E/Z equilibrium in tertiary amides - Part 3: N-acyl-N′-arylhexahydro- 1,3-diazepines

Article abstract of DOI:10.1016/j.molstruc.2012.05.025

The ¹H and ¹³C NMR spectroscopic study of a series of N-acyl-N′-arylhexahydro-1,3-diazepines 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,

Full text of DOI:10.1016/j.molstruc.2012.05.025

Journal of Molecular Structure 1026 (2012) 65–70
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
E/Z equilibrium in tertiary amides – Part 3: N-acyl-N0-arylhexahydro-1,3-diazepines
⇑
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
h i g h l i g h t s
"
"
"
"
"
We present the NMR spectral characterization of N-acyl-N0-arylhexahydrodiazepines 1.
Compounds 1 display E/Z isomerism and display two sets of signals.
Differential assignment was made by analysis of ASIS effects, NOESY and HSQC spectra.
The influence of both N-substituents and ring size on the E/Z equilibrium is analyzed.
This is the first stereochemical study on N-acylhexahydrodiazepines in the literature.
a r t i c l e i n f o
a b s t r a c t
13
The 1H and C NMR spectroscopic study of a series of N-acyl-N0-arylhexahydro-1,3-diazepines 1 is pre-
Article history:
Received 15 March 2012
Received in revised form 12 April 2012
Accepted 2 May 2012
sented. 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 their 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 corre-
sponding 13C signals were unambiguously attributed by HSQC experiments. The influence of steric and
electronic features of the substituents on the relative populations of E/Z rotamers is analyzed. The effect
of the ring size was also investigated by comparison with the corresponding hexahydropyrimidine
homologs.
Available online 24 May 2012
Keywords:
NMR
Hindered rotation
Amides
Cyclic aminals
Hexahydrodiazepines
ASIS
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
the reaction does not tolerate bulky substituents in either the aryl
or the acyl moieties.
Cyclic aminals are compounds of interest due to their pharmaco-
logical and chemical properties. The five and six membered
heterocyclic aminals (imidazolidines and hexahydropyrimidines,
respectively) are found in many bioactive compounds, like anti-
inflammatory and analgesic agents, fungicides, antibacterials,
parasiticides and antivirals [1–4]. They also behave as prodrugs of
pharmacologically active di [5] and polyamines [6] and as protect-
ing groups in the selective functionalization of such compounds.
Although imidazolidines and hexahydropyrimidines have received
a great deal of attention, their higher homologs (hexahydro-1,3-dia-
zepines) have been less studied, maybe due to the intrinsical
difficulty of ring closure reactions leading to seven-membered
cyclic aminals [7]. In previous work, we developed a method for
the synthesis of N-acyl-N0-arylhexahydro-1,3-diazepines 1 using
microwave irradiation [8]. A limitation of such procedure is that
Structural features of amides have been widely studied by NMR
spectroscopy and molecular modeling, as they represent model
compounds for the peptide bond [9]. In particular, the E/Z equilib-
rium in heterocyclic tertiary amides and related compounds has
been reviewed [10]. 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
[11], while E/Z isomerization is a key process involved in protein
folding and biocatalysis [12].
The partial double bond character of the (O)C–N linkage in
amides causes a substantial rotational barrier, which ranges be-
tween 15 and 23 kcal/mol [13,14]. For unsymmetrically N-substi-
tuted amides, hindered rotation entails the existence of non
isolable E/Z diastereoisomers. In the NMR spectra, the rotamers
can be observed as two different sets of signals unless the equilib-
rium is highly biased towards one of them.
In previous work we investigated the E/Z equilibrium in tertiary
amides derived from the hexahydropyrimidine core [15]. The
absence of literature data on N-acyl derivatives of the homologous
⇑
Corresponding author. Tel./fax: +54 1149648250.
E-mail address: lorelli@ffyb.uba.ar (L.R. Orelli).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.05.025

66
J.Á. Bisceglia et al. / Journal of Molecular Structure 1026 (2012) 65–70
seven membered cyclic aminals (hexahydrodiazepines) led us to
investigate the E/Z equilibrium in compounds 1 employing NMR
spectroscopy, as part of ongoing research on nitrogen derivatives
with hindered rotation [15–22]. The compounds under study are
of interest as synthetic analogs of the natural polyamine
putrescine.
aqueous formaldehyde under microwave irradiation [8], and puri-
fied by column chromatography.
Yields and analytical data for new compounds 1d,f are as
follows:
1-Formyl-3-phenyl hexahydrodiazepine 1d was obtained as an
oil (73%). MS (EI), m/z 204. IR
m: 3060.44, 2924.22, 2853.25,
1667.67, 1598.01, 1359.82, 970.58, 751.18, 693.19 cmꢀ1, among
others. Anal Calcd. for C12H16N2O: C, 70.56; H, 7.89; N, 13.71, found
C, 70.49; H, 7.94; N, 13.69.
2. Experimental
1-Acetyl-3-(4-bromophenyl)hexahydrodiazepine 1f was ob-
tained as off-white needles (60%), Mp 95–96 °C (dichlorometh-
2.1. Chemistry
ane/hexane). MS (EI), m/z 296 and 298. IR m: 2917.65, 2849.52,
Compounds 1a–h were prepared by condensation of the
corresponding N-acyl-N0-aryl-1,4-butanediamines [23] and excess
1634.81, 1589.71, 1412.64, 1249.92, 1177.09, 810.37, 500.8
9 cmꢀ1, among others. Anal. Calcd. for C13H17BrN2O: C, 52.54; H:
5.77; N: 9.43, found: C, 52.61; H: 5.73; N: 9.40.
Table 1
N-Acyl-N0-arylhexahydrodiazepines 1a-h.
2.2. Spectra
1H, 13C NMR, HSQC, and phase-sensitive NOESY spectra were re-
corded 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 standard concentration of the samples was 10 and
40 mg/mL for 1H and 13C NMR, respectively. Chemical shifts are re-
ported 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), double triplet (dt), triple triplet (tt),
quartet (q), multiplet (m) and broad signal (bs). IR spectra were
run in a Perkin Elmer Spectrum one FT-IR spectrometer.
Compound 1
G
R
a
b
c
d
e
f
4-Cl
4-Cl
4-Cl
H
H
CH3
C2H5
H
CH3
CH3
C6H5
C6H5
3. Results and discussion
H
4-Br
4-Cl
4-CH3
The compounds described in this work are shown in Table 1. 1H
NMR chemical shifts and multiplicities of E/Z diastereoisomers of
g
h
Table 2
1H NMR signals of compounds 1a-h (CDCl3).
Cpd
2
7
4
5, 6
Aromatics
R
G
–
1a (Z)
5.06 (s)
3.23–3.25 (m)
3.61–3.63 (m)
1.74–1.89 (m)*
20,60: 6.71 (d, 9.2)
30,50: 7.19–7.22 (m)
20,60: 6.67 (d, 9.2)
30,50: 7.19–7.22 (m)
20,60: 6.70 (d, 9.1)
30,50: 7.19 (d, 9.1)
20,60: 6.65 (d, 9.2)
30,50: 7.21 (d, 9.2)
20,60: 6.69 (d, 9.1)
30,50: 7.17 (d, 9.1)
20,60: 6.64 (d, 8.9)
30,50: 7.20 (d, 8.9)
20,40,60: 6.75–6.83 (m)
30,50:7.24–7.28 (m)*
20,40,60: 6.73–6.79 (m)
30,50:7.24–7.28 (m)*
20,40,60: 6.74–6.79 (m)
30,50: 7.24–7.29 (m)*
20,40,60: 6.79–6.83 (m)
30,50: 7.24–7.29 (m)*
20,60: 6.63 (d, 9.2)
30,50: 7.30 (d, 9.2)
20,60: 6.58 (d, 9.1)
30,50: 7.32 (d, 9.1)
20,60: 6.78 (d, 8.9)
30,50: 7.24 (d, 8.9)
20,60: 6.43 (d, 8.9)
30,50: 7.12 (d, 8.9)
20,60: 6.75 (d, 8.2)
30,50: 7.09 (d, 8.2)
20,60: 6.43 (d, 8.2)30,50: 6.98 (d, 8.2)
8.23 (s)
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)
1h (Z)
1h (E)
4.90 (s)
5.13 (s)
4.93 (s)
5.14 (s)
4.92 (s)
5.09 (s)
4.93 (s)
5.16 (s)
4.97 (s)
5.10 (s)
4.90 (s)
5.32 (s)
4.94 (s)
5.30 (s)
4.91 (s)
3.42–3.44 (m)
3.26–3.30 (m)
3.50–3.54 (m)*
3.28–3.30 (m)
3.49–3.52 (m)*
3.23–3.25 (m)
3.43–3.45 (m)
3.29–3.31 (m)
3.52–3.54 (m)
3.26–3.28 (m)
3.47–3.49 (m)*
3.23–3.25 (m)
3.53 (bs)
3.50–3.52 (m)
3.56–3.58 (m)
8.28 (s)
2.14 (s)
2.15 (s)
–
1.78–1.94 (m)
1.50 (bs)
–
–
3.54–3.56 (m)
1.75–1.83 (m)
1.66–1.74 (m)
1.73–1.77 (m), 1.85–1.89 (m)
1.80–1.83 (m)
1.77–1.85 (m)
1.72–1.76 (m)
1.71–1.80 (m)*
CH3: 1.16 (t, 7.3)
CH2: 2.36 (q, 7.3)
CH3: 1.19 (t, 7.3)
CH2: 2.35 (q, 7.3)
8.24 (s)
–
–
3.64–3.66 (m)
3.53–3.55 (m)
3.60–3.62 (m)
3.55–3.57 (m)
3.52–3.54 (m)
–
8.30 (s)
–
2.14 (s)
–
2.16 (s)
–
2.10 (s)
–
2.12 (s)
-
3.65–3.67 (m)
3.61 (bs)
1.80–1.84 (m), 1.70–1.74 (m)
1.93 (bs), 1.87 (bs)
7.36–7.43 (m)
7.45–7.53 (m)
7.37 (bs)
7.44 (m)
–
–
3.21–3.23 (m)
3.52 (bs)
3.65–3.67 (m)
3.59 (bs)
1.76–1.81 (m), 1.64–1.69 (m)
1.84 (bs), 1.88 (bs)
2.27 (s)
2.22 (s)
*
Overlapping signals.

J.Á. Bisceglia et al. / Journal of Molecular Structure 1026 (2012) 65–70
67
Table 3
1H NMR signals of compounds 1a,b,e,g (C6D6).
Cpd.
2
7
4
5
6
Aromatics
R
1a (Z)
4.68 (s)
2.30–2.32 (m)
2.74–2.77 (m)
1.00–1.05 (m)
0.85–0.89 (m)
20,60: 6.39 (dd, 9.16, 3.43)
30,50: 7.09–7.11 (m)*
20,60: 6.08 (dd, 9.16, 3.43)
30,50: 7.09–7.11 (m)*
20,60: 6.46 (dd, 9.16, 3.43)
30,50: 7.11–7.14 (m)
20,60: 6.11 (dd, 9.16, 3.43)
30,50: 7.11–7.14 (m)
20,40,60: 6.84–6.87 (m)
30,50: 7.29–7.32 (m)*
20,60: 6.11 (d, 7.68)
30,50: 7.29–7.32 (m)*
40: 6.90 (tt, 7.10, 1.14)
20,60: 6.61 (bs)
7.82 (s)
1a (E)
1b (Z)
1b (E)
1e (Z)
1e (E)
3.82 (s)
4.88 (s)
4.01 (s)
5.17 (s)
4.33 (s)
3.04–3.06 (m)
2.48–2.50 (m)
3.22–3.24 (m)
2.69–2.71 (m)
3.42–3.44 (m)
2.65–2.68 (m)
2.78–2.80 (m)
2.73–2.75 (m)
3.09–3.11 (m)
3.04–3.06 (m)
1.05–1.09 (m)
1.08–1.13 (m)
1.29–1.33 (m)
1.27–1.36 (m)*
1.27–1.36 (m)*
1.15–1.19 (m)
0.96–1.00 (m)
1.36 (bs)
7.83 (s)
1.67 (s)
1.65 (s)
1.82 (s)
1.83 (s)
1.13–1.17 (m)
1.44–1.46 (m)
1g (Z)
1g (E)
5.21 (s)
2.91 (bs)
3.51 (bs)
2.96 (bs)*
2.95 (bs)*
1.21 (bs)
1.53 (bs)
1.08 (bs)
0.78 (bs)
7.15–7.25 (m)*
7.15–7.25 (m)*
3,50: 7.44 (bs)*
4.46 (bs)
20,60: 6.16 (bs)
30,50: 7.44 (bs)*
*
Partially overlapping signals.
Table 4
13C NMR signals of compounds 1a-h (CDCl3).
Cpd.
2
7
4
5, 6
10
20,60
30,50
40
R
C = O
G
1a (Z)
1a (E)
1b (Z)
1b (E)
1c (Z)
1c (E)
1d (Z)
1d (E)
1e (Z)
1e (E)
1f (Z)
1f (E)
1 g (Z)
60.07
63.62
61.08
64.62
61.27
63.72
60.19
63.51
61.29
64.59
60.95
64.48
62.16
46.54
42.97
46.72
43.84
45.66
43.94
46.35
42.86
46.46
43.66
46.67
43.82
48.35
50.92
49.65
50.49
50.04
50.46
49.99
50.78
49.46
50.34
49.95
50.38
49.87
51.13
25.49, 28.01
25.47, 27.18
26.04, 27.49
26.07, 27.24
26.06, 27.26
26.03, 27.33
25.64, 28,21
25.51, 27.29
25.97, 27.78
26.18, 27.30
25.96, 27.42
25.98, 27.17
26.03, 27.54
144.61
145.34
144.80
145.57
144.90
145.61
145.84
146.01
146.20
146.21
145.19
ND
113.82
114.22
113.69
113.96
113.72
113.89
112.48
113.00
112.42
112.82
114.16
114.38
113.60
129.47
129.42
129.36
129.40
129.33
129.37
129.61
129.53
129.60
129.57
132.22
132.24
129.72
122.94
ND
–
–
162.34
161.73
170.62
169.62
173.80
172.85
162.29
161.83
170.52
ND
–
–
–
–
–
–
–
–
–
–
–
–
–
122.41
122.90
122.32
122.32
117.95
118.24
117.55
118.06
109.54
109.97
122.68
22.36
22.52
27.54, 9.40
27.46, 9.27
–
–
22.41
22.49
22.30
22.46
170.57
ND
171.54
144.67
100: 131.44
200,600: 126.84
300,500: 128.46
400: 129.48
100: 131.46
200,600: 127.22
300,500: 128.52
400: 129.22
100: 136.83
200,600: 126.84
300,500: 128.39
400: 129.53
100: 136.98
200,600: 127.19
300,500: 128.49
400: 129.70
1 g (E)
1 h (Z)
1 h (E)
65.50
62.59
65.74
44.89
48.08
44.65
50.18
50.93
50.27
25.96, 26.75
26.06, 27.91
26.15, 26.96
145.03
143.73
143.69
113.71
112.32
112.67
129.73
130.24
129.93
123.14
129.97
129.88
169.45
171.40
ND
–
20.23
14.18
compounds 1a–h (CDCl3) are given in Table 2. 1H NMR chemical
shifts and multiplicities of compounds 1a,b,e,g in C6D6 are shown
in Table 3. 13C NMR chemical shifts of compounds 1a–h (CDCl3) are
given in Table 4. Relative populations of E/Z rotamers of com-
pounds 1 and of the corresponding hexahydropyrimidine deriva-
tives 2 (CDCl3) [15] are listed in Table 5.
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. As expected, two unequally populated
sets of signals are present in the spectrum of 1a, corresponding
to E/Z diastereoisomers (Fig. 1). Ring inversion in compounds 1 is
expected to be a fast process in the NMR timescale at room tem-
perature, resulting in dynamic averaging of both hydrogens within
each methylene group. This is in accordance with the number of
signals observed in the 1H NMR spectra of hexahydrodiazepines 1.
Like many other compounds, amides display the so called ASIS
(anisotropic solvent induced shifts) effect [24]. Signals of N-alkyl
groups trans to the carbonyl oxygen experience a stronger diamag-
netic shift (Dd) on changing the solvent from CDCl3 to C6D6 than
their cis counterparts [13]. This effect can be diagnostic for the dif-
ferential assignment of cis and trans N-substituents. In our experi-
ence, it is more reliable than assignment based on chemical shifts
in model compounds, especially for amides containing additional
anisotropic substituents [20]. Fig. 2 shows, as an example, the dif-
ferential ASIS effect experienced by the N–CH2 signals of com-
pound 1a. Following the afore mentioned criterion for this
compound, the singlet corresponding to CH2 (2) of the major dia-
stereoisomer (d = 5.06 ppm) was attributed to the cis N-methylene,
and the one corresponding to the minor species (d = 4.90 ppm) as
trans to the carbonyl oxygen (
Dd = 0.38 and 1.08 ppm, respectively,
Fig. 2). Signals centered at 3.62 and 3.24 ppm were tentatively

68
J.Á. Bisceglia et al. / Journal of Molecular Structure 1026 (2012) 65–70
spectrum (CDCl3). 1H and 13C NMR signals of formamide 1d were
assigned by analogy with 1a.
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-chlorophenyl) substituted 1-acyl derivatives were analyzed.
1H NMR spectra of amides 1b,c all display two unequally populated
sets of signals. Resonances of amide N-methylenes (positions 2 and
Table 5
E/Z ratios for compounds 1a–h (n = 1) and their six membered ring homologs 2 (n = 0)
[15]
O
Ar
R
N
N
7) of 1b were assigned on the basis of their
Dd (Tables 2 and 3): for
the major diastereoisomer, the singlet at 5.13 ppm was attributed
as cis, while the one at 4.93 ppm (minor rotamer) as trans to the
n
carbonyl oxygen (
the upfield multiplet centered at 3.28 ppm was assigned as trans
(major diastereoisomer, d 0.79 ppm) and the signal centered at
and 3.52 ppm as cis (minor diastereoisomer, 0.29 ppm)
Dd 0.25 and 0.92 ppm, respectively). Conversely,
Compound 1,2
Ar
R
E:Z (n = 1)
E:Z (n = 0)
D
a
b
c
d
e
f
4-ClC6H4
4-ClC6H4
4-ClC6H4
C6H5
C6H5
4-BrC6H4
4-ClC6H4
H
CH3
29:71
20:80
20:80
33:67
25:75
20:80
26:74
31:69
39:61
28:72
26:74
48:52
37:63
ND
D
d
N-methylenes. The remaining signals were attributed to the major
and minor species on the basis of their relative integration. This
assignment was confirmed by the correlations observed in the
NOESY spectrum of 1b (Fig. 3). 1H NMR spectra of propionamide
1c and acetamides 1e,f were assigned by analogy. The E/Z ratios
determined for compounds 1a-f (Table 5) shows, in all cases, a
preference for the Z rotamer.
CH2CH3
H
CH3
CH3
g
h
C6H5
C6H5
41:59
ND
4-CH3C6H4
At variance with the previous examples, in the 1H and 13C NMR
spectra of benzoyl derivatives 1g,h the signals of both species show
line broadening, indicative of a comparatively lower barrier for the
interconversion of the E/Z diastereoisomers. This feature was previ-
ously observed in other benzamides, and is attributed to competi-
tive resonance stabilization between the amide moiety and the
phenyl substituent, which lowers the partial (O)C–N double bond
character [13]. Interestingly, line broadening is more pronounced
in the minor rotamer, as shown in Fig. 4 for 1g. It has to be taken into
account that E/Z interconversion is a unique process that would in-
volve both diastereoisomers. The observed difference could indicate
that a dynamic process different from E/Z interconversion, probably
ring inversion, is comparatively slower in the NMR timescale for this
rotamer at room temperature. However, it cannot be excluded that
assigned to positions 4 and 7 of the major diastereoisomer. The sig-
nal centered at 3.24 ppm (major diastereoisomer) shows a stronger
diamagnetic shift (
diastereoisomer,
D
d = 0.93 ppm) than the one at 3.43 ppm (minor
D
d = 0.38 ppm), indicating that the former is trans
to the carbonyl oxygen. As expected, the diamagnetic shifts expe-
rienced by the signals corresponding to CH2 (4) are very similar
for both rotamers, while signals arising from CH2 (7) show very dif-
ferent
group.
Dd depending on their situation with respect to the carbonyl
The remaining signals were attributed to the major and minor
species on the basis of their relative integration. This assignment
was confirmed in the NOESY spectrum of 1a (Fig. 3), which also con-
firmed the assignment of positions 4 and 7 of both species. The exis-
tence of NOe between signals belonging to the N-aryl and the formyl
proton in the Z rotamer shows that in the averaged conformation of
the heterocycle both substituents are in a cisoid relationship, in
which the N-aryl is not coplanar with the heterocyclic ring.
The 13C spectrum of 1a also displays separate signals for both
rotamers around the (O)C–N bond. Unambiguous differential
assignment of the resonances (Table 4) was performed on the basis
of the correlations observed in the HSQC spectrum.
this efffect could arise from differences in
Dd for both rotamers.
Analysis of the NOESY spectrum of 1g (Fig. 3) shows that, also in this
case, the Z rotamer is the major species.
For compounds 1b,g, unambiguous differential assignment of
the 13C resonances of both rotamers (Table 3) was performed on
the basis of the correlations observed in their HSQC spectra.
Analysis of data reported in Table 5 shows that the Z rotamer is
the most stable species in compounds 1. It can also be observed that
this preference is influenced by the nature of both N-substituents. In
Relative populations of E/Z rotamers of 1a (Table 5) were deter-
mined by integration of well resolved resonances in the 1H NMR
Fig. 1. 1HNMR spectrum of 1a (CDCl3).

J.Á. Bisceglia et al. / Journal of Molecular Structure 1026 (2012) 65–70
69
Fig. 2. Detail of the 1HNMR spectra of 1a in CDCl3 (A) and C6D6 (B). In the formulae, ꢁ indicates the signal experiencing the strongest ASIS for each rotamer.
Fig. 3. Relevant NOESY correlations for 1a,b,g.
the series of 3-(4-chlorophenyl)-1-acyl hexahydrodiazepines 1a–c,
replacement of R = H (1a) by CH3 (1b) in the acyl group significantly
enhances the Z preference. The equilibrium distribution is not fur-
ther affected when replacing R = CH3 by C2H5 (1c). It is noteworthy

70
J.Á. Bisceglia et al. / Journal of Molecular Structure 1026 (2012) 65–70
Fig. 4. Detail of the 1HNMR spectrum of benzamide 1g showing line broadening.
that benzamide 1d shows an intermediate E/Z ratio between form-
amide 1a and acetamide 1b. This apparently lower effective size of
the phenyl might be a consequence of a larger N–CO bond distance
due to cross conjugation or may alternatively be indicative of addi-
tional (non purely steric) interactions.
Acknowledgements
This work was supported by the University of Buenos Aires
(20020100100935) and by CONICET (PIP 286).
Introduction of a halogen atom in the 40 position of the N-aryl
group also increases the Z preference. The proportion is roughly
the same for acetamides and formamides, independently of the
nature of the halogen. The same trend is evident when comparing
benzamides 1h and 1g, indicating that replacement of a phenyl by
a p-tolyl group has little influence on the E/Z ratio.
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4. Conclusions
We report here the complete 1H and 13C NMR characterization
of a series of 1-acyl-3-arylhexahydro-1,3-diazepines 1. Such com-
pounds display E/Z isomerism due to partial (O)C–N double bond
character, showing two unequally populated sets of signals in their
1H and 13C NMR spectra. The 1H NMR resonances of both rotamers
of some selected compounds were assigned on the basis of ASIS ef-
fects and the assignments confirmed by NOESY. 13C NMR signals
were attributed by HSQC experiments for 1a,b,g. For all the com-
pounds, the E/Z equilibrium favours the Z diastereoisomer. This
preference is sensitive to steric hindrance in the carbonyl substitu-
ent R, and, to a lesser extent, to electron withdrawing groups in the
N-aryl. A comparison with the corresponding six membered
aminals shows the existence of a ring size effect which enhances
the preference for the Z rotamer.
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To our knowledge, this is the first stereochemical study on this
novel family of seven membered heterocyclic compounds and one
of the few reports on hexahydrodiazepines in the literature.