E/Z equilibrium in tertiary amides. Part 2: N-acyl-N′-arylhexahydropyrimidines

Article abstract of DOI:10.1016/j.molstruc.2009.12.011

The ¹H and ¹³C NMR spectroscopic study of a series of novel N-acyl-N′-arylhexahydropyrimidines 1 is presented. Due to hindered rotation around the (O)C-N bond, tertiary amides 1 exist as a mixture of non-separable E/Z diastereoisomers, which show separate signals in the NMR spectra. For some selected derivatives, differential assignment of the ¹H resonances of the E/Z rotamers was made on the basis of the magnitude of ASIS (anisotropic solvent induced shifts) effects and confirmed by NOESY. The corresponding ¹³C signals were unambiguously attributed by HSQC and HMBC experiments. The detailed conformational study of two representative members was performed employing the ab initio RHF/6-311G++ method. The influence of steric and electronic features of the N-substituents on the relative populations of E/Z rotamers is also analyzed.

Full text of DOI:10.1016/j.molstruc.2009.12.011

Journal of Molecular Structure 966 (2010) 79–84
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
E/Z equilibrium in tertiary amides. Part 2: N-acyl-N0-arylhexahydropyrimidines
*
Juan Á. Bisceglia, Ma. Cruz Mollo, Liliana R. Orelli
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Junín 956, 1113 Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
The 1H and 13C NMR spectroscopic study of a series of novel N-acyl-N0-arylhexahydropyrimidines 1 is pre-
sented. Due to hindered rotation around the (O)C–N bond, tertiary amides 1 exist as a mixture of non-sep-
arable E/Z diastereoisomers, which show separate signals in the NMR spectra. For some selected derivatives,
differential assignment of the 1H resonances of the E/Z rotamers was made on the basis of the magnitude of
ASIS (anisotropic solvent induced shifts) effects and confirmed by NOESY. The corresponding 13C signals
were unambiguously attributed by HSQC and HMBC experiments. The detailed conformational study of
two representative members was performed employing the ab initio RHF/6-311G++ method. The influence
of steric and electronic features of the N-substituents on the relative populations of E/Z rotamers is also
analyzed.
Article history:
Received 6 November 2009
Received in revised form 7 December 2009
Accepted 7 December 2009
Available online 8 January 2010
Keywords:
NMR
Hindered rotation
Amides
Cyclic aminals
ASIS
Ó 2009 Elsevier B.V. All rights reserved.
Molecular modeling
1. Introduction
and 23 kcal/mol [12,13]. For unsymmetrically N-substituted
amides, hindered rotation entails the existence of non-isolable
Cyclic aminals are compounds of interest due to their pharma-
cological and chemical properties. The five membered heterocyclic
aminal (imidazolidine) core is found in many bioactive compounds
like antiinflammatory and analgesic agents [1], fungicides, antibac-
terials, parasiticides and antivirals [1,2]. Six membered cyclic ami-
nals (hexahydropyrimidines) also show biological activity as
analgesics, parasiticides [3], antifungals and antibacterials [4]. Be-
sides, hexahydropyrimidines also behave as prodrugs of pharma-
cologically active di [5] and polyamines [6]. Such compounds
have recently been applied as pro-perfumes, in the controlled re-
lease of volatile aldehydes and ketones [7]. In synthetic organic
chemistry, cyclic aminals are useful as protecting groups in the
selective functionalization of di and polyamines.
E/Z diastereoisomers. In the NMR spectra, the rotamers can be ob-
served as two different sets of signals unless the equilibrium is
highly biased towards one of them.
The absence of literature data on the stereochemistry of N-acyl
derivatives of cyclic aminals led us to investigate the E/Z equilib-
rium in compounds 1 employing NMR spectroscopy and theoreti-
cal methods, as part of ongoing research on nitrogen heterocycles
with hindered rotation [14–17].
2. Experimental
2.1. Chemistry
Structural features of amides have been widely studied by NMR
spectroscopy and molecular modeling, as they represent model
compounds for the peptide bond [8]. In particular, the E/Z equilib-
rium in heterocyclic tertiary amides and related compounds has
been reviewed [9]. The planar arrangement of the substituents in
amides, due to partial (O)C–N double bond character, has a strong
influence on the superstructure of peptides and proteins [10],
while E/Z isomerization is a key process involved in protein folding
and biocatalysis [11].
Compounds 1a–i were prepared by condensation of the corre-
sponding N-acyl-N0-aryl-1,3-propanediamines [18,19] and excess
aqueous formaldehyde. A methanolic solution of the reactants
was stirred at room temperature for 12–36 h. The desired com-
pounds were purified by column chromatography. Yields and ana-
lytical data of compounds 1a–i are as follows.
1-Formyl-3-(4-chlorophenyl)hexahydropyrimidine (1a) was
obtained as an oil (69%). MS (EI), m/z 224 (M+.). Anal. Calcd. for
C11H13ClN2O: C, 58.80; H, 5.83; N, 12.47, found: C, 58.71; H,
5.91; N, 12.42.
The partial double bond character of the (O)C–N bond in amides
causes a substantial rotational barrier, which ranges between 15
1-Acetyl-3-(4-chlorophenyl)hexahydropyrimidine (1b) was ob-
tained as a white solid (64%), Mp 60–62 °C (cyclohexane). MS (EI),
m/z 238 (M+.). Anal. Calcd. for C12H15ClN2O: C, 60.38; H, 6.33; N,
11.73, found: C, 60.24; H, 6.39; N, 11.76.
* Corresponding author. Tel./fax: +54 1149648250.
E-mail addresses: lorelli@ffyb.uba.ar, von_orelli@yahoo.com (L.R. Orelli).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.12.011

80
J.Á. Bisceglia et al. / Journal of Molecular Structure 966 (2010) 79–84
Table 1
1-Propionyl-3-(4-chlorophenyl)hexahydropyrimidine (1c) was
N-acyl-N0-arylhexahydropyrimidines 1a–i.
obtained as an oil (61%). MS (EI), m/z 252 (M+.). Anal. Calcd. for
C13H17ClN2O: C, 61.78; H, 6.78; N, 11.08, found: C, 61.71; H,
6.82; N, 11.10.
3´
2´
4´
O
G
5´
2
5
1-Isobutyryl-3-(4-chlorophenyl)hexahydropyrimidine (1d) was
obtained as an oil (16%). MS (EI), m/z 266 (M+.). Anal. Calcd. for
C14H19ClN2O: C, 63.03; H, 7.18; N, 10.50, found: C, 62.94; H,
7.21; N, 10.45.
1´
N
R
N
6´
4
6
1-Formyl-3-phenylhexahydropyrimidine (1e) was obtained as a
white solid (64%), Mp 68–70 °C (cyclohexane). MS (EI) m/z 190
(M+.). Anal. Calcd. for C11H14N2O: C, 69.45; H, 7.42; N, 14.72, found:
C, 69.38; H, 7.45; N, 14.68.
1-Acetyl-3-phenylhexahydropyrimidine (1f) was obtained as an
oil (63%). MS (EI), m/z 204 (M+.). Anal. Calcd. for C12H16N2O: C,
70.56; H, 7.89; N, 13.71, found: C, 70.42; H, 7.94; N, 13.73.
1-Acetyl-3-(4-methoxyphenyl)hexahydropyrimidine (1g) was
obtained as an oil (49%). MS (EI), m/z 234 (M+.). Anal. Calcd. for
C13H18N2O2: C, 66.64; H, 7.74; N, 11.96, found: C,66.58; H, 7.79;
N, 11.94.
Compound 1
G
R
a
b
c
d
e
f
g
h
i
4-Cl
4-Cl
4-Cl
4-Cl
H
H
CH3
C2H5
iso-C3H7
H
CH3
CH3
C6H5
CH3
H
4-OCH3
4-Cl
2-Cl
1-Benzoyl-3-(4-chlorophenyl)hexahydropyrimidine (1h) was
obtained as a white solid (68%), Mp 86–88 °C (cyclohexane). MS
(EI), m/z 300 (M+.). Anal. Calcd. for C17H17ClN2O: C, 67.88; H,
5.70; N, 9.31, found: C, 67.79; H, 5.76; N, 9.30.
1-Acetyl-3-(2-chlorophenyl)hexahydropyrimidine (1i) was ob-
tained as an oil (71%). MS (EI), m/z 238 (M+.). Anal. Calcd. for
C12H15ClN2O: C, 60.38; H, 6.33; N, 11.73, found: C, 60.29; H,
6.37; N, 11.70.
less the equilibrium is highly biased towards one of them. As ex-
pected, two unequally populated sets of signals are present in
the spectrum of 1a, corresponding to E/Z diastereoisomers. The
multiplicity of the signals indicates that ring inversion is a fast pro-
cess in the NMR timescale at room temperature, resulting in dy-
namic averaging of both hydrogens within each methylene
group. This is in accordance with data previously reported for N-
aryl-N0-alkylhexahydropyrimidines [21] and for N,N0-dimethyl-
hexahydropyrimidine [22]. Like many other compounds, amides
display the so called ASIS (anisotropic solvent induced shifts) effect
[23]. Interestingly, signals of N-alkyl groups trans to the carbonyl
2.2. Spectra
1H and 13C NMR spectra were recorded on a Bruker Avance II
500 MHz spectrometer. Spectra were acquired from samples as
solutions at room temperature in 5 mm tubes. Unless otherwise
indicated, deuterochloroform was used as the solvent. The stan-
dard concentration of the samples was 10 and 40 mg/ml for 1H
and 13C NMR, respectively. Chemical shifts are reported in ppm
(d) relative to TMS as an internal standard. Coupling constants
are reported in Hz. Multiplicities are quoted as singlet (s), doublet
(d), triplet (t), quartet (q), heptet (h), multiplet (m) and broad sig-
nal (bs). HSQC, HMBC and phase-sensitive NOESY spectra were re-
corded on a Bruker Avance II 500 spectrometer.
oxygen experience a stronger diamagnetic shift (Dd) on changing
the solvent from CDCl3 to C6D6 than their cis counterparts [12].
This effect can be diagnostic for the differential assignment of cis
and trans N-substituents, and in our experience is more reliable
than assignment derived from chemical shifts in model com-
pounds, specially for amides containing additional anisotropic sub-
stituents [24]. Following this criterion, in compound 1a, the singlet
corresponding to the major diastereoisomer was attributed to the
cis N-methylene group, and the one corresponding to the minor
species as trans to the carbonyl oxygen
(
D
d = ꢁ0.33 and
ꢁ0.83 ppm, respectively). Signals corresponding to positions 4
and 6 of the major diastereoisomer partially overlap in the spec-
trum run in CDCl3. The first one (d = 3.57 ppm) was tentatively
attributed to methylene 6. Such resonance experiences a stronger
diamagnetic shift in C6D6 than the triplet corresponding to the
2.3. Computational study
Input geometries for both rotamers of compounds 1e,f were
preoptimized with the semiempirical method AM1. Structures
thus obtained were then optimized with the HF/3-21G method.
The resulting minima were further optimized either with the ab
initio HF (6-31Gꢀꢀ or 6-311Gꢀꢀ basis sets) or DFT B3LYP/6-311Gꢀꢀ
methods [20]. The resulting minima were subjected to frequency
calculations with non-imaginary frequencies obtained.
minor species (
D
d = ꢁ0.73 and ꢁ0.37 ppm, respectively), and was
attributed to the N-methylene trans to the oxygen. The remaining
signals were attributed to the major and minor species on the basis
of their relative integration. This tentative assignment was con-
firmed in the NOESY spectrum of 1a (Fig. 1), which also confirmed
the assignment of positions 4 and 6 of both species. The 13C spec-
trum of 1a also displays separate signals for both rotamers around
the (O)C–N bond. Unambiguous differential assignment of the res-
onances (Table 4) was performed on the basis of the correlations
observed in the HSQC and HMBC spectra. The 1H and 13C NMR sig-
nals of formamide 1e were attributed by analogy. In both cases, a
slight preference for the Z stereoisomer is observed.
3. Results and discussion
The compounds described in this work are shown in Table 1. 1H
NMR chemical shifts, multiplicities and relative populations of E/Z
diastereomers of compounds 1a–i (CDCl3) are given in Table 2. 1H
NMR chemical shifts, multiplicities and relative populations of E/Z
diastereomers of compounds 1a,b,i (C6D6) are given in Table 3.
13C NMR chemical shifts of compounds 1a–i (CDCl3) are given in
Table 4.
As mentioned before, unsymmetrically N,N-disubstituted
amides display E/Z stereoisomerism due to restricted rotation
around the (O)C–N bond. Consequently, their NMR spectra usually
show two sets of signals corresponding to both stereoisomers, un-
In order to assess the influence of the amide substituent R on
the spectral features and E/Z ratio of compounds 1, some 3-(4-chlo-
rophenyl) substituted 1-acyl derivatives were analyzed. 1H NMR
spectra of amides 1b–d all display two unequally populated sets
of signals. Resonances of amide N-methylenes (positions 2 and 6)
of 1b were attributed on the basis of their
Dd. Thus, the singlet cor-
responding to the major diastereoisomer (d = 4.96 ppm) was
attributed to the methylene group cis to the carbonyl oxygen,

J.Á. Bisceglia et al. / Journal of Molecular Structure 966 (2010) 79–84
81
Table 2
1H NMR signals and relative populations of compounds 1a–i (CDCl3).
Compd.
2
6
4
5
Aromatics
R
%
1a
(Z)
1a
(E)
1b
(Z)
1b
(E)
1c
4.92 (s)
3.57
3.59
1.72–1.76 (m)
20,60: 6.96 (d, 9.0)
30,50: 7.23 (d, 9.0)
20,60: 6.86 (d, 9.0)
30,50: 7.26 (d, 9.0)
20,60: 6.94 (d, 8.9)
30,50: 7.18 (d, 8.9)
20, 60: 6.86 (d, 8.8)
30,50: 7.24 (d, 8.8)
20,60: 6.93 (d, 8.9)
30,50: 7.18 (d, 8.9)
20,60: 6.86 (d, 8.8)
30,50: 7.23 (d, 8.8)
20,60: 6.94 (d, 9.0)
30,50: 7.20 (d, 9.0)
20,60: 6.87 (d, 8.3)
30,50: 7.25 (d, 8.3)
20,40,60: 6.85–7.04 (m)
30,50: 7.23–7.32 (m)
8.04 (s)
61
(t, 5.8)a
3.70
(t, 5.8)b
3.49
4.68 (s)
4.96 (s)
4.73 (s)
4.96 (s)
4.71 (s)
4.99 (s)
4.76 (s)
4.69 (s)
4.86 (s)
4.99 (s)
1.77–1.82 (m)
1.70–1.75 (m)
1.76–1.81 (m)
1.69–1.74 (m)
1.69–1.74 (m)
1.71–1.75 (m)
1.81 (bs)
8.19 (s)
2.09 (s)
2.16 (s)
39
72
28
74
26
76
24
52
48
63
(t, 5.5)
3.61
(t, 5.7)
3.71
(t, 5.8)
3.60
(t, 5.7)
3.70
(t, 5.8)
3.68
(t, 5.6)
3.72
(bs)
3.51–3.56
(m)
(t, 5.6)
3.51
(t, 5.5)
3.36
(t, 5.6)
3.49
(t, 5.5)
3.37
(t, 5.5)
3.53
(t, 5.5)
3.35
(bs)
3.50–3.61
(m)
2.32 (q, 7.4)
1.13 (t, 7.4)
2.41 (q, 7.4)
1.13 (t, 7.4)
2.78 (h, 6.8)
1.13 (d, 6.8)
2.88 (bs)
(Z)
1c
(E)
1d
(Z)
1d
(E)
1e
(Z)
1e
(E)
1f
1.13 (d, 6.8)
8.02 (s)
1.71–1.79 (m)
1.71–1.80 (m)
1.70–1.74 (m)
3.68
(t, 5.9)
3.67
3.51–3.56
(m)
3.53
8.17 (s)
2.09 (s)
7.02 (d, 8.7)
(Z)
(t, 5.8)
(t, 5.5)
6.85 (t, 7.3)
7.23–7.32 (m)
6.94 (d, 8.7)
1f
4.76 (s)
4.87 (s)
3.61
(t, 5.8)
3.69
3.39
(t, 5.6)
3.41
1.76–1.80 (m)
1.71–1.78 (m)
2.18 (s)
2.10 (s)
37
61
(E)
1g
(Z)
7.23–7.32 (m)
20, 60: 6.85 (d, 7.2)
30,50: 6.93 (d, 7.2)
OCH3: 3.75 (s)
20, 60: 6.82 (d, 7.2)
30,50: 6.97 (d, 7.2)
OCH3: 3.78 (s)
7.40 (bs)
(t, 5.8)
(t, 5.4)
1g
4.73 (s)
3.59
(t, 5.8)
3.27
(t, 5.5)
1.71–1.78 (m)
2.15 (s)
39
(E)
1h
(Z)
1h
(E)
1i
5.11 (bs)
4.69 (bs)
4.59 (s)
4.86 (s)
3.87 (bs); 3.54 (bs); 3.43 (bs)
1.64
(bs)
1.89
(bs)
3.41
(t, 5.4)
3.28
6.50 (bs) 7.01–7.21 (bs, m)
6.50 (bs) 7.01–7.21 (bs, m) 7.40 (bs)
1.80–1.86 (m)
59b
7.40 (bs)
41b
3.73
6.93–7.41 (m)
6.93–7.41 (m)
2.12 (s)
2.15 (s)
56
44
(E)
1i
(t, 5.8)
3.64–3.70
(m)
1.69–1.76 (m)
(Z)
(t, 5.4)
a
Partially overlapping signals.
Integration is approximate due to line broadening.
b
Table 3
1H NMR signals and relative populations of compounds 1a,b,i (C6D6).
Compd.
2
6
4
5
Aromatics
R
%
1a
(Z)
1a
(E)
1b
(Z)
1b
(E)
1i
4.59 (s)
2.84
(t, 5.5)
3.33
(t, 5.8)
2.86
(t, 5.5)
3.51
2.53
(t, 5.8)
2.68
(t, 5.5)
2.71
(t, 5.8)
2.67
0.85–0.92 (m)
1.07–1.14 (m)
0.97–0.99 (m)
1.25–1.27 (m)
1.27–1.35 (m)
20, 60: 6.79 (d, 6.8); 30, 50:
7.15–7.24 (m)
7.65 (s)
7.91 (s)
1.65 (s)
1.80 (s)
1.83 (s)
57
3.85 (s)
4.79 (s)
4.07 (s)
4.01 (s)
20, 60: 6.32 (d, 9.0); 30, 50:
7.15–7.24 (m)
43
70
30
60
20, 60: 6.87 (d, 9.0); 30, 50:
7.15–7.19 (m)
20, 60: 6.39 (d, 8.8); 30, 50:
7.15–7.19 (m)
(t, 5.7)
3.51
(t, 5.5)
2.68
7.12–7.24 (m);
(E)
(t, 5.8)
(t, 5.6)
6.76–6.99 (m);
6.58–6.68 (m)
1i
4.75 (s)
3.05
(t, 5.5)
2.68
(t, 5.6)
0.98–1.08 (m)
7.12–7.24 (m); 6.76–6.99 (m);
6.58–6.68 (m)
1.63 (t)
40
(Z)
and the one corresponding to the minor species (d = 4.73 ppm) to
the trans methylene (
d = ꢁ0.17 and ꢁ0.66 ppm, respectively).
Conversely, triplets at 3.61 and 3.71 ppm were assigned as trans
and cis N-methylenes (
The remaining signals were attributed to the major and minor spe-
cies on the basis of their relative integration. This assignment was
confirmed by the correlations observed in the NOESY spectrum of
1b (Fig. 1). 1H NMR spectra of hexahydropyrimidines 1c,d are
similar to that of compound 1b, and were assigned by analogy
(Table 2). Interestingly, in compound 1d the signals of the minor
species display line broadening. This feature, absent in the major
diastereoisomer, may indicate that a dynamic process different
from E/Z interconversion, probably ring inversion, is rather slow
in the NMR timescale at room temperature. The previous
assignment was confirmed by NOESY for propionamide 1c and iso-
butyramide 1d (Fig. 1). For compounds 1b–d, unambiguous differ-
ential assignment of the 13C resonances of both rotamers (Table 4)
was performed on the basis of the correlations observed in their
D
D
d = ꢁ0.75 and ꢁ0.20 ppm, respectively).

82
J.Á. Bisceglia et al. / Journal of Molecular Structure 966 (2010) 79–84
Table 4
13C NMR signals of compounds 1a–i (CDCl3).
Compd.
2
6
4
5
R
10
20,60
30,50
40
C@O
1a (Z)
1a (E)
1b (Z)
1b (E)
1c (Z)
1c (E)
1d (Z)
1d (E)
1e (Z)
1e (E)
1f (Z)
1f (E)
1g (Z)
1g (E)
57.73
64.76
59.24
66.95
59.55
65.10
59.58
64.98
57.80
64.72
59.33
66.01
60.44
67.40
45.43
39.63
46.09
41.52
45.20
41.67
45.20
41.68
45.40
39.63
46.01
41.52
45.86
41.28
50.20
49.65
49.38
49.10
49.46
49.26
49.62
49.31
49.95
49.50
49.13
48.95
50.04
50.18
23.85
23.13
23.72
23.72
23.82
23.82
23.94
23.94
23.94
23.20
23.77
23.67
23.67
23.80
23.79*
–
146.44
146.68
146.40
147.32
146.86
147.46
146.82
ND
118.32
129.27
118.25
129.42
117.95
129.15
118.52
129.32
117.93
129.15
118.51
129.31
117.91
129.06
118.46
129.23
116.99
129.32
116.93
129.43
116.63
129.21
117.23
129.33
118.52
114.34
119.61
114.43
118.01*
129.08*
125.87
125.26
124.68
125.39
124.67
ND
160.73
160.54
170.18
168.95
172.39
ND
–
21.25
21.35
9.24
26.33
9.24
26.33
19.12
29.96
19.12
29.61
–
124.55
ND
175.45
ND
147.84
148.02
148.13
148.61
142.15
142.63
146.67*
120.27
120.79
119.82
120.82
153.58
154.46
160.65
160.57
168.97
168.97
168.84
168.93
170.28*
–
21.18
21.18
21.17
21.17
1h (Z)
1h (E)
66.70*
60.15*
49.70*
48.65*
47.56*
40.97
135.22*
129.96*
128.42*
21.15
126.98*
125.02*
1i (E)
66.55
50.61
50.42
24.07
24.12
146.27
146.55
128.80
127.58
121.44
130.39
128.03
127.35
121.50
130.51
124.58
168.88
168.51
1i (Z)
60.96
45.62
21.35
123.73
*
Broad signal.
Fig. 1. Relevant correlations observed in the NOESY spectra (CDCl3) of compounds 1a–d,i.
HSQC and HMBC spectra, while acetamides 1f,g were assigned by
At variance with the previous examples, in the 1H and 13C NMR
analogy.
spectra of benzoyl derivative 1h the signals of both species show

J.Á. Bisceglia et al. / Journal of Molecular Structure 966 (2010) 79–84
83
Table 5
significant line broadening, indicative of a lower barrier for the
Relative energies (kcal molꢁ1) for the conformational minima of compounds 1f,e.
interconversion of the E/Z diastereoisomers. This feature was pre-
viously observed for other benzamides, and is attributed to com-
petitive resonance stabilization between the amide moiety and
the phenyl substituent which lowers the partial (O)C–N double
bond character [12].
In all the previous cases, the Z diastereoisomer was the predom-
inant species. Quite surprisingly, this preference is reversed in
acetamide 1i, bearing an ortho substituent in the N-aryl. Applying
Compd.
Structure
D
Hfa
D
Hfb
D
Hfc
D
Hfd
1f
Z (A)
Z (B)
E (A)
E (B)
0
0
0
0
4.56
2.45
3.48
1.65
0.98
1.58
1.40
0.67
1.44
1.48
0.97
1.88
1e
Z (A)
Z (B)
E (A)
E (B)
–
–
–
–
–
–
–
–
0
–
–
–
–
0.26
0.55
0.97
the
D
d criterion for 1i, singlets at 4.59 ppm (
D
d = ꢁ0.58 ppm)
and 4.86 ppm (
D
d = ꢁ0.11 ppm) were respectively assigned as
a
b
c
HF/3-21G.
HF/6-31G**.
HF/6-311G**.
trans and cis to the carbonyl oxygen. Conversely, signals centered
at 3.73 and 3.67 ppm were assigned as cis and trans N-methylenes
d
(
D
d = ꢁ0.22 and ꢁ0.62 ppm, respectively). The remaining reso-
B3LYP/6-311G**.
nances in 1i were attributed to the major and minor rotamers on
the basis of their relative integration. The assignment was con-
firmed by the correlations observed in the NOESY spectrum of 1i
(Fig. 1).
analogous results, being the energy differences between conform-
ers and also between E/Z rotamers lower than for acetamide 1f
(Table 5). The calculated E/Z DDHf values are in line with the
experimental trends (relative populations) measured by integra-
tion of the 1H NMR signals for 1e,f (Table 2).
Two model compounds were investigated computationally,
namely acetamide 1f and formamide 1e. For compound 1f, results
employing the HF ab initio method applying either the 3-21G, 6-
31Gꢀꢀ or 6-311Gꢀꢀ basis sets were compared with those obtained
with the DFT B3LYP 6-311Gꢀꢀ method. Four initial minima were
identified for each rotamer at the AM1 level. After HF/3-21G opti-
mization, only two minima were located for each distereoisomer,
which were then optimized with the indicated ab initio or DFT
methods. For each rotamer, the two minima were labelled as A
and B. Structures obtained at the HF/6-311Gꢀꢀ level for 1f are
shown in Fig. 2. In all cases, the heterocyclic ring has approxi-
mately a chair conformation, distorted by the nitrogen atoms bear-
Analysis of data reported in Table 2 shows that the relative
populations of E/Z rotamers are influenced by the nature of both
N-substituents. The preference for the Z diastreoisomer in N-(4-
chlorophenyl) hexahydropyrimidines 1a–d increases with increas-
ing volume of the carbonyl substituent R in the series H < CH3 <
C2H5 < iso-C3H7. The E/Z ratio is also sensitive to steric and elec-
tronic features of substituents in the aryl moiety. A comparison be-
tween acetamides 1b,f,g shows that para substitution with an
electron donor does not influence significatively the E/Z equilib-
rium, which is more shifted towards the Z rotamer in the 4-chloro
derivative (1b). The same effect is observed in formamides 1a,e.
Steric hindrance in the aryl moiety (compound 1i) clearly destabi-
lizes the Z diastereoisomer, which becomes the minor species. This
change may be the result of a twisted conformation for the aryl
group in the ground state.
ing
p-conjugating substituents. Relative energies for the different
conformations are shown in Table 5. The E/Z DDHf was estimated
in each case considering the more stable conformations, being the
Z rotamer always preferred. The magnitude of the energy differ-
ences either between two conformations of the same rotamer or
between E/Z rotamers varies according to the method employed
for the calculation. It is clearly overestimated with the 3-21G basis
set, which predicts an E/Z difference above 2 kcal molꢁ1. The calcu-
lated gap decreases on going from 3-21G ? 6-31Gꢀꢀ ? 6-311Gꢀꢀ
and also comparing B3LYP/6-311Gꢀꢀ and HF/6-311ꢀꢀG methods.
The best agreement between experimental results and calculations
is found with the ab initio HF/6-311Gꢀꢀ method. The same analysis
performed on formamide 1e with the HF/6-311Gꢀꢀ method led to
4. Conclusions
We performed the 1H and 13C NMR spectroscopic study of a ser-
ies of novel tertiary amides derived from the hexahydropyrimidine
core. The compounds under study display E/Z isomerism due to re-
stricted (O)C–N rotation, showing two unequally populated sets of
signals in their 1H and 13C NMR spectra. The 1H NMR resonances of
both rotamers of 1a,b,i were assigned on the basis of ASIS effects
and the assignments confirmed by NOESY. 13C NMR signals were
attributed by HSQC and HMBC experiments for 1a–d. In general,
the E/Z equilibrium favours the Z diastereoisomer. This preference
was accentuated with increasing steric hindrance in the carbonyl
substituent R, and also by electron withdrawing groups in the
N-aryl. The E/Z ratio was reversed in the compound bearing an
ortho substituent in the aryl group. Results of the complete confor-
mational study of compounds 1f,e performed with the ab initio HF/
6-311Gꢀꢀ method were in good agreement with the experimentally
determined E/Z ratios.
Acknowledgement
This work was supported by the University of Buenos Aires
(B-096 Grant).
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Fig. 2. Conformational minima for compound 1f at the HF/6-311Gꢀꢀ level.

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