Elucidation of the E-Amide Preference of N-Acyl Azoles

Article abstract of DOI:10.1021/acs.joc.7b01759

The conformational properties of N-acyl azoles (imidazole, pyrazole, and triazole) were examined. The N-2′,4′,6′-trichlorobenzoyl azoles were stable in methanol at room temperature, and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid or 5% triethylamine in CDCl₃. The high stability may be explained by the double-bond amide character caused by the steric hindrance due to the ortho-substituents in the benzoyl group. While specific E-amide preferences were observed in N-acyl pyrazoles/triazoles, the amides of the imidazoles gave a mixture of E and Z. One of the conceivable ideas to rationalize this conformational preference may be repulsive interaction between two sets of lone-pair electrons on the pyrazole 2-nitrogen (n_N) and the carbonyl oxygen atoms (n_O) in the Z-conformation of N-acyl pyrazoles/triazoles. However, analysis of orbital interactions suggested that in the case of the E-conformation of N-acyl pyrazoles, such electron repulsion is small because of distance. The interbond energy calculations suggested that the Z-conformer is involved in strong vicinal σ-σ repulsion along the amide linkage between the σ_N1N2 and σ_C1C2 orbitals in the anti-periplanar arrangement and between the σ_N1C5 and σ_C1C2 orbitals in the syn-periplanar arrangement, which lead to the overwhelming E-preference in N-acyl pyrazoles/triazoles. In the case of N-acyl imidazoles, similar vicinal σ-σ repulsions were counterbalanced, leading to a weak preference for the E-conformer over the Z-conformer. The chemically stable and E-preferring N-acyl azoles may be utilized as scaffolds in future drug design.

Full text of DOI:10.1021/acs.joc.7b01759

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Article
Elucidation of the E-Amide Preference of N-Acyl Azoles
Yuka Takahashi, Hirotaka Ikeda, Yuki Kanase, Kosho Makino, Hidetsugu Tabata, Tetsuta Oshitari,
Satoshi Inagaki, Yuko Otani, Hideaki Natsugari, Hideyo Takahashi, and Tomohiko Ohwada
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01759 • Publication Date (Web): 02 Oct 2017
Downloaded from http://pubs.acs.org on October 6, 2017
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Elucidation of the E-Amide Preference of NꢀAcyl
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Azoles
Yuka Takahashi,† Hirotaka Ikeda,‡ Yuki Kanase,† Kosho Makino, † Hidetsugu Tabata,† Tetsuta
Oshitari,† Satoshi Inagaki,‡ Yuko Otani,‡ Hideaki Natsugari,† Hideyo Takahashi,†, * Tomohiko
Ohwada‡, *
†Faculty of Pharma Sciences, Teikyo University, 2ꢀ11ꢀ1 Kaga, Itabashiꢀku, Tokyo 173ꢀ8605,
Japan
‡Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7ꢀ3ꢀ1 Hongo,
Bunkyoꢀku, Tokyo 113ꢀ0033, Japan
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Abstract
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The conformational properties of Nꢀacyl azoles (imidazole, pyrazole, and triazole) were
examined. The Nꢀ2',4',6'ꢀtrichlorobenzoyl azoles were stable in methanol at room temperature,
and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid
or 5% triethylamine in CDCl3. The high stability may be explained by the doubleꢀbond amide
character caused by the steric hindrance due to the orthoꢀsubstituents in the benzoyl group.
While specific Eꢀamide preferences were observed in Nꢀacyl pyrazoles/triazoles, the amides of
the imidazoles gave a mixture of E and Z. One of the conceivable ideas to rationalize this
conformational preference may be repulsive interaction between two sets of loneꢀpair electrons
on the pyrazole 2ꢀnitrogen (nN) and the carbonyl oxygen atoms (nO) in the Zꢀconformation of
Nꢀacyl pyrazoles/triazoles. However, analysis of orbital interactions suggested that in the case of
the Eꢀconformation of Nꢀacyl pyrazoles, such electron repulsion is small because of distance.
The interbond energy calculations suggested that the Zꢀconformer is involved in strong vicinal
σ−σ repulsion along the amide linkage between the σN1N2 and σC1C2 orbitals in the
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antiꢀperiplanar arrangement and between the σN1C5 and σC1C2 orbitals in the synꢀperiplanar
arrangement, which lead to the overwhelming Eꢀpreference in Nꢀacyl pyrazoles/triazoles. In the
case of Nꢀacyl imidazoles, similar vicinal σ–σ repulsions were counterbalanced, leading to a
weak preference for the Eꢀconformer over the Zꢀconformer. The chemically stable and
Eꢀpreferring Nꢀacyl azoles may be utilized as scaffolds in future drug design.
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Introduction
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In 1962, Staab described Nꢀacyl azoles as reactive heterocyclic amides, which have a high
degree of reactivity in nucleophilic reactions (e.g., hydrolysis or alcoholysis).1 Since then, Nꢀacyl
azoles have been considered to be mild acylating agents as alternatives to acyl halides and
anhydrides.2 Recently, it has been revealed that the sterically hindered Nꢀacylimidazoles show
better stability toward nucleophiles than unhindered ones, and several stability studies of various
Nꢀacylimidazoles have been published.3 In the course of our stereochemical and physicochemical
analyses of biologically active molecules,4 we also found that the 2',6'ꢀdisubstituted Nꢀbenzoyl
imidazoles were unexpectedly stable.5 We presumed that the steric hindrance of
2',6'ꢀdisubstituents restricts the benzene ring to being orthogonal to the coplanar structures
consisting of the carbonyl group and imidazole, which provides a stable doubleꢀbond amide
character. These results encouraged us to study the conformations of various Nꢀacyl azoles
utilizing NMR studies, Xꢀray crystallography, and calculations. In this report, the conformations
of Nꢀacyl azoles, especially the Eꢀamide preference of the chemically stable
Nꢀ2',4',6'ꢀtrisubstituted benzoylated azoles (imidazole, pyrazole, and triazole) are discussed.
Furthermore, the elucidation of the origin of the stereoselectivities of amide isomerism by
calculation was examined. Our results suggest that the stereospecific, stable conformations found
in these azole derivatives should be useful for the next phase of molecular design.
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Results and discussion
Amide Conformations of N-Acyl Azoles
The simplest N-acetyl azoles: Initially, the conformations of Nꢀacetyl azoles (Nꢀacetyl
imidazole 1,6a,b Nꢀacetyl pyrazole 2,6a,b Nꢀacetylꢀ1,2,3ꢀtriazole 3,6a and Nꢀacetylꢀ1,2,4ꢀtriazole
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46a) were examined using H NMR. Through the examination of the VT NMR spectrum
(CD2Cl2) of Nꢀacetyl imidazole 1, we found two sets of resonances in a 2:1 ratio at –90 °C,
which were assumed to be the E/Zꢀamide conformers around the N–(C=O) bond (Figure 1).
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Figure 1. E/Z-amide conformers of N-acetyl azoles.
We assigned the E/Zꢀconformations based on the H2ꢀchemical shift. While H2 in the major
conformer is observed at δ = 8.04 ppm, H2 in the minor conformer is observed at δ = 8.26 ppm.
This downfield shift is caused by a deshielding effect of the carbonyl group in the acetyl moiety,
meaning that the minor conformer adopts the Zꢀconformation, and thus the major conformer
adopts the Eꢀconformation. The activation free energy barrier to rotation of the N—C axis of
E/Zꢀamide rotamers (ꢀG‡)7 was estimated by VT NMR in two conventional methods,
‡
coalescence method and line shape analysis (coalescence method: ꢀGc = 9.9 kcal/mol; line
shape analysis: ꢀG‡ (at ꢀ50 °C) = 9.9 kcal/mol)8 (see the Supporting Information: Figure S1).
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Considering this low energy barrier, Nꢀacetyl imidazole 1 should exist as E/Zꢀconformational
mixtures at room temperature. In contrast, for Nꢀacetyl pyrazole 2, Nꢀacetylꢀ1,2,3ꢀtriazole 3, and
Nꢀacetylꢀ1,2,4ꢀtriazole 4, only one set of resonances was observed in the VT NMR spectra
irrespective of the temperature (–90 °C–100 °C). The fact that H5 is observed at δ = 8.22–8.92
ppm in compounds 2–4 caused by a deshielding effect of the carbonyl group in the acetyl moiety
confirms that these compounds exist in the Eꢀform, as shown in Figure 1. It is true that Nꢀacetyl
azoles 1–4 are less stable so that they are prone to hydrolyzation at ambient temperature.
However, it should be noted that 2–4 exist in a specific conformation (Eꢀisomer) in solvent
irrespective of temperature.
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N-Benzoyl azoles: We next examined Nꢀbenzoyl azoles with 2',4',6'ꢀtrisubstituents. Following
the established method, compounds (5–14) were synthesized as shown in Scheme 1 (yields and
the details of the synthesis are described in experimental).
Scheme 1. Synthesis of N-benzoyl azoles.
The conformations determined by VT NMR of Nꢀbenzoyl azoles (5–8) (the details are shown in
the Supporting Information: Figures S2~S4) are shown in Table 1.
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Table 1. E/Z-amide conformers of N-benzoyl azoles.
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Entry
E/Z
Tc (°C)
coalescence
line shape analysis
ꢀG ‡ (at Tc)
ꢀGc‡ (kcal/mol)
(kcal/mol)
5a3
5b
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—
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N
H
2.5:1
–50
–20
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13.3
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5c3 2.8:1
6a9 10:–
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N
H
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7a10 10:–
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N
H
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For Nꢀbenzoyl imidazole 5a3, only one set of resonances was observed in the VT NMR
spectrum irrespective of temperature (–90 °C–100 °C).11 In contrast, Nꢀ2',4',6'ꢀtrichlorobenzoyl
imidazole 5b provided two sets of resonances at –90 °C, which are similar to those of the
E/Zꢀamide conformers of Nꢀacetyl imidazole 1. Thus, we assigned the E/Zꢀconformations based
on the H2 shift. Considering the downfield shift of H2 (8.48 ppm) in the minor conformer and
the upfield shift of H2 (7.76 ppm) in the major conformer, we determined that the minor
conformer adopts the Zꢀconformation,12 and thus the major conformer adopts the Eꢀconformation
(E/Z = 2.5:1). Based on VT NMR, the activation free energy barrier to rotation of the N—C axis
of E/Zꢀamide conformers of 5b was estimated (coalescence method: ꢀGc‡= 11.8 kcal/mol; line
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shape analysis: ꢀG‡ (at ꢀ50 °C) = 12.1 kcal/mol). Similarly, the two sets13 of resonances at –90
°C (E/Z = 2.8:1) were observed in Nꢀ2',4',6'ꢀtrimethylbenzoyl imidazole 5c3, and the activation
free energy barrier to rotation of the E/Zꢀamide conformers was estimated by VT NMR
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(coalescence method: ꢀGc = 13.3 kcal/mol; line shape analysis: ꢀG‡ (at ꢀ20 °C) = 13.3 kcal/mol).
We next examined the VT NMR spectra of Nꢀbenzoyl pyrazole 6a9,
Nꢀ2',4',6'ꢀtrichlorobenzoyl pyrazole 6b, and Nꢀ2',4',6'ꢀtrimethylbenzoyl pyrazole 6c. Only one set
of resonances for the Eꢀamide conformer, which was confirmed by the H5 downfieldꢀshift (δ =
8.40–8.42 ppm), was observed in compounds 6a, 6b, and 6c irrespective of temperature (–90
°C–100 °C). Similarly, in Nꢀbenzoyl 1,2,3ꢀtriazole 7a10, Nꢀ2',4',6'ꢀtrichlorobenzoyl 1,2,3ꢀtriazole
7b, and Nꢀ2',4',6'ꢀtrimethylbenzoyl 1,2,3ꢀtriazole 7c, only one set of resonances was observed in
the VT NMR spectra irrespective of temperature (–90 °C–100 °C). The downfield shift of H5 (δ
= 8.39–8.45 ppm) observed in them confirmed that compounds 7a–7c adopt the specific
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conformation (Eꢀconformer) irrespective of temperature. Similar results were obtained in the
examination of the VT NMR of Nꢀbenzoyl 1,2,4ꢀtriazole 8a, Nꢀ2',4',6'ꢀtrichlorobenzoyl
1,2,4ꢀtriazole 8b, and Nꢀ2',4',6'ꢀtrimethylbenzoyl 1,2,4ꢀtriazole 8c. Only one set of resonances
for the Eꢀamide conformer, which was confirmed by the H5 downfield shift, was observed in
compounds 8a and 8b irrespective of temperature (–90 °C–100 °C). Meanwhile, the minor
Zꢀconformer was observed at –90 °C in 8c (E/Z = 10:1). The activation free energy barrier to
rotation of the N—C axis of the E/Zꢀamide conformers of 8c was estimated by VT NMR
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‡
(coalescence method: ꢀGc = 10.7 kcal/mol; line shape analysis: ꢀG‡ (at ꢀ60 °C) = 12.0 kcal/mol).
Figure 2 Xꢀray crystal structures of compounds 6b, 7b, and 8b.
So far, it has been revealed that Nꢀacylated (Nꢀacetyl, Nꢀ2',4',6'ꢀtrichlorobenzoyl,
Nꢀ2',4',6'ꢀtrimethylbenzoyl) imidazoles 1, 5b, and 5c and Nꢀ2',4',6'ꢀtrimethylbenzoyl
1,2,4ꢀtriazole 8c exist in an equilibrium state in solution (E/Z = 2:1–10:1). On the other hand,
other Nꢀacyl azoles exclusively adopt the Eꢀconformation irrespective of temperature (–90
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°C–100 °C) in solution. Fortunately, we succeeded in obtaining 6b, 7b, and 8b as single crystals.
Their Xꢀray analysis supported the stereospecific Eꢀconformation (Figure 2) and yielded good
information on the conformation of the 2',4',6'ꢀtrisubstituted compounds. The dihedral angle (φ
C5–N–C7'–O) of 172.2–177.6° confirmed the planarity of the amide moiety in compounds 6b,
7b, and 8b (crystal data on 6b, 7b, and 8b are described in the Supporting Information). The
dihedral angle (φ C2'–C1'–C7'–O) of 79.5–83.5° also confirmed that the benzene ring is nearly
orthogonal to the carbonyl group. It is apparent that the substituents at the 2'ꢀ and 6'ꢀpositions of
the benzoyl moiety affect the C7'—C1' axis to form a twisted conformation, and hence the
coplanar structures consisting of the carbonyl group and azole ring provide the stable
doubleꢀbond amide character in Nꢀacyl azoles.
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In order to examine the stability of the Nꢀacylated azoles, we followed the acidic/basic, or
1
nucleophilic cleavage of Nꢀ2',4',6'ꢀtrichlorobenzoyl azoles 5b, 6b, 7b, and 8b in H NMR at
room temperature. The acidic/basic stability studies were performed in 5% (v/v) trifluoroacetic
acid (TFA) or 5% (v/v) triethylamine (TEA) in CDCl3. All of the compounds were so stable that
no hydrolyzed products were observed over 7 days. Similarly, one equivalent amount of
diethylamine was treated with the CDCl3 solution of 5b, 6b, 7b, and 8b for 1 day, and no
reaction occurred (the details are described in the Supporting Information: Figures S9–S12).
These results confirmed that steric hindrance introduced by the orthoꢀsubstituents provides the
stable doubleꢀbond amide character in Nꢀbenzoyl azoles. These Nꢀbenzoyl azoles are also stable
in methanol.
Effect of 2- and/or 5-substitution of imidazoles on amide equilibrium: We next investigated
the conformations of 2ꢀ and/or 5ꢀsubstituted imidazoles (9b–12c) using VT NMR (Table 2) (the
details are shown in the Supporting Information: Figures S5–S8). In 2ꢀmethylimidazole
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derivatives 9b and 9c, two sets of resonances at –90 °C were observed. Based on the upfield shift
of H5 (δ = 6.80 ppm for 9b, δ = 6.70 ppm for 9c), we determined that the major conformer
adopts the Zꢀconformation (E/Z = 1:20 for 9b, E/Z = 1:23 for 9c). The activation free energy
barrier to rotation of the N—C axis of E/Zꢀamide rotamers (ꢀG‡) was estimated by VT NMR
(coalescence method: ꢀGc‡= 11.9 kcal/mol; line shape analysis: ꢀG‡ (at ꢀ40 °C) = 12.7 kcal/mol
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for 9b, coalescence method: ꢀGc‡= 10.3 kcal/mol; line shape analysis: ꢀG‡ (at ꢀ70 °C) = 10.3
kcal/mol for 9c). It is important to note that the high selectivity for the Zꢀconformation was
observed at –90 °C in 9b and 9c, which is in contrast to that of the unsubstituted imidazole
derivatives 1, 5b, and 5c. In 5ꢀmethyl derivatives 10b and 10c, we found one set of resonances
for the Eꢀconformer irrespective of temperature (–90 °C–100 °C), which was confirmed from the
H2 upfield shift (δ = 7.38 ppm for 10b, δ = 7.38 ppm for 10c) at –90 °C. These results imply that
the conformation, which has the C=O group on the same side of the substituted methyl group, is
preferred in 9 and 10.
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Table 2. E/Z-amide conformers of N-benzoyl imidazoles with 2/5 substituents.
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Entry
E/Z Tc (°C)
coalescence
ꢀGc‡ (kcal/mol)
11.9
line shape analysis
ꢀG ‡ (at Tc) (kcal/mol)
1
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1:20 –40
1:23 –70
10:–
12.7
10.3
9b
10.3
9c
10b
10c
10:–
5
6
7
8
1:2
–10
0
13.2
14.1
12.6
13.1
11b
11c
12b
12c
–:10
4:1
10:–
In a similar manner, the conformations of 2ꢀ or 5ꢀphenylꢀsubstituted imidazoles (11b–12c) were
examined by VT NMR. In Nꢀ2,4,6ꢀtrichlorobenzoylꢀ2ꢀphenyl imidazole 11b, two sets of
resonances at –90 °C were observed. Based on the downfield shift of H5 (δ = 7.81 ppm) in the
minor conformer, we determined that the major conformer adopts the Zꢀconformation (E/Z = 1:2).
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The activation free energy barrier to rotation of the N—C axis of the E/Zꢀamide rotamers (ꢀG‡)
5
6
7
8
was estimated by VT NMR (coalescence method: ꢀGc‡= 13.2 kcal/mol; line shape analysis: ꢀG‡
(at ꢀ10 °C) = 12.6 kcal/mol). Meanwhile, the corresponding Nꢀ2,4,6ꢀtrimethylbenzoyl derivative
11c provided only one set of spectra at 22 °C, which was determined to be the Zꢀconformation
based on the upfield shift of H5 (δ = 7.06 ppm). Although the separated sharp peaks became
broad as the temperature was lowered, no minor conformer was observed at –90 °C in 11c.
Although it is difficult to explain these broad peaks at the lower temperature, the partly reduced
rotation of the C2—Ph bond may be responsibe. In Nꢀ2,4,6ꢀtrichlorobenzoylꢀ5ꢀphenyl imidazole
12b14, broad peaks were observed at 22 °C, which became sharp as the temperature decreased.
Based on the downfield shift of H2 (δ = 8.42 ppm) in the minor conformer, we determined that
the major conformer adopts the Eꢀconformation (E/Z = 4:1) and the activation free energy barrier
to rotation of the N—C axis of the E/Zꢀamide rotamers (ꢀG‡) was estimated by VT NMR
9
10
11
12
13
14
15
16
17
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21
22
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(coalescence method: ꢀGc‡= 14.1 kcal/mol; line shape analysis: ꢀG‡ (at 0 °C) = 13.1 kcal/mol).
In contrast, the corresponding Nꢀ2,4,6ꢀtrimethylbenzoyl derivative 12c14 provided only one set of
spectra at 22 °C, which was determined to be the Eꢀconformation based on the upfield shift of
H2 (δ = 7.63 ppm). Similar to 11c, the separated peaks became broad as the temperature
decreased, and no minor conformer was observed at –90 °C in 12c. Considering these results, it
was suggested that the C=O bond preferentially faced in the same direction as the phenyl group
in 2ꢀ or 5ꢀphenylꢀsubstituted imidazole derivatives (11 and 12).
Amide conformation of 3- and 5-disubstituted pyrazoles: We further investigated the
conformations of 3ꢀ and 5ꢀdisubstituted pyrazoles (13b and 13c) using VT NMR (Table 3). In
the spectra of Nꢀacylꢀ3,5ꢀdimethylpyrazoles (13b, 13c), only one set of resonances for the
Eꢀamide conformer, which was confirmed by the 5ꢀCH3 downfield shift (δ = 2.6ꢀ2.7 ppm), was
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observed irrespective of temperature (–90 °C–100 °C). Similarly, the corresponding
3,5ꢀdiphenylpyrazoles (14b and 14c) provided only one set of resonances presumed to take the
Eꢀconformation. All these results make it clear that the conformation, which has the C=O group
on the same side of the 5ꢀ methyl or 5ꢀphenyl group, is exclusively the preferred orientation in 13
and 14.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. E/Z-amide conformers of N-benzoyl pyrazoles with 5 substituents.
Entry
E/Z
1
2
3
4
10:–
10:–
10:–
10:–
13b
13c
14b
14c
Since imidazole derivatives 9b and 11b and pyrazole derivatives 13b and 14b were obtained
as single crystals, we performed their Xꢀray structure analysis (crystal data on 9b, 11b, 13b, and
14b are described in the Supporting Information). As shown in Figure 3, the conformations of
9b, 13b, and 14b were consistent with the results observed in the NMR spectra. However,
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Nꢀ2,4,6ꢀtrichlorobenzoylꢀ2ꢀphenyl imidazole 11b exhibited the Eꢀconformation, which is the
minor orientation in solution. The presence of the Eꢀconformation in the crystal could be a
fortuitous crystal packing arrangement effected by π–πꢀstacking of two phenyl groups.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. X-ray crystal structures of compounds 9b, 11b, 13b, and 14b.
Computational study of the relative stability of E/Z-amide conformations
DFT calculations were carried out to evaluate the relative stability of the Eꢀ and Zꢀamide
conformations of the experimentally studied molecules and simplified molecules. The relative
energy differences of two conformers were estimated on the basis of geometries fully optimized
with B3LYP/6ꢀ311++G(d,p) with energy calculations with B3LYP/6ꢀ311++G(d,p) on the
SCRF/IEFPCM model in CH2Cl2. Zero point energy (ZPE) correction was made on the basis of
the frequency calculation with B3LYP/6ꢀ311++G(d,p). We found that in the cases of
Nꢀ2,4,6ꢀtrimethylbenzoylꢀsubstituted amides (6c, 7c, and 8c), the dispersion effects between
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methyl groups and the other fragments were affected by the solvation model (i.e.,
overestimation), and the energy difference between E and Z conformations were seriously
underestimated. Therefore, in order to estimate the dispersion effects accurately in the solvent
model, we used the energy difference based on the SCRF/IEFPCM model in CH2Cl2 in
M06ꢀ2X/6ꢀ311G(d,p) with the M06ꢀ2X/6ꢀ311G(d,p) fully optimized structures. Zero point
energy (ZPE) correction was also made on the basis of the frequency calculation with
M06ꢀ2X/6ꢀ311G(d,p). The similar methods were also applied to the related imidazole (5c),
Nꢀ2,4,6ꢀtrichorobenzoylꢀsubstituted amides (5b, 6b, 7b, and 8b) and Nꢀbenzoylꢀsubstituted
amides (5a, 6a, 7a, and 8a) for comparison. The trends and magnitudes of the relative energies
based on B3LYP/6ꢀ311++G(d,p) and M06ꢀ2X/6ꢀ311G(d,p) were comparable in the cases of
Nꢀ2,4,6ꢀtrichorobenzoylꢀsubstituted amides (5b, 6b, 7b, and 8b) and Nꢀbenzoylꢀsubstituted
amides (5a, 6a, 7a, and 8a). The relative energy differences were represented in terms of
difference in Gibbs free energy estimated after correction of vibration energies at 300 K (27 °C).
All the values are compiled in Tables 4–7. All the optimized structures are shown in Supporting
Information. We cited the M06ꢀ2X/6ꢀ311G(d,p) solvent model energies, if they were available,
and otherwise the B3LYP/6ꢀ311++G(d,p) solvent model energies were cited in the text.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
33
34
35
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38
39
40
41
42
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50
51
52
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54
55
56
57
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59
60
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Table 4. Calculated Energy Difference (in kcal/mol) of Amide Isomers of Imidazole
Derivatives a
7
8
9
Experimental
compound
B3LYP/
6ꢀ31G(d)
B3LYP/
IEFPCMꢀB3LYP/ ꢀꢀG (Z-E)
c
Ratio of E/Z
6ꢀ311++G(d,p)
optimization
6ꢀ311++G(d,p)
single point
(CH2Cl2)
(at 300K)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
optimization
ꢀꢀH(ZꢀE)
E : Z
ꢀꢀΗ(Ζ−Ε)
+0.19
+0.30
+0.18
+0.21
2 : 1
1
(N-acetyl)
+0.39
+0.32
+0.32
+0.47
+0.46
+0.46
+0.35
[+0.22]b
+0.37
[+0.23] b
+0.40
[+0.38] b
ꢀ1.77
+0.32
[+0.22]b
+0.34
[+0.18] b
+0.44
[+0.67] b
ꢀ1.32
ND
5a
5b
5c
2.5 : 1
2.8 : 1
ꢀ2.18
ꢀ2.18
+2.32
+2.47
ꢀ1.16
ꢀ1.30
+1.22
+1.50
+0.41
ꢀ2.38
+2.42
ꢀ0.14
ꢀ1.79
ꢀ2.18
+2.22
+2.47
ꢀ0.58
ꢀ1.26
+0.85
+1.64
+0.56
ꢀ2.22
+2.42
ꢀ0.08
1 : 20
1 : 23
10 : ꢀ
10 : ꢀ
1 : 2
ꢀ : 10
4 : 1
10 : ꢀ
ND
9b
9c
10b
10c
11b
11c
12b
12c
ꢀ1.93
ꢀ2.69
+1.94
+2.01
ꢀ1.16
+3.70
+2.46
ꢀ2.17
ꢀ1.55
ꢀ3.19
+1.44
+1.84
+0.53
ꢀ1.91
+2.10
+3.91
+0.48
ꢀ1.97
N-formyl
N-acetyl-2-Me
N-acetyl-5-Me
N-acetyl-2,5-diMe
ND
ND
ND
+1.79
ꢀ0.29
+1.80
ꢀ0.18
a) The energy difference (Z form – E form) was shown. Positive values showed E form is more
stable, and negative values showed Z form is more stable.
b) Due to adequate evaluation of dispersion effect, the value was obtained by the single point
calculation with energy estimation with M06ꢀ2X/6ꢀ311G(d, p) on the basis of the optimized
structure with M06ꢀ2X/6ꢀ311G(d, p).
c) The ratios of E/Z conformations observed experimentally (600 MHz, CD2Cl2, at ꢀ90 °C).
ND=not determined.
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Table 5. Calculated Energy Difference (in kcal/mol) of Amide Isomers of Pyrazole
Derivatives a
7
8
9
Experimental
compound
B3LYP/
B3LYP/
IEFPCMꢀB3LYP/ ꢀꢀG (Z-E)
c
Ratio of E/Z
6ꢀ31G(d)
optimization
ꢀꢀH(ZꢀE)
6ꢀ311++G(d,p)
optimization
6ꢀ311++G(d,p)
single point
(CH2Cl2)
(at 300K)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
E : Z
ꢀꢀΗ(Ζ−Ε)
+6.45
+6.35
+2.99
+3.05
10 : ꢀ
2
(N-acetyl)
+5.12
+4.76
+2.17
+4.55
+4.55
+3.24
+1.77
[+1.66]b
+2.34
+1.85
[+2.10] b
+2.30
10 : ꢀ
10 : ꢀ
10 : ꢀ
6a
6b
6c
[+2.30] b
+1.36
[+2.38] b
[+1.52] b
+4.93
+3.80
+4.91
+3.73
+4.30
+3.56
+3.66
+3.62
[+1.49] b
+6.71
+4.13
+6.90
+3.97
+4.98
+4.79
+4.10
+4.97
+7.98
+6.54
+6.89
+6.54
+6.65
+5.03
+6.35
+5.03
+7.51
+6.02
+7.48
+5.97
+6.04
+4.81
+5.73
+4.84
ND
ND
10 : ꢀ
10 : ꢀ
ND
ND
10 : ꢀ
10 : ꢀ
5-me Cl
5-me Me
13b
13c
5-ph Cl
5-ph Me
14b
14c
a) The energy difference (Z form – E form) was shown. Positive values showed E form is more
stable, and negative values showed Z form is more stable.
b) Due to adequate evaluation of dispersion effect, the value was obtained by the single point
calculation with energy estimation with M06ꢀ2X/6ꢀ311G(d, p) on the basis of the optimized
structure with M06ꢀ2X/6ꢀ311G(d, p).
c) The ratios of E/Z conformations observed experimentally (600 MHz, CD2Cl2, at ꢀ90 °C).
ND=not determined.
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Table 6. Calculated Energy Difference (in kcal/mol) of Amide Isomers of 1,2,3-Triazole
Derivatives a)
6
7
8
9
Experimental
compound
B3LYP/
6ꢀ31G(d)
B3LYP/
IEFPCMꢀB3LYP/
6ꢀ311++G(d,p)
single point
ꢀꢀG (E-Z)
c
Ratio of E/Z
6ꢀ311++G(d,p)
optimization
(at 300K)
optimization
ꢀꢀH(ZꢀE)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
E : Z
ꢀꢀΗ(
Ζ−
Ε
)
(CH2Cl2)
+6.38
+6.51
+3.03
+3.08
10 : ꢀ
3
(N-acetyl)
+5.10
+4.61
+3.79
+4.75
+4.63
+3.50
+1.84
[+1.81] b
+2.43
+1.83
[+1.83] b
+2.33
10 : ꢀ
10 : ꢀ
10 : ꢀ
7a
7b
7c
[+2.14] b
+1.54
[+1.77] b
[+1.52] b
[+1.49] b
a) The energy difference (Z form – E form) was shown. Positive values showed E form is more
stable, and negative values showed Z form is more stable.
b) Due to adequate evaluation of dispersion effect, the value was obtained by the single point
calculation with energy estimation with M06ꢀ2X/6ꢀ311G(d, p) on the basis of the optimized
structure with M06ꢀ2X/6ꢀ311G(d, p).
c) The ratios of E/Z conformations observed experimentally (600 MHz, CD2Cl2, at ꢀ90 °C)
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Table 7. Calculated Energy Difference (in kcal/mol) of Amide Isomers of 1,2,4-Triazole
Derivatives a)
8
9
compound
Experimental
c
B3LYP/
6ꢀ31G(d)
B3LYP/
IEFPCMꢀB3LYP/
6ꢀ311++G(d,p)
single point
ꢀꢀG (E-Z)
Ratio of E/Z
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
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34
35
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37
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41
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6ꢀ311++G(d,p)
optimization
(at 300K)
optimization
ꢀꢀH(ZꢀE)
E : Z
ꢀꢀΗ(
Ζ−
Ε
)
(CH2Cl2)
+5.75
+5.64
+2.56
+2.53
10 : ꢀ
4
(N-acetyl)
+4.46
+3.97
+3.05
+3.86
+3.73
+2.57
+1.30
[+1.72]b
+1.79
+1.45
[+2.02] b
+1.71
10 : ꢀ
10 : ꢀ
10 : 1
8a
8b
8c
[+1.76] b
+0.92
[+1.62] b
[+0.85] b
[+1.18] b
a) The energy difference (Z form – E form) was shown. Positive values showed E form is more
stable, and negative values showed Z form is more stable.
b) Due to adequate evaluation of dispersion effect, the value was obtained by the single point
calculation with energy estimation with M06ꢀ2X/6ꢀ311G(d, p) on the basis of the optimized
structure with M06ꢀ2X/6ꢀ311G(d, p).
c) The ratios of E/Z conformations observed experimentally (600 MHz, CD2Cl2, at ꢀ90 °C)
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Energetics of N-Aroyl Derivatives
5
6
7
8
Imidazoles (Table 4): The optimized structures of Nꢀsubstituted benzoyl imidazoles 5b and 5c
take bisected structures in which the aromatic ring is perpendicular with respect to the amide
plane, consistent with the Xꢀray structures (Figure 3: 9b, 11b). Therefore, the benzene moiety is
unconjugated with the amide, indicating that the benzene π system has little effect on the bias of
amide E–Zꢀconformations in the ground state. The calculated energy differences of the amide
E/Zꢀconformers of 5b (Eꢀisomer, favored by 0.18 kcal/mol (ꢀꢀG (EꢀZ) (at 300K)) and 5c
(Eꢀisomer, favored by 0.67 kcal/mol) are consistent with the observed ratios of the isomers (E:Z
= 2–3:1) in 1H NMR spectroscopy (Table 1).
9
10
11
12
13
14
15
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28
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34
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45
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47
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49
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60
1’
2’
1’
5
1’
5
1
4
1
4
2
2
5
2’
3
3
2
2’
3
4
5a-TS1
5a-TS2
5a E-form
for amide rotation
for phenyl rotation
∠
C2ꢀN1ꢀCꢀO = +180.0°
∠
∠
C2ꢀN1ꢀCꢀO = ꢀ89.8°
N1ꢀCꢀC1’ꢀC2’ = +0.50°
∠
C2ꢀN1ꢀCꢀO = ꢀ157.7°
∠
N1ꢀCꢀC1’ꢀC2’ = +0.00°
∠
N1ꢀCꢀC1’ꢀC2’ = +39.3°
Figure 4. DFT optimized structures of compound 5a E-form and transition state
structures for amide rotation (5a-TS1) and for phenyl rotation (5a-TS2).
In the case of Nꢀbenzoyl imidazole 5a, although giving a single set of signals in the 1H NMR
experiment, the calculated energy difference of the E/Z amide conformers of 5a (Eꢀisomer,
favored by 0.22 kcal/mol) was of similar magnitude to those of 5b and 5c. Thus, we calculated
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the activation energies for the rotation of amide rotation (5a-TS1) and that for the phenyl group
(5a-TS2) (Figure 4) and found that the activation energies for the rotation of the phenyl group
(5.56 kcal/mol; PCM model in CH2Cl2) is comparable in magnitude to that for amide rotation
(5.83 kcal/mol; PCM model in CH2Cl2). Furthermore, the rotational barrier of the latter amide is
much smaller than those of the conventional amides (15–20 kcal/mol). Therefore, we cannot
distinguish the amide Eꢀ and Zꢀconformations of 5a on the NMR time scale, which will lead to
an unresolved single set of signals in the NMR experiments.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
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59
60
On the other hand, the calculated activation energies for the amide E–Z rotation of
Nꢀ2',4',6'ꢀtrisubstituted benzoyl imidazoles 5b and 5c are 16.80 kcal/mol from the Eꢀisomer of 5b
and l1.80 kcal/mol from the Eꢀisomer of 5c, respectively. These values of 5b and 5c are much
larger than that of Nꢀunsubsituted benzoyl derivative 5a (5.83 kcal/mol). The magnitude of these
values matches the experimentally observed values of 12.1 kcal/mol for 5b (at –50 °C) and 13.0
kcal/mol for 5c (at –20 °C).
Experimentally, we found that the substitution of a methyl group at the 2ꢀposition of Nꢀaroyl
imidazoles (9b and 9c) distinctly switched the conformational preference to the Zꢀconformation,
whereas the 2ꢀunsubstituted prototypes (5b and 5c) showed a weak preference for the Eꢀform
(Tables 1, 2). The calculated energy difference of the Zꢀ and Eꢀconformers of 2ꢀmethyl
derivatives (9b and 9c) was 1.32 and 2.69 kcal/mol, respectively, which is consistent with a
strong preference for the Zꢀconformation. Other experimental substitution effects were consistent
with the calculations (see the Supporting Information).
Pyrazoles (Table 5): NꢀAroylꢀpyrazoles 6a, 6b, and 6c favored Eꢀconformations (Table 1).
Calculations showed that the energy differences between the Eꢀ and Zꢀconformations are 2.10,
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2.38, and 1.49 kcal/mol, respectively, which is consistent with the overwhelming experimental
bias. When methyl (13b and 13c) or phenyl (14b and 14c) substituents were introduced at the 3ꢀ
and 5ꢀpositions of pyrazoles, a strongly biased preference for the Eꢀconformation was found
(Table 3). This is consistent with the increase in the calculated energy differences of 6.90
kcal/mol (13b), 3.97 kcal/mol (13c), 4.10 kcal/mol (14b), and 4.97 kcal/mol (14c), respectively.
The substituent at the 3ꢀposition is distal, and it is expected that the 3ꢀsubstituent will have little
influence on the conformational preference. The calculated energy difference (6.71 kcal/mol) of
the E/Zꢀconformers of the 5ꢀmonomethylꢀsubstituted derivative is similar in magnitude to that of
the 3,5ꢀdimethyl 13b (6.90 kcal/mol). A similar situation is found in the case of phenyl
substitution: energy differences of the E/Zꢀamide conformers of the corresponding
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5ꢀmonophenylꢀsubsitututed
pyrazole
derivatives
derivative)
were
4.98
4.79
kcal/mol
kcal/mol
(Nꢀtrichlorobenzoylꢀ5ꢀPhꢀprazole
and
(Nꢀtrimethylbenzoylꢀ5ꢀphenylꢀprazole derivative), respectively, which are very similar in
magnitude to those of 3,5ꢀdiphenylꢀprazole derivatives, i.e., 4.10 kcal/mol for 14b and 4.97
kcal/mol for 14c. An overwhelming preference for the Eꢀconformation is consistent among the
series of compounds comprising 3,5ꢀunsubstituted (6a–6c, Table 1), virtual 5ꢀsubstituted, and
3,5ꢀdisubstituted derivatives (13b, 13c, 14b, and 14c), even though a steric demand introduced
by substitution at the 5ꢀposition of pyrazole is present. Therefore, the conformational preference
can again be derived from nonsteric factors, and probably the determining factor is the
unfavorable interaction between the 2ꢀnitrogen atom and the N–(C=O) groups intrinsic in the
Zꢀconformation.
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1,2,3-Triazoles (Table 6): NꢀAroylꢀ1,2,3ꢀtriazoles 7a, 7b, and 7c favored Eꢀconformations
(Table 1). Calculations showed that the energy differences between the Eꢀ and Zꢀconformations
are 1.83, 1.77, and 1.49 kcal/mol respectively, which is consistent with the overwhelming
experimental Eꢀbias.
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1,2,4-Triazoles (Table 7): In a manner similar to Nꢀaroylꢀ1,2,3ꢀtriazoles, calculations showed
that the energy differences between the E and Z conformations of Nꢀaroylꢀ1,2,4ꢀtriazoles (8a, 8b,
and 8c) are 2.02, 1.62 and 1.18 kcal/mol, respectively, which is consistent with the experimental
E bias (Table 1). In the case of 8c, the equilibrating Zꢀform can be observed due to the
intermediate magnitude of the energy difference.
Energetics of N-Acetyl Derivatives
While simple Nꢀacetyl derivatives of imidazole (1) gave a slightly biased mixture of Eꢀ and
Zꢀisomers (E:Z = 2:1) (see the Supporting Information: Figure S1), Nꢀacetyl derivatives of
pyrazole (2), 1,2,3ꢀtriazole (3), and 1,2,4ꢀtriazole (4) gave a single conformation
(Eꢀconformation) (Figure 1). The magnitude of the calculated energy differences of the Eꢀ and
Zꢀconformers is reasonably consistent with this experimental trend: 1, 0.21 kcal/mol; 2, 3.05
kcal/mol; 3, 3.08 kcal/mol; and 4, 2.53 kcal/mol favoring the Eꢀconformation. In both the
experimental and theoretical results, the conformational preferences of Nꢀacetyl derivatives
(Figure 1) completely coincided with those of Nꢀaroyl derivatives (Table 1). In the cases of
pyrazole (2), 1,2,3ꢀtriazole (3), and 1,2,4ꢀtriazole (4), the Nꢀacetyl group can induce complete
bias of E–Z isomerization. This result supported the hypothesis that conformational preferences
can be derived from nonsteric factors, probably due to the presence of the 2ꢀnitrogen atom in the
heterocyclic molecules.
Origin of the stereoselectivities of amide isomerism
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We focused on analysis of Nꢀacetyl pyrazole 2 and Nꢀ2',4',6'ꢀtrichlorobenzoyl pyrazole 6b to
determine the origin of the Eꢀconformer preference. The electronic structures of the molecules
were analyzed using bond model analysis,15 which is able to evaluate the bond orbital
interactions in molecules.16
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Analysis of Orbital Interactions
Vicinal σ–σ electron repulsion
Pyrazole (Table 8): The interactions to be considered are the repulsive interactions between the
σ orbitals (σ electrons), vicinal around the C–N amide linkage, connecting the pyrazole nitrogen
atom and the acetyl carbonyl carbon atom of the Nꢀacetyl pyrazole 2 since the magnitude of the
interactions is reasonably affected by the rotation around the C–N amide bond. The calculated
interbond energies (IBEs) are listed in Table 8. The IBEs showed that the repulsions between the
σ orbitals, vicinal with respect to the amide linkage, differed greatly in energy between the Eꢀ
and Zꢀconformers of 2. The repulsion of the C1–C2 σ orbital of the acetyl group against the
N1–N2 σ orbital of the pyrazole ring is surprisingly strong in the Zꢀconformer (+0.198 au
[hartree]) in comparison with that of the C1–C2 σ orbital against the N1–N2 σ orbital in the
Eꢀconformer (+0.062 au) (Figure 5). It is worth noting that in the Zꢀconformer, the N1–N2 and
C1–C2 bonds are in the anti-periplanar configuration and the corresponding bonds (i.e., N1–N2
and C1–C2 bonds) in the Eꢀconformer are in the synꢀperiplanar configuration. On the other hand,
the repulsion of the carbonyl C1–C2 σ bond against the pyrazole N1–C5 σ bond in the
Zꢀconformer is greater (+0.193 au) than that of the carbonyl C1–C2 σ bond against the N1–C5 σ
bond in the E-conformer (+0.072 au). The σ orbitals in the Zꢀconformation are in the
syn-periplanar configuration, and the σ orbitals in the Eꢀconformation are in the anti-periplanar
configuration, respectively (see Figure 5).
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Furthermore, a similar antiꢀperiplanar vicinal electron repulsion between σ−σ orbitals is also
found in the combination of the pyrazole N1–N2 σ bond against the carbonyl C1–O σ bonds in
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Table 8 IBEs (au,hartree) of bond orbitals in Nꢀacetyl pyrazole 2a
a) au. =627.51 kcal/mol
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σC1C2
σC1C2
2
2
O
O
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1
N1
1
destabilizing
destabilizing
σNN
N1
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N2
N2
σ
5
5
NN
>
more
repulsive
E conformer (2)
Z conformer (2)
(IBE=+0.198 au)
(IBE=+0.062 au)
Figure 5. Isosurfaces of the σNN and σCC orbitals of Nꢀacetyl pyrazole 2.
Isovalue 0.067 was used.
the Eꢀconformation (+0.118 au), which was slightly larger than the antiꢀperiplanar vicinal
repulsion of the pyrazole N1–C5 σ bond against the carbonyl C1–O σ bonds in the
Zꢀconformation (+0.082 au). These repulsion interactions arising from the carbonyl C1–O σ
bonds almost compensate for each other in the Eꢀ and Zꢀconformations. Therefore, strong
repulsions of the carbonyl C–C2 σ bond against the pyrazole N1–N2 and N1–C5 bonds in the
Zꢀconformer are detected and these are likely the predominant factors in destabilizing the
Zꢀconformer, leading to biased preference for the Eꢀconformer.
N-2',4',6'-Trichlorobenzoyl pyrazole: The electronic structure of Nꢀ2',4',6'ꢀtrichlorobenzoyl
pyrazole 6b was also analyzed. The σN1N2 and σC1C2 orbitals of 6b are shown in Figure 6 together
with the values of IBEs. The calculated IBEs are shown in Supporting Table S1. The IBEs
indicate strong repulsion between the σN1N2 and σC1C2 orbitals in the antiꢀperiplanar arrangement
(Zꢀconformer). In a manner similar to 2, a strong repulsion of the carbonyl C1–C2 σ bond
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against the pyrazole N1–C5 bonds in the synꢀperiplanar arrangement (Zꢀconformer) was found,
contributing to destabilization of the synꢀperiplanar interaction in the Zꢀconformer. Therefore,
the stability of the Zꢀconformer of 6b is also controlled by the repulsion of the σ orbitals.
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Figure 6. Isosurfaces of the σNN and σCC orbitals of Nꢀ2', 4', 6'ꢀtrichlorobenzoyl pyrazole 6b.
Isovalue 0.067 was used.
n–n Electron Repulsion One of the conceivable ideas to rationalize the conformational
preference may be repulsive interaction between two sets of loneꢀpair (nonbonding) electrons on
the pyrazole 2ꢀnitrogen (nN) and the carbonyl oxygen atoms (nO) in the Zꢀconformation of
Nꢀacetyl pyrazole 2 (Figure 7(a)). The repulsion energy of nO–nN in the Zꢀconformation of 2 is
+0.016 au (hartree), according to the IBE. In the case of the Eꢀconformation of 2, the electron
repulsion between the 2ꢀnitrogen loneꢀpair electrons (nN) and the carbonyl oxygen loneꢀpair
electrons (nO) is negligible; therefore the energy difference in the repulsive interaction of nO–nN
between the Zꢀ and Eꢀconformations is much smaller than that of the aboveꢀmentioned σ–σ
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electron repulsion (vide infra). This is because these two nonbonding orbitals are distal, and the
interaction is insignificant.
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n–σ* Electron Delocalization Another possible interpretation is the difference in the
stabilization interaction of the pyrazole 2ꢀnitrogen loneꢀpair electrons with the C=O σ* orbital in
the Eꢀconformation (Figure 7(b)) or with the C–C σ* orbital in the Zꢀconformation (Figure 7(c))
of Nꢀacetyl pyrazole 2. However, the former interaction is approximately null (IBE = –0.001 au),
and the latter interaction is as small as –0.010 au (IBE). The interaction is insignificant. This is
also likely because the distances of these orbitals are distal. Therefore, unexpectedly the N2
loneꢀpair electrons of the pyrazole and related heterocycles are not a determinant factor for the
stereoselection of amides.
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