNAH, calculated distances ROꢄ ꢄ ꢄN (Å) and energies (kcal/mol).
C
,
2D
C
, calculated d
r
13C/dRNH
,
1D
N
Obs
, dNHObs,
Obs
Obs
13
13
d
15
d
d
Comp.
d
C
(ppm)
2D
C
(ppm)
d
r
13C/dRNH (ppm)
1D
N (ppm)
Obs
dNHObs (ppm)
Calc. RN–H (Å)
Calc. ROꢄ ꢄ ꢄN (Å)
Energiesd (kcal/mol)
Obs
Obs
1
2
3
4
5
6
7
174.8
174
0.168
0.159
0.162
0.079
0.149
0.174
0.168
0.175
0.158
0.168
0.135
0.166
0.135
0.167
0.137
0.16
0.134
0.241
0.235
0.244
0.272
0.104
0.259
0.183
0.095
0.165
0.167
0.173
0.144
0.062
0.142
0.165
0.147
0.185
0.139
0.174
0.137
0.171
0.148
0.169
0.149
0.161
0.144
0.269
0.274
0.238
0.293
0.121
0.292
0.176
0.113
0.142
1.16a
n.m.b
n.m.
n.m.
n.m.
n.m.
n.m.
1.02a
0.91a
n.m.
n.m.
n.m.
n.m.
n.m.
n.m.
n.m.
n.m.
1.25
1.3
11.32
11.7
11.68
6.33
1.0278
1.03
2.6053
2.6105
2.6027
2.86
ꢁ443330.06
ꢁ610988.66
ꢁ635659.34
ꢁ684997.71
ꢁ859628.83
ꢁ780649.23
ꢁ803176.47
ꢁ346774.31
ꢁ346774.44
ꢁ539103.82
ꢁ539103.04
ꢁ563779.68
ꢁ563779.04
ꢁ588454.71
ꢁ588454.20
ꢁ684097.09
ꢁ684096.23
ꢁ278545.00
ꢁ327887.18
ꢁ278540.78
ꢁ278542.74
ꢁ278534.04
ꢁ278548.31
ꢁ301081.14
ꢁ301072.73
ꢁ301083.47
178.3
166.7
170.8
173.4
173.7
172.1
171.2
175.7
175.1
175.8
175.3
176
175.5
176.1
175.6
n.m.
148.3
n.m.
1.0311
1.0142
1.0296
1.0299
1.0288
1.0265
1.0249
1.0293
1.0276
1.0293
1.0272
1.0293
1.0276
1.029
1.0267
1.0233
1.024
1.0235
1.0253
1.0095
1.0297
1.0187
1.0073
1.0194
11.43
11.78
11.72
11.05
10.09
11.32
10.38
11.33
10.44
11.3
10.49
11.25
10.46
10.15
10.2
9.7
9.7
4.45
10.8
7.3
4.6
8.2
2.639
2.5921
2.6026
2.7297
2.7342
2.7697
2.7125
2.7691
2.7085
2.7671
2.7057
2.7684
2.7132
2.6876
2.6781
2.6656
2.6263
–
8_b
8_d
9_b
9_d
10_b
10_d
11_b
11_d
12_b
12_d
13_Zc
14_Zc
15_Zc
16_Zc
16_Ec
17_Zc
18_Zc
18_Ec
19_Zc
1.18
1.33
0.84
1.44
0.93
0.69
0.97
151.5
147.3
161.5
152.2
148.5
163
2.6515
2.6946
–
2.7074
a
b
c
Obtained for 15N enriched sample.
Not measured.
13
15
2D
C
Obs
,
1D
N
Obs
and dNHObs for 13_Z to 19_Z are taken from Ref. [4].
d
Geometries for all the enaminocarbonyl were optimized at the B3LYP level of theory and using a 6-31G(d,p) basis set.
Fig. 9. (a) Calculated structure of 4 (twisted) and (b) calculated structure of 4 (twisted).
Fig. 10. Calculated RNAH bond length values plotted against the experimentally
Fig. 11. Calculated RNAH bond length values plotted against the experimentally
observed 1D15N(D)Obs
observed dNHObs
.
.

S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
385
OH groups intramolecularly hydrogen bonded to carbonyl groups
of nitro substituted o-hydroxy acylaromatics [66].
5.1. Coupling constants
1
d
15N for the cyclic compounds correlate with JNH (plot now
shown). d15N increases with decreasing JNH coupling constant. A
decrease in JNH can either be ascribed to more positive charge
1
1
on nitrogen [33] or to a decrease of the NAH bond order. In the
present case a partial positive charge will build up as a function
of conjugation with both of the C@OX groups. From the very lim-
ited data set it seems like the C@OX group involved in hydrogen
bonding is the determining one as seen from the finding that
1JNH for 8_d is larger than for 8_b as the conjugation is to an ester
in 8_b rather than to a carbonyl group (the Mulliken charges con-
firm the less positive charge on 8_d).
Fig. 12. Relationships between the experimental and B3LYP/6-31G(d,p) 1H nuclear
shieldings of all the compounds given in Scheme 3. All NAH protons are at the top,
aromatic protons in the middle and non-aromatic protons at the bottom.
5.2. Isotope effect on 13C chemical shifts
The secondary isotope effects on 13C chemical shifts due to the
deuterium substitution at the NAH site clearly reflect the strength
of the hydrogen bond [22,67]. Inspection of Table 1 gives a compar-
ison for selected enaminocarbonyl. The 2DC(ND) of the enamino-
diesters are larger than for enamino-esters, an indication of stron-
ger hydrogen bond in the diester compounds. A plot of RNꢄ ꢄ ꢄO vs.
2DC(ND) (Fig. 17) shows that hydrogen bonding to a ketone moiety
gives a larger 2DC(ND) for the same Nꢄ ꢄ ꢄO distance.
NH chemical shifts are also expected to reflect the hydrogen
bond strength [7]. Nevertheless, a plot of 2DC(ND) vs. dNHObs re-
sults in separate lines for the cyclic and the linear compounds.
The former having an extra carbonyl or ester group in conjugation
with the NH group and thereby leading to a larger positive charge.
This extra positive charge is apparently influence the NH chemical
shift more than it influences 2DC(ND).
Fig. 13. The linear regression between the experimental and B3LYP/6-31G(d,p) 13
nuclear shieldings of all the compounds given in Scheme 3.
C
5.3. Isotope effect on 15N chemical shifts
The 15N chemical shifts and one-bond deuterium isotope effects
on nitrogen nuclear shieldings are known to be very useful tools in
the investigation of NHꢄ ꢄ ꢄO (Nꢄ ꢄ ꢄHO) hydrogen-bonded systems
[67–69].
Simple amines and amides in general show 1 15N(D) isotope ef-
D
fects of the order of 0.65 ppm [27]. An interesting finding is that for
intermolecular hydrogen-bonded systems as seen, e.g. in proteins
1D15N(D) decrease with shortening of the Nꢄ ꢄ ꢄO@C distance [67]
whereas for enaminones and esters 1D15N(D) increases with
increasing hydrogen bond strength [4]. The present study was
undertaken to investigate this phenomenon further. As seen in
Fig. 14. Plot of calculated 15N nuclear shieldings vs. observed 15N chemical shifts.
A value of 13.8 Hz was obtained for 1J(N, D) coupling constant
for 1_15N. For 8_15N both couplings were 14.1 Hz. In both cases
broad line widths prevented a very accurate determination.
Fig. 6 1 15N(D) correlates with dNHObs but on separate correlation
D
lines for cyclic and non-cyclic compounds. 1D15N(D) is like
2DC(ND) a gauge for hydrogen bond strength. 1 15N(D)Obs also cor-
D
15
relates to some degree to d
N
Obs
(Fig. 18).
Like JNH 1D15N(D) depends on the charge. The less positive
charge on nitrogen the larger the isotope effect [70]. In addition,
the potential will be more asymmetric for the stronger hydrogen
bonded compounds, thereby explaining the larger one-bond iso-
tope effects.
1
5. Discussion
The DFT calculations give access to NAH bond lengths and Mul-
liken charges in addition to NMR parameters. The plot of calculated
NAH bond lengths vs. observed NH chemical shifts show as seen in
Fig. 10 a very good correlation. For intermolecular hydrogen-
bonded systems Limbach et al. have also observed a correlation be-
tween NH chemical shifts but in that case to a function of valence
bond order and limiting chemical shifts [65].
A correlation of dNHObs vs. Mulliken charges is seen in Fig. 16.
One outliner is for the twisted compound 4. The correlation indi-
cates that the NH chemical shift to a large extent is governed by
the charge. A similar finding was made for OH chemical shifts of
5.4. 1H, 13C and 15N chemical shifts
Experimental and predicted chemical shifts for both 1H, 13C and
15N nuclei are presented in Figs. 12–14. All the figures reveal good
correlation coefficients. Data points for 4 are less good possibly
indicating that the single conformation shown in Fig. 9a is not
the only populated one.

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S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
Fig. 15. Coupling constants.
5.5. Calculations
The DFT calculations provide geometries, nuclear shieldings and
changes in nuclear shieldings. The two latter properties could be
proportional [49]. This is clearly not the case for 13C or for 15N as
seen from Figs. 18 and 19. According to Eq. (1) the 2DC(ND) can
be calculated by knowing d
r
13C/dRNH as well as [h
D
rXHi ꢁ h rXDi].
D
13
A plot of d
r
13C/dRNH vs. d
C
Obs
shows a very good correlation
(Fig. 8). This is rather unusual as for o-hydroxyacylaromatics it
was found that
13C/dROH was rather invariant, whereas
[h rXHi ꢁ h rXDi] was the determining factor [38].
For calculated
15N a correlation is found to the NAH bond
length (Fig. 20).
d
r
D
D
r
It can be summarized that 15N chemical shifts can be calculated
well in RAHB systems.
Fig. 16. Plot of Mulliken charges on NH vs. dNHObs
.
Fig. 17. 2DC(ND) plotted vs. Nꢄ ꢄ ꢄO distance.
Fig. 18. Plot of 1D15N(D) vs. d
N
Obs
.
15

S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
387
tance of conjugation and resonance. The importance of resonance
is also supported by the correlation between Mulliken charges
and observed NH chemical shifts (Fig. 16). Such a trend was seen
very clearly in o-hydroxynitroacyl aromatics [66]. The Nꢄ ꢄ ꢄO dis-
tance is not very important but again seems to depend more on
the type of acceptor than the Nꢄ ꢄ ꢄO distance (Fig. 17). The acceptor
is important for the resonance. Finally, if the acceptor was not act-
ing in a RAHB way it would give rise to a decrease in 1 15N(D) with
D
decreasing Nꢄ ꢄ ꢄO distance as seen in proteins [67] and ammonium
ions [34].
6. Conclusions
Fig. 19. Plot of 2DC(ND) vs. observed carbon chemical shifts (C-9 or C-1).
Intramolecular hydrogen bonded and non-hydrogen bonded
acyclic and cyclic enaminocarbonyl can be characterized by means
of secondary deuterium isotope effects on 13C as well as on 15N
chemical shifts. The strength of intramolecular hydrogen bond
can be estimated by 2DC(ND), 1D15N(D) and dNH. However, the
two former correlate but not in a simple way with dNH. All the
structures of enaminocarbonyl including dr
13C/dRNH, RNAH bond
lengths and chemical shifts are calculated theoretically to a good
accuracy using DFT methods. A very good correlation is found be-
tween calculated NAH bond lengths and NH chemical shifts. Reso-
nance Assisted Hydrogen Bonding is found to be important for
explaining the isotope effects.
For sterically hindered compounds like 4, a twist in the bond
angle around the six-membered hydrogen bond system is
observed.
7. Experimental
Fig. 20. Plot of calculated NAH bond lengths vs. calculated 15N nuclear shieldings.
7.1. Chemicals
Compounds Glycine ethyl ester hydrochloride, L-Phenylalanine
ethyl ester hydrochloride, L-Tyrosine methyl ester hydrochloride,
Methylmagnesium bromide solution 3.0 M in diethyl ether,
Methylamine hydrochloride, Methylamine–15N hydrochloride 98
atom% 15N were purchased from Aldrich Chemicals, Weinheim,
Germany, Tetrahydrofuran–2,4-dione from TCI Europe nv, Bel-
gium. All organic solvents were of analytical grade and used as
received.
7.2. Synthesis of Enaminocarbonyl (cyclic-esters)
The synthesis of acyl Meldrum’s acid [73], acyltetronic acids
[24] and 5-(bis(methylthio)methylene)-2,2-dimethyl-1,3-diox-
ane-4,6-dione and 3-(bis(methylthio)methylene)furan-2,4-dione
[74] was accomplished according to the literature methods. The
synthesis of all cyclic enaminocarbonyl is done by following the
representative procedures below.
Fig. 21. Plot of observed NH chemical shifts vs. calculated ones.
A plot of the observed NH chemical shift vs. the calculated ones
shows as seen in Fig. 21 a rather good correlation for the Z-type
enaminocarbonyl, whereas the E-type fall off the line. This could
indicate that solvent effects are important for the experimental
NH chemical shifts.
7.2.1. Representative procedure (1)
The title compounds were prepared according to the literature
method [75].
To a well stirred solution of 5-(bis(methylthio)methylene)-2,2-
dimethyl-1,3-dioxane-4,6-dione (2.5 mmol) in dry tetrahydrofuran
(5 ml) or 3-(bis(methylthio)methylene)furan-2,4-dione (5 mmol)
in dry tetrahydrofuran (5 ml) at ꢁ4 °C was added a solution of
Grignard reagent (7.5 mmol) in diethyl ether drop wise over a per-
iod of 10 min under nitrogen environment and the resulting mix-
ture was stirred at room temperature for further one hour.
Amine salts (4%, 10 ml) were added to the reaction mixture and
the solution was stirred for additional 15 min. The organic layer
was separated and the aqueous layer was extracted with CH2Cl2
(3 ꢅ 10 ml). The combined organic layer and extracts were washed
5.6. Resonance Assisted Hydrogen Bonding
It has recently been claimed that RAHB plays very little role for
the NMR properties [71,72]. 1D15N(D) are markedly larger for the
Z-derivative than for the E-derivative (Table 1). In addition
1D15N(D) is larger for ketones as acceptors than for esters as accep-
tors (Table 1). This supports that Resonance Assisted hydrogen
bonding is important in the Z-isomer. In the present study we also
find that the NH chemical shift is proportional to the NAH bond
length both for E- and Z-derivatives (Fig. 10) illustrating the impor-

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S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
with water (3 ꢅ 30 ml), dried over MgSO4, filtered and solvent was
evaporated under reduced pressure. The residue of 2a, 6 and 7) was
chromatographed on silica gel (Sigma–Aldrich, 200–400 mesh,
60A) using chloroform–acetone (90:10 v/v) as eluent. The raw
product was recrystallised from tetrahydrofuran–petroleum ether
to yield pure product.
7.2.3.4. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)pro-
pylamino)acetate (3). The title compound was prepared by follow-
ing the representative procedure 2. Yield 0.53 g (37%), white
crystals; mp 104–105 °C, 1H NMR (CDCl3, 300 MHz) d (ppm):
11.68 (s, NH), 4.30 (q, J = 7.2 Hz, H25), 4.24 (d, J = 5.4 Hz, H16),
3.03 (q, J = 7.5 Hz, H10), 1.69 (s, H7-8), 1.33 (t, J = 7.2 Hz, H26),
1.25 (t, J = 7.5 Hz, H11); 13C NMR (CDCl3, 75 MHz) d (ppm) 178.3
(C9), 167.6 (C24), 167.5 (C4), 162.5 (C6), 102.6 (C2), 84.8 (C5),
62.5 (C25), 44.8 (C16), 26.6 (C7-8), 23.9 (C10), 14.2 (C26), 11.6
(C11); IR (KBr) mmax 3172, 2991, 2944, 2924, 2883, 1746, 1703,
1665, 1583, 1225, 1015 cmꢁ1; MS (ESI+) for C13H19NO6 (MNa+)
309.9. Elemental analysis: calc. for C13H19NO6: C, 54.73; H, 6.71;
N, 4.91. Found: C, 54.47; H, 6.73; N, 4.91.
7.2.2. Representative procedure (2)
To a stirred solution of aminoester hydrochloride (5 mmol) in
dry toluene (15 ml) at 0 °C under nitrogen supply, triethylamine
(5 mmol) was added drop wise over a period of 15 min. Then Mel-
drum’s acid derivatives (5 mmol) were added to the solution and
the mixture was stirred at reflux for 3 h. The cooled solution was
filtered and evaporated under reduced pressure. The residue was
chromatographed on silica gel (Sigma–Aldrich, 200–400 mesh,
60A) using chloroform–acetone (90:10 v/v) as eluent. The solvent
was evaporated from the pooled fractions and recrystallised from
chloroform–petroleum ether to afford pure product.
7.2.3.5. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-
2,2-dimethylpropylamino)acetate (4). The title compound was pre-
pared by following the representative procedure 2. Yield 0.47 g
(30%), yellow oil; 1H NMR (CDCl3, 300 MHz) d (ppm): 6.33 (s,
NH), 4.22 (q, J = 7.2 Hz, H25), 4.02 (d, J = 5.1 Hz, H16), 1.29 (t,
J = 7.2 Hz, H26), 1.24 (s, H11-12-13), 1.23 (s, H7-8); 13C NMR
(CDCl3, 75 MHz) d (ppm) 184.2 (C6), 178.9 (C9), 170.4 (C24),
169.6 (C4), 101.5 (C2), 78.0 (C5), 61.5 (C25), 41.6 (C16), 38.7
(C10) 27.4 (C11-12-13), 26.5 (C7-8), 14.1 (C26); IR (KBr) mmax
2928, 2855, 1740, 1663, 1602, 1515, 1466, 1377, 1353 cmꢁ1; MS
(ESI+) for C15H23NO6 (MNa+) 336.30.
7.2.3. Representative procedure (3)
To a stirred solution of aminoester hydrochloride (4 mmol) in
dry toluene (15 ml) at 0 °C under nitrogen supply, triethylamine
(4 mmol) was added drop wise over a period of 15 min. Then
tetronic acid derivatives (4 mmol) were added to the solution
and the mixture was stirred at reflux for 3 h. The cooled solution
was filtered and hexane was added to force crystallisation. The sol-
vent was filtered and residue was recrystallised from diethylether–
dichloromethane–n-hexane to afford pure product.
7.2.3.6. Ethyl 2-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(4-
nitrophenyl)methylamino)acetate (5). The title compound was pre-
pared by following the representative procedure 2. Yield 0.66 g
(35%), white crystals; mp 134–135 °C 1H NMR (CDCl3, 300 MHz)
d (ppm): 11.43 (s, NH), 8.37 (d, J = 9.0 Hz, ArH), 7.42 (d, J = 9.0 Hz,
ArH), 4.20 (q, J = 7.2 Hz, H25), 3.82 (d, J = 6.0 Hz, H16), 1.74 (s,
H7-8), 1.25 (t, J = 7.2 Hz, H26); 13C NMR (CDCl3, 75 MHz) d (ppm)
170.8 (C9), 167.3 (C4), 166.7 (C24), 161.4 (C6), 148.6 (C10), 139.1
(CAr), 127.7 (CAr), 124.3 (CAr), 103.7 (C2), 86.8 (C5), 62.5 (C25),
46.2 (C16), 26.8 (C7-8) 14.0 (C26); IR (KBr) mmax 3163, 3088,
2987, 2943, 2856, 1750, 1721, 1660, 1603, 1249, 1022 cmꢁ1; MS
(ESI+) for C17H18N2O8 (MNa+) 400.9; found 309.9. Elemental analy-
sis: calc. for C17H18N2O8: C, 53.97; H, 4.80; N, 7.40. Found: C, 54.62;
H, 5.01; N, 7.17.
7.2.3.1. 2,2-dimethyl-5-(1-methylamino-ethylidene)-1,3-dioxane-4,6-
dione (1). The compound was prepared by following the represen-
tative procedure 1. Yield 0.46 g (93%), white crystals; mp 116–
117 °C. 1H NMR (CDCl3, 300 MHz) d (ppm): 11.32 (s, NH), 3.14 (d,
J = 5.1 Hz, H16), 2.63 (s, H10), 1.69 (s, H7-8); 13C NMR (CDCl3,
75 MHz) d (ppm) 174.8 (C9), 167.4 (C4), 163.2 (C6), 102.5 (C2),
84.6 (C5), 30.6 (C16), 26.4 (C7-8), 17.5 (C10); IR (KBr) mmax 3224,
3155, 3099, 2993, 2945, 1709, 1659, 1578, 1266, 1067 cmꢁ1;MS
(ESI+) for C9H13NO4 (MNa+) 221.9. Elemental analysis: calc. for
C9H13NO4: C, 54.26; H, 6.58; N, 7.03. Found: C, 54.03; H, 6.53; N,
7.04.
7.2.3.2. 2,2-dimethyl-5-(1-methylamino-ethylidene)-1,3-dioxane-4,6-
dione (1_15N). The title compound (15N labelled) was prepared by
following the representative procedure 1. Yield 0.46 g (93%), white
crystals; 1H NMR (CDCl3, 300 MHz) d (ppm): 11.32 (dq, 1J = 90.6 Hz,
NH), 3.14 (dd, 3J = 5.1 Hz, H16), 2.63 (d, 3J = 2.7 Hz, H10), 1.69 (s,
H7-8); 13C NMR (CDCl3, 75 MHz) d (ppm) 174.872, 174.678
(CAN, 1J = 14.8 Hz) (C9), 167.398 (C4), 163.204, 163.180 (CAN,
3J = 1.8 Hz) (C6), 102.435 (C2), 84.599, 84.607 (CAN, 2J = 0.5 Hz)
(C5), 30.653, 30.508 (CAN, 1J = 10.9 Hz) (C16), 26.366 (C7-8),
17.525 (C10). 15N NMR (60 MHz; CDCl3) d (ppm) ꢁ245.5 (N1AH),
ꢁ246.66 (N1AD).
7.2.3.7. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)eth-
ylamino)-3-phenylpropanoate (6). The title compound was pre-
pared by following the representative procedure 2 and 1. Yield
0.61 g (34%) with procedure 2 and 0.77 g (85%) with procedure 1,
yellow viscous oil; 1H NMR (CDCl3, 300 MHz) d (ppm): 11.78 (d,
J = 8.4 Hz NH), 7.18–7.34 (ArH, 5H), 4.57 (ddd, J = 4.8 Hz, H16),
4.25 (q, J = 7.2 Hz, H25), 3.30 (dd, J = 13.8 Hz, H17), 3.10 (dd,
J = 13.8 Hz, H17), 2.28 (s, H10), 1.67 (s, H7-8), 1.28 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz) d (ppm) 173.4 (C9), 169.3 (C4),
167.1 (C25), 163.0 (C6), 134.8 (CAr), 129.4 (CAr), 129.0 (CAr),
127.8 (CAr), 102.5 (C2), 85.6 (C5), 62.4 (C25), 58.5 (C16), 39.5
(C17), 26.5 (C7-8) 17.6 (C10), 14.1 (C26); IR (KBr) mmax 2927,
2855, 1741, 1710, 1660, 1588, 1270, 1022 cmꢁ1; MS (ESI+) for
7.2.3.3. Ethyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)eth-
ylamino)acetate (2). The title compound was prepared by following
the representative procedure 2 and 1. Yield 0.54 g (40%) with pro-
cedure 2 and 0.62 g (91%) with procedure 1, white crystals; mp
104–105 °C, 1H NMR (CDCl3, 300 MHz) d (ppm): 11.70 (s, NH),
4.30 (q, J = 7.2 Hz, H25), 4.22 (d, J = 5.4 Hz, H16), 2.60 (s, H10),
1.69 (s, H7-8), 1.33 (t, J = 7.2 Hz, H26); 13C NMR (CDCl3, 75 MHz)
d (ppm) 174.0 (C9), 167.3 (C24), 167.1 (C4), 163.0 (C6), 102.6
(C2), 85.74 (C5), 62.4 (C25), 45.3 (C16), 26.5 (C7-8), 18.2 (C26),
14.1 (C10); IR (KBr) mmax 3239, 3185, 3103, 2997, 2939, 2909,
2873, 1740, 1713, 1656, 1611, 1228, 1019 cmꢁ1; MS (ESI+) for
C
19H23NO6 (MNa+) 383.8.
7.2.3.8. Methyl 2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yli-
dene)ethylamino)-3-(4-hydroxyphenyl)propanoate (7). The title
compound was prepared by following the representative proce-
dure 2 and 1. Yield 0.60 g (33%) with procedure 2 and 0.73 g
(80%) with procedure 1, yellow viscous oil; 1H NMR (CDCl3,
300 MHz) d (ppm): 11.72 (d, J = 8.7 Hz, NH), 7.02 (d, J = 8.4 Hz,
ArH), 6.78 (d, J = 8.7 Hz, ArH), 6.47 (s, OH), 4.57 (dt, J = 4.5 Hz,
H16), 3.81 (s, H25), 3.24 (dd, J = 14.1 Hz, H17), 3.03 (dd,
J = 14.1 Hz, H17), 2.29 (s, H10), 1.65 (s, H7–8); 13C NMR (CDCl3,
75 MHz) d (ppm) 173.7 (C9), 169.9 (C4), 167.3 (C24), 163.4 (C6),
C
12H17NO6 (MNa+) 293.8. Elemental analysis: calc. for C12H17NO6:
C, 53.13; H, 6.32; N, 5.16. Found: C, 53.09; H, 6.35; N, 5.10.

S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
389
156.0 (CAr), 130.5 (CAr), 125.8 (CAr), 116.0 (CAr), 102.8 (C2), 85.4
(C5), 58.6 (C16), 53.1 (C25), 38.6 (C17), 26.4 (C7-8) 17.8 (C10); IR
(KBr) mmax 3620, 2927, 2855, 1748, 1709, 1660, 1589, 1518, 1271,
1018 cmꢁ1; MS (ESI+) for C18H21NO7 (MNa+) 385.8.
H7_d), 1.34 (t, J = 7.2 Hz, H26_b), 1.33 (t, J = 7.2 Hz, H26_d), 1.25
(t, J = 7.5 Hz, H11_b), 1.22 (t, J = 7.5 Hz, H11_d); 13C NMR (CDCl3,
75 MHz) d (ppm) 200.6 (C6b), 195.9 (C6d), 175.8 (C9b), 175.3
(C9d), 175.2 (C4d), 170.8 (C4b), 167.2 (C24d), 167.1 (C24b), 91.0
(C5b), 90.0 (C5d), 79.4 (C2d), 77.3 (C2b), 62.6 (C25b), 62.5
(C25d), 44.3 (C16b), 44.0 (C16d), 21.3 (C10d), 21.1 (C10b), 17.1
(C7b), 17.1 (C7d), 14.1 (C26b), 14.1 (C26d), 11.4 (C11b), 11.3
(C11d); IR (KBr) mmax 3190, 3051, 2978, 2934, 2872, 1728, 1651,
1603, 1513, 1248, 1240, 1027 cmꢁ1; MS (ESI+) for C12H17NO5
(MNa+) 278.2. Anal. Calc. for C12H17NO5: C, 56.46; H, 6.71; N,
5.49. Found: C, 56.97; H, 6.90; N, 5.35.
7.2.3.9. 3-(1-methylamino)ethylidene)furan-2,4(5H)-dione (8). The
title compound was prepared by following the representative pro-
cedure 1. Yield 0.35 g (45%), yellow crystals; mp 106–107 °C. 1H
NMR (CDCl3, 300 MHz) d (ppm): 11.04 (s, 0.66NH_b), 10.09 (s,
0.34NH_d), 4.42 (s, H2_b), 4.41 (s, H2_d), 3.16 (d, J = 5.4 Hz,
H16_b), 3.14 (d, J = 5.1 Hz, H16_d), 2.61 (s, H10_d), 2.56 (s,
H10_b); 13C NMR (CDCl3, 75 MHz) d (ppm) 197.2 (C6b), 193.5
(C6d), 176.4 (C4d), 172.4 (C4b), 172.1 (C9b), 171.2 (C9d), 92.1
(C5b), 90.6 (C5d), 72.1 (C2d), 70.0 (C2b), 30.1 (C16b), 29.8
(C16d), 14.2 (C10d), 13.9 (C10b); IR (KBr) mmax 3216, 2980, 2945,
2926, 1727, 1651, 1504, 1254, 1228, 1022 cmꢁ1; MS (ESI+) for
C7H9NO3 (MNa+) 178.0. Elemental analysis: calc. for C7H9NO3: C,
54.19; H, 5.85; N, 9.03. Found: C, 53.70; H, 5.80; N, 8.67.
7.2.3.13. Ethyl 2-(1-(5,5-dimethyl-2,4-dioxo-dihydrofuran(5H)-3-yli-
dene)propylamino)acetate (11). The title compound was prepared
by following the representative procedure 3. Yield 1.08 g (85%),
white crystals; mp 66 °C, 1H NMR (CDCl3, 300 MHz) d (ppm):
11.30 (s, 0.72NH_b), 10.49 (s, 0.28NH_d), 4.32 (q, J = 6.9 Hz,
H25_b), 4.30 (q, J = 6.9 Hz, H25_d), 4.27 (d, J = 5.7 Hz, H16_b),
4.26 (d, J = 6.0 Hz, H16_d), 2.97 (q, J = 7.8 Hz, H10_b), 2.96 (q,
J = 7.5 Hz, H10_d), 1.43 (s, H7-8_b), 1.41 (s, H7-8_d), 1.34 (t,
J = 7.2 Hz, H26_b), 1.33 (t, J = 7.2 Hz, H26_d), 1.26 (t, J = 7.5 Hz,
H11_b), 1.22 (t, J = 7.5 Hz, H11_d); 13C NMR (CDCl3, 75 MHz) d
(ppm) 202.7 (C6b), 198.1 (C6d), 176.0 (C9b), 175.5 (C9d), 174.4
(C4d), 170.0 (C4b), 167.3 (C24d), 167.2 (C24b), 89.9 (C5b), 89.8
(C5d), 85.7 (C2d), 83.4 (C2b), 62.6 (C25b), 62.5 (C25d), 44.3
(C16b), 44.0 (C16d), 23.9 (C7-8b), 23.8 (C7-8d), 21.2 (C10b), 21.1
(C10d), 14.1 (C26b), 14.1 (C26d), 11.5 (C11b), 11.4 (C11d); IR
(KBr) mmax 3211, 3144, 3108, 2983, 2941, 2909, 2878, 1747, 1744,
1740, 1737, 1671, 1643, 1614, 1611, 1607, 1215, 1203,
1010 cmꢁ1; MS (ESI+) for C13H19NO5 (MNa+) 292.1. Elemental anal-
ysis: calc. for C13H19NO5: C, 57.98; H, 7.11; N, 5.20. Found: C, 58.01;
H, 7.11; N, 5.27.
7.2.3.10.
3-(1-methylamino)ethylidene)furan-2,4(5H)-dione
(8_15N). The title compound (15N labelled) was prepared by fol-
lowing the representative procedure 1. Yield 0.35 g (45%), 1H
NMR (CDCl3, 300 MHz)
d
(ppm): 11.04 (dq, 1J = 91.8 Hz,
0.66NH_b), 10.09 (dq, 1J = 92.4 Hz, 0.34NH_d), 4.42 (s, H2_b),
4.41 (s, H2_d), 3.16 (dd, 3J = 4.5 Hz, H16_b), 3.14 (dd, 3J = 4.2 Hz,
H16_d), 2.61 (d, 3J = 2.7 Hz, H10_d), 2.56 (d, 3J = 2.7 Hz, H10_b);
13C NMR (CDCl3, 75 MHz)
d (ppm) 197.197 (C6b), 193.553,
193.533 (CAN, 3J = 1.5 Hz) (C6d), 176.408 (C4d), 172.448,
172.411 (CAN, 3J = 2.8 Hz) (C4b), 172.175, 171.978 (CAN,
1J = 14.8 Hz) (C9b), 171.268, 171.064 (CAN, 1J = 15.3 Hz) (C9d),
92.056 (C5b), 90.624 (C5d), 72.129 (C2d), 69.980 (C2b), 30.180,
30.035 (CAN, 1J = 10.9 Hz) (C16b), 29.904, 29.761(CAN,
1J = 10.7 Hz) (C16d), 14.231 (C10d), 13.853 (C10b). 15N NMR
(60 MHz; CDCl3) d (ppm) ꢁ239.8 (N10AH, tautomer-d), ꢁ240.71
(N10AD, tautomer-d), ꢁ241.2 (N1AH, tautomer-b), ꢁ242.22
(N1AD, tautomer-b).
7.2.3.14. Ethyl 2-(1-(2,4-dioxo-5-phenyl-dihydrofuran(5H)-3-yli-
dene)propylamino)acetate (12). The title compound was prepared
by following the representative procedure 3. Yield 0.64 g (80%),
white crystals; mp 66 °C, 1H NMR (CDCl3, 300 MHz) d (ppm):
11.25 (s, 0.61NH_b), 10.46 (s, 0.39NH_d), 7.28–7.44 (m, ArH),
5.46 (s, H2_b), 5.40 (s, H2_d), 4.28 (q, J = 6.9 Hz, H25_b), 4.25 (q,
J = 6.9 Hz, H25_d), 4.21 (d, J = 5.7 Hz, H16_b), 4.20 (d, J = 6.0 Hz,
H16_d), 2.96 (q, J = 7.8 Hz, H10_b), 2.94 (q, J = 7.5 Hz, H10_d),
1.32 (t, J = 7.2 Hz, H26_b), 1.30 (t, J = 7.2 Hz, H26_d), 1.25 (t,
J = 7.5 Hz, H11_b), 1.17 (t, J = 7.5 Hz, H11_d); 13C NMR (CDCl3,
75 MHz) d (ppm) 197.4 (C6b), 192.7 (C6d), 176.1 (C9b), 175.7
(C9d), 175.4 (C4d), 170.8 (C4b), 167.1 (C24d), 167.0 (C24b), 135.0
(CAr), 128.6 (CAr), 128.5 (CAr), 125.8 (CAr), 90.1 (C5b), 90.0
(C5d), 83.3 (C2d), 81.5 (C2b), 62.6 (C25), 62.6 (C25), 44.3 (C16b),
44.1 (C16d), 21.4 (C10d), 21.3 (C10b), 14.0 (C26), 14.0 (C26), 11.4
(C11b), 11.3 (C11d); IR (KBr) mmax 3204, 3062, 3037, 2983, 2946,
1732, 1643, 1603, 1512, 1252, 1233, 1019 cmꢁ1; MS (ESI+) for
7.2.3.11. Ethyl 2-(1-(2,4-dioxo-dihydrofuran(5H)-3-ylidene)propyla-
mino)acetate (9). The title compound was prepared by following
the representative procedure 3. Yield 0.87 g (90%), white crystals;
mp 120–121 °C, 1H NMR (CDCl3, 300 MHz) d (ppm): 11.32 (s,
0.77NH_b), 10.38 (s, 0.23NH_d), 4.45 (s, H2_b), 4.42 (s, H2_d),
4.31 (q, J = 7.2 Hz, H25_b), 4.30 (q, J = 7.2 Hz, H25_d), 4.27 (d,
J = 5.7 Hz, H16_b), 4.26 (d, J = 6.0 Hz, H16_d), 2.98 (q, J = 7.8 Hz,
H10_b), 2.94 (q, J = 7.5 Hz, H10_d), 1.34 (t, J = 7.2 Hz, H26_b),
1.33 (t, J = 7.2 Hz, H26_d), 1.25 (t, J = 7.5 Hz, H11_b), 1.23 (t,
J = 7.5 Hz, H11_d); 13C NMR (CDCl3, 75 MHz) d (ppm) 197.8
(C6b), 193.0 (C6d), 176.1 (C9b), 175.7 (C9d), 175.1 (C4d), 171.5
(C4b), 167.2 (C24d), 167.1 (C24b), 91.6 (C5b), 90.4 (C5d), 72.1
(C2d), 70.2 (C2b), 62.6 (C25b), 62.5 (C25d), 44.3 (C16b), 44.0
(C16d), 21.4 (C10d), 21.1 (C10b), 14.1 (C26d), 14.1 (C26b), 11.4
(C11b), 11.3 (C11d); IR (KBr) mmax 3453, 3355, 3196, 3130, 2988,
2939, 1732, 1710, 1673, 1667, 1599, 1227, 1200, 1014 cmꢁ1; MS
(ESI+) for C11H15NO5 (MNa+) 264.1. Elemental analysis: calc. for
C
17H19NO5 (MNa+) 340.1. Elemental analysis: calc. for C13H17NO5:
C, 64.34; H, 6.04; N, 4.41. Found: C, 64.31; H, 6.11; N, 4.44.
7.3. Instrumentation
C11H15NO5: C, 54.76; H, 6.27; N, 5.81. Found: C, 54.65; H, 6.28; N,
5.80.
7.3.1. NMR
NMR spectra were recorded on a Varian Mercury 300 or an
Unity-Inova 600 spectrometer with operating frequency at 300 or
600 MHz (5 mm triple-resonance gradient probe) for 1H, 75 or
150 MHz for 13C and 60 MHz (1H 600 MHz) for 15N. 2D experi-
ments were run by using the standard Varian software. TMS was
used as an internal standard both for 1H and 13C spectra while
for 15N the data were referenced to formamide as external stan-
dard. These values are converted to nitromethane as reference sub-
tracting 269.7 ppm. The spectra for a range of samples were
recorded between 223 and 298 K. Deuterium Isotope Effects on
7.2.3.12. Ethyl 2-(1-(5-methyl-2,4-dioxo-dihydrofuran(5H)-3-yli-
dene)propylamino)acetate (10). The title compound was prepared
by following the representative procedure 3. Yield 0.89 g (87%),
white crystals; mp 117–118 °C. 1H NMR (CDCl3, 300 MHz) d
(ppm): 11.32 (s, 0.67NH_b), 10.43 (s, 0.33NH_d), 4.58 (q,
J = 6.9 Hz, 2H_b), 4.43 (q, J = 6.9 Hz, H2_d), 4.32 (q, J = 7.2 Hz,
H25_b), 4.30 (q, J = 7.2 Hz, H25_d), 4.25 (d, J = 5.7 Hz, H16_b),
4.24 (d, J = 6.0 Hz, H16_d), 2.96 (q, J = 7.8 Hz, H10_b), 2.92 (q,
J = 7.5 Hz, H10_d), 1.45 (d, J = 6.9 Hz, H7_b), 1.44 (d, J = 6.9 Hz,

390
S. Ullah et al. / Journal of Molecular Structure 976 (2010) 377–391
13C and 15N chemical shifts were measured in one-tube experi-
ments. Mestrec software was used in order to process and analysed
NMR data [59]. The compounds enaminocarbonyl were dissolved
in CDCl3, while deuteriation for low temperature work was done
by dissolution of the compounds in CD2Cl2 and D2O (50:50), stirred
for 5–10 min, separating the organic layer and this was dried over
anhydrous sodium sulphate overnight. Samples of 60 mg of 2,
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60 mg of 11, 52 mg of 1_15N (15N labelled) and 22 mg of 8_15
15N labelled) were dissolved in 650 l of CDCl3. 1D 1H and 2D
N
(
l
1H–13C HSQC, HMBC; 2D 1H–15N HMQC, HMBC spectra were re-
corded at 25 °C. For 1H–13C HSQC and HMBC, an acquisition time
of 0.4 s, 8 K data points with a spectral window of 10,000 Hz in
the F2 (1H) dimension and 256 data points with a spectral window
of 35,000 Hz in the F1 (13C) dimension, a 2.0 s relaxation delay and
288 transient per increment were recorded. The tau delay in HMBC
was 0.063 s. For 1H–15N HMQC and HMBC, an acquisition time of
0.2 s, 4 K data points with a spectral window of 10,000 Hz in the
F2 (1H) dimension and 512 data points with a spectral window
of 1200 Hz in the F1 (15N) dimension, a 2.6 s relaxation delay and
32 transient per increment were recorded. The tau delay in HMBC
was 0.1 s.
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7.3.2. IR
Infrared spectra were recorded on a Perkin Elmer FTIR 2000
spectrometer in KBr or CHCl3, respectively.
7.3.3. LC–MS
LC–MS measurements were performed on HPLC instrument (a
TSP Spectra system and equipped with an AS3000 auto sampler,
P4000 gradient pump, and a UV 6000 LP diode array detector)
and mass detector (LCQ-Deca ion trap instrument from Thermo-
Finnigan equipped with an electrospray ionization interface (ESI)
run in the positive mode).
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Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K.
Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J.
Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L.
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7.3.4. Melting points
Melting points were determined on a Buchi-510 equipped with
Mettler TM-15 counter and are uncorrected.
7.4. Computational work
All the theoretical calculations were carried out using the
Gaussian 03 code [41] and the molecular geometries were fully
optimized using the B3LYP variant of the Density Functional The-
ory (DFT) [76,77] with the 6-31G(d,p) basis set. The NMR nuclear
shieldings were calculated with the same level of theory and basis
set using the GIAO method [42,78]. The obtained nuclear shiel-
dings are converted in chemical shifts by comparison with calcu-
lated values of tetramethylsilane.
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Acknowledgements
The authors express their thanks to R. Buch for recording NMR
spectra. Thanks are also due to Associate Professor Fritz Duus and
Dr. Fadhil S. Kamounah for their helpful discussions and to Jan Phil-
lipp Hofmann for providing tetronic acids and for initial
calculations.
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