Contribution of Solvents to Geometrical Preference in the Z/ E Equilibrium of N-Phenylthioacetamide

Article abstract of DOI:10.1021/acs.joc.1c00801

We studied the Z/E preference of N-phenylthioacetamide (thioacetanilide) derivatives in various solvents by means of 1H NMR spectroscopy, as well as molecular dynamics (MD) and other computational analyses. Our experimental results indicate that the Z/E isomer preference of secondary (NH)thioamides of N-phenylthioacetamides shows substantial solvent dependency, whereas the corresponding amides do not show solvent dependency of the Z/E isomer ratios. Detailed study of the solvent effects based on molecular dynamics simulations revealed that there are two main modes of hydrogen (H)-bond formation between solvent and (NH)thioacetamide, which influence the Z/E isomer preference of (NH)thioamides. DFT calculations of NH-thioamide in the presence of one or two explicit solvent molecules in the continuum solvent model can effectively mimic the solvation by multiple solvent molecules surrounding the thioamide in MD simulations and shed light on the precise nature of the interactions between thioamide and solvent. Orbital interaction analysis showed that, counterintuitively, the Z/E preference of NH-thioacetamides is mainly determined by steric repulsion, while that of sterically congested N-methylthioacetamides is mainly determined by thioamide conjugation.

Full text of DOI:10.1021/acs.joc.1c00801

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Article
Contribution of Solvents to Geometrical Preference in the Z/E
Equilibrium of N‑Phenylthioacetamide
Shuyi Song, Tadashi Hyodo, Hirotaka Ikeda, Kim Anh L. Vu, Yulan Tang, Erika S. Chan, Yuko Otani,
Satoshi Inagaki, Kentaro Yamaguchi, and Tomohiko Ohwada*
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ABSTRACT: We studied the Z/E preference of N-phenylthioacetamide (thioacetanilide) derivatives in various solvents by means
of 1H NMR spectroscopy, as well as molecular dynamics (MD) and other computational analyses. Our experimental results indicate
that the Z/E isomer preference of secondary (NH)thioamides of N-phenylthioacetamides shows substantial solvent dependency,
whereas the corresponding amides do not show solvent dependency of the Z/E isomer ratios. Detailed study of the solvent effects
based on molecular dynamics simulations revealed that there are two main modes of hydrogen (H)-bond formation between solvent
and (NH)thioacetamide, which influence the Z/E isomer preference of (NH)thioamides. DFT calculations of NH-thioamide in the
presence of one or two explicit solvent molecules in the continuum solvent model can effectively mimic the solvation by multiple
solvent molecules surrounding the thioamide in MD simulations and shed light on the precise nature of the interactions between
thioamide and solvent. Orbital interaction analysis showed that, counterintuitively, the Z/E preference of NH-thioacetamides is
mainly determined by steric repulsion, while that of sterically congested N-methylthioacetamides is mainly determined by thioamide
conjugation.
Z/E isomerism of thioamides seems simple (Figure 2), the
chemistry has been reviewed only once, in the 1970s,3 and
there are discrepancies between the review and some of the
cited papers; for example, the review mentioned Z/E isomer
ratios of thioamides that were not given in the original papers.
Furthermore, only benzene, nitromethane, and pyridine have
been investigated as solvents, in addition to chloroform.4 While
several more recent studies reported solvent dependency of
thioamide rotation and Z/E ratios,5 the chemistry of N-
methylthioamides still needed to be updated recently.6
Therefore, there is a need to reinvestigate the Z/E preferences
INTRODUCTION
■
The thioamide bond, which is an analogue of the amide bond,
takes a planar structure due to the double-bond character of
the C(S)−N bond (Figure 1),1 and replacement of the amide
carbonyl oxygen atom with a sulfur atom increases the
magnitude of the bond rotation barrier. This is important
because there is increasing interest in applications of
thioamides, for example, to prepare peptide analogues,
protein-folding probes, and synthetic intermediates.2 Although
Special Issue: Solvation Effects in Organic Chemistry
Received: April 7, 2021
Figure 1. Thioamide resonance.
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A

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NMR spectra in widely used NMR solvents, CDCl3, CD2Cl2,
acetone-d6, CD3OD, and DMSO-d6. The NMR spectra of
secondary thioamides (1a−10a), NH-thioacetamides (X = H)
bearing a different aromatic substituent (Y) and those (8a, 9a)
bearing a different alkyl substituent (R) (Table 1) showed the
signals of two isomers, which were assigned as the E and Z
isomers with respect to the thioacetamides. Structural
assignment of Z/E isomers of the thioacetamides were based
on 2D NMR spectra analysis and GIAO calculations7 (Figures
S1−S3 and Table S1). The isomer ratio was solvent dependent
(Table 2). In order to assess the effect of the hydrogen atom
on the nitrogen atom (NH, X = H), we also examined the Z/E
isomer preference of the N-methyl derivatives of N-phenyl-
thioacetamides (X = Me) (1b−10b).
The E ratio of NH-thioacetamides increased as the polarity
of the solvent was increased from chloroform (dielectric
constant = 4.8), dichloromethane (9.1), acetone (20.6),
methanol (32.6), to DMSO (47.2) (Table 2). However,
there is no direct correlation between the dielectric constant of
the solvent and the thioamide Z/E ratio, and the relationship is
not linear: the E ratio was maximal in methanol but remained
similar in DMSO. This trend is consistent with previous
reports on the solvent dependence of rotational barriers of
thioamides: the magnitude of the rotational barriers does not
simply correlate with the polarity of the solvent, particularly in
the cases of methanol and DMSO.5a As described later, we
found that the conformational preferences of the N-phenyl-
thioacetamides can be attributed to the hydrogen bond donor/
acceptor ability of the solvent. Methanol can be considered as a
hydrogen-bond-donating solvent, whereas the others are
hydrogen-bond acceptors. However, our calculations showed
that methanol can also work as a hydrogen-bond acceptor,
probably due to the acidity difference between thioamide NH
(pKa = 18.5 for thioacetamide)8 and methanol (pKa = 29.0).9
Some NH-thioacetamides show different Z and E ratios in
CDCl3 and in CD2Cl2 (Table 2): 1a: Z/E 45:55 (CDCl3);
33:67 (CD2Cl2), 2a: Z/E 47:53 (CDCl3); 35:65 (CD2Cl2), 3a:
Z/E 49:51 (CDCl3); 36:64 (CD2Cl2), 4a: Z/E 31:69
(CDCl3); 27:73 (CD2Cl2). However, in d6-DMSO, the E
conformer is strongly favored: 1a: Z/E 7:93 (d6-DMSO); 2a:
Z/E 9:91 (d6-DMSO); 3a: Z/E 8:92 (d6-DMSO); 4a: Z/E
9:91 (d6-DMSO). Thus, aromatic substituents (1a−7a) appear
to have relatively little effect on the Z/E isomer preference in a
given solvent (Table 2), though NH-thioacetamides (6a and
7a) with an electron-withdrawing group are insoluble in
CDCl3 and CD2Cl2. In the case of NH-thioamides, solvent-
dependent variation in the Z/E conformer ratios seemed larger
in the case of electron-rich aromatic 2a than electron-deficient
6a or 7a: for example, in acetone, 2a gave a Z/E ratio of 12:88,
while 6a and 7a give practically only the E conformation
(1>:>99). This is consistent with the involvement of hydrogen
bonding of the acidic NH proton of the NH-thioamides in the
solvent effect (vide infra); that is, 6a and 7a have a more acidic
NH proton that facilitates hydrogen bonding with the solvent.
Furthermore, the amide 3c corresponding to thioamide 3a
showed no solvent effect on the Z/E ratio and the
predominant isomer is E (>99:1<) in all of the solvents
studied here (3c, Table 2).
Figure 2. Z/E isomerism of N-phenylthioacetamide and N-
methylthioamide.
of N-phenylthioacetamides (N-anilides), particularly the effect
of solvents. In this paper, we studied the Z/E preference of
various N-phenylthioacetamide compounds and their N-
methyl derivatives (Figure 2 and Table 1) by means of
NMR spectroscopy in standard solvent sets (Table 2).
Table 1. Substituents of N-Phenylthioacetamide Derivatives
a
1a−10a and 1b−10b
compd
R
X
Y
NH-thioamide
1a
2a
3a
4a
5a
6a
7a
8a
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
OMe
Me
Cl
F
CN
NO2
H
H
H
9a
10a
cyclohexyl
H
N-Me-thioamide
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
OMe
Me
Cl
F
CN
NO2
H
H
H
cyclohexyl
H
a
R, X, and Y are substitutents of thioamides shown in Figure 1.
We also conducted extensive molecular dynamics and other
computational analyses, which indicate that the origin of the
Z/E preference of NH-thioacetamides can be understood in
terms of steric repulsion, while that of N-methylthioacetamides
can be understood in terms of thioamide conjugation.
In the case of thioformamide 10a (R = H) (Table 2), the
major structure is Z by definition (see Figure 2) because the
relationship of the substituent R (= H in 10a) and the N-
phenyl group is Z. The Z isomer predominates (10a: Z/E 95:5
in CDCl3), suggesting that the repulsion between n(S)-Ph in
RESULTS AND DISCUSSION
Solvent Effect on the Z/E Preference of N-Phenyl-
thioacetamides. The Z/E ratios of N-phenylthioacetamides
■
1
1a−10a and 1b−10b (Table 1) were evaluated from the H
B
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a
Table 2. Z/E Ratios of N-Phenylthioacetoamides in Various Solvents
a
compd
Z/E ratio
NH-thioamide
CDCl3
CD2Cl2
acetone-d6
CD3OD
DMSO-d6
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
45:55
47:53
49:51
31:69
34:64
b
33:67
35:65
36:64
24:76
27:73
b
9:91
12:88
11:89
6:94
8:92
10:90
9:91
5:95
6:94
<1:>99
<1:>99
<1:>99
<1:>99
88:12
<1:>99
<1:> 99
<1:>99
7:93
9:91
8:92
9:91
7:93
<1:>99
<1:>99
<1:>99
<1:>99
90:10
<1:>99
<1:>99
<1:>99
7:93
<1:>99
<1:>99
<1:>99
<1: > 99
90:10
2:98
b
b
25:75
10:90
95:5
3:97
3:97
<1:>99
<1:>99
<1:>99
95:5
4:96
4:96
2:98
<1:>99
(amide) 3c
<1:>99
NMe-thioamide
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
a
b
At 298 K. See structures shown in Figure 1. Ratio values of <1:>99 or >99:< 1 indicate that practically only one rotamer can be observed. The
NMR spectrum could not be measured due to low solubility.
the E conformation is larger than that between n(S)-H(N) in
the Z conformation, or that the repulsion between R (= H)-
H(N) in the E conformation is larger than that between R (=
H)-Ph in the Z conformation. This is consistent with the result
of the bond model analysis of 1a in the present work (see
Figure 10 and Table S2(1)). In the case of thioformamide 10a,
solvent dependence of the Z/E ratio was also observed, and the
trend is consistent with that of other NH-phenylthioaceta-
mides 1a−9a: from CDCl3 and CH2Cl2 to CD3OD through
acetone-d6, the E ratio increased slightly (5% to 10% and 12%).
The solvent dependence of the Z/E preference of NH-
phenylthioacetamides 1a−10a arises from the involvement of
the interaction between the methyl (or alkyl R) group attached
to the thiocarbonyl carbon atom, and the N-phenyl group.
Rotational Barriers of 3a. We also measured the rotational
barriers of thioamide 3a in CDCl2CDCl2 (we need a higher
boiling point solvent than CDCl3) and in DMSO-d6 by means
of the coalescence method: in CDCl2CDCl2, coalescence
temperature Tc = 107.2 °C (380 K) ΔGc⧧ = 18.2 kcal/mol; in
DMSO-d6, Tc = 72.9 °C (346 K) ΔGc⧧ = 18.7 kcal/mol. The
rotational barrier of 3a in polar DMSO-d6 is larger than that in
CDCl3, which is consistent with the report on N,N-
dimethylthioacetamide.5a However, the previous report did
not clearly address the reason for these phenomena.5a In
CDCl2CDCl2, we also analyzed the dynamic NMR to obtain
the rotational barrier from the E form to the TS and that from
Z form by 0.2 kcal/mol, is also consistent with the
experimental ratio of the isomer, i.e., Z/E = 47:53 in
CDCl2CDCl2 at 298 K, the value close to that of CDCl3 (Z/
E = 49:51, Table 2).
Effect of Alkyl Substituent (R) in N−H Phenylthioaceta-
mides. The Z/E ratios of various N−H thioacetamide
derivatives varied significantly depending on the alkyl
substituent R (1a, 8a, and 9a, Table 2). For a given solvent,
the ratio of the E isomer increased as the size of the acyl alkyl
group increased from methyl (1a) to ethyl (8a) to cyclohexyl
(9a): 1a: Z:EZ/E 45:55; 8a: Z/E 25:75; 9a: Z/E 10:90 in
CDCl3. The Z/E ratio of 8a and 9a also changed dramatically
depending upon the solvent: increasing solvent H-bond-
forming ability (vide infra), not simply polarity, from
chloroform, to dichloromethane, acetone, methanol, and
DMSO leads to a sharply increased predominance of the E
isomer (Table 2). Such a complete shift of the equilibrium to E
thioamide was not seen in simple N-phenylthioacetamides
(1a−5a)) (Table 2). This can be plausibly explained in terms
of steric effect, i.e., the magnitude of repulsion between S and
the aromatic moiety and between the acyl alkyl group and
aromatic moiety may determine the Z/E ratio of thioamides.
N-Methylation of Phenylthioacetamides. N-Methylation
of phenylthioacetamides (1b−10b) biased the Z/E equili-
brium toward Z conformation (Table 2). All the N-Me
phenylthioacetamides studied here (1b−10b) showed practi-
cally complete Z preference independently of the bulkiness of
the acyl alkyl group, the solvent, and the aromatic substituent.
This result is consistent with a recent report.6
the Z form to the TS: ΔG⧧
= 18.9 kcal/mol, ΔG⧧
=
E→TS
Z→TS
18.7 kcal/mol at 298 K (see Tables S1−4). These values are
consistent with the results obtained with the coalescence
method. The difference between the two rotational energies,
that is, the observation that the E form is more stable than the
A More Complicated Thioamide System. We also studied
the NH-thioamide of a more complicated structure, 12a, an
C
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Figure 3. continued
D
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Figure 3. Crystal structures and related DFT structures of the N-phenylthioacetoamides (a), N-phenylacetoamides (b), and a more complexed
thioacetamide 12a (c). (a) Absolute value of the dihedral angle C−N−C(ipso)−C(ortho) is shown. The larger value is shown, with the smaller
angle in parentheses. 180° (0°) indicates a planar structure of the thioamide bond with respect to the phenyl ring. (b) Optimized structures with
M062X/6-311++G(d) in the PCM solvent model.
amino acid thioamide (Figure 2). Compound 12a also favored
the E thioamide conformer, but in halogenated solvents a small
amount of Z conformer was observed (Table 2). Thus, the
conformation is solvent-dependent, even though the magni-
tude of the effect is small. This solvent effect and E conformer
preference are consistent with those of other NH-thioamides.
X-ray Crystallographic Analysis of N-Phenylthioaceta-
mides. We next determined the crystal structures of the E
isomers of secondary N−H thioamides 3a10 and the
corresponding N−H amides 3c11 (Figure 3a, 3b and see
Figures S4−S10). The E isomer of 3a is the major isomer in
polar solvents, and in the case of amide 3c, the E isomer of 3c
is the major isomer in all the solvents studied here. In the
crystal structures, the N-aromatic ring is rotated with respect to
the thioamide plane in thioamide 3a, whereas the N-aromatic
ring is almost coplanar with the amide plane in amide 3c:
thioamide 3a has a highly twisted N−Ar torsion angle (59.6°)
as compared with that of the corresponding amide 3c (18.1°).
These angles represent the minimum absolute value of two
possible rotational angles with respect to the Ar−N bond
(Figure 3a). These results are consistent with a significant
repulsive effect between the sulfur atom and the benzene ring
in 3a (vide infra). In 3a and 3c, the thioamide and amide
moieties both have planar structures (see Figure 1).
another molecule in the crystal state, which is analogous to
solvation in the solution state (vide infra). In the crystal state,
the CS bond of 3a is longer than the CO bond of the
corresponding amide 3c by 0.441 Å, and the N−C (X), (X
= S or O) bond in 3a (1.329 Å) is shorter than that of the
amide (3c, 1.353 Å). The thioamide bond of 3a is slightly
shorter than the amide bond of 3c by 0.024 Å, and this is
consistent with our DFT-optimized structural parameters
(0.030 Å difference in bond length between E and Z) (vide
infra). The coplanarity of the N-aromatic ring in the crystal
structure of amide 3c provides a sharp contrast to the
corresponding thioamide 3a. The planarity of acetamides was
also confirmed in the crystal structures of other NH-
phenylacetamides ((1c,15 p-H) (17.5°) and (2c: p-OMe)
(20.0°) (Figure 3b).
Finally, we are successful to obtain the crystal structure of a
more complicated thioamide 12a (Figure 3c and Figure S10).
The crustal structure of 12a is the E conformer, which is
consistent with the E conformer preference in solution (Table
2). While the thioamide group takes a nonplanar structure with
an N-phenyl group, intriguingly, the N−Ar torsion angle is
rather small (39.9°) (Figure 3). This may be related to the
small fraction of the Z conformation even in halogenated
solvents (Table 2).
The twisting of the N-aromatic ring in the thioamide was
also confirmed in the crystal structure of the thioamide 5a12
(57.9°, Figure 3a). In the unit cell of the crystal of NH-
thioamide 3a, Hirshfeld surface analysis13 and the 2D
fingerprint14 indicated a strong intermolecular interaction
between the N−H and the sulfur atom of another molecule
(Figure S4-2). Therefore, the thioamide is coordinated with
DFT-Optimized Structures in the Continuum Inexplicit
Solvent Model. Furthermore, DFT-optimized E structures of
thioamide 3a (p-Me) and amide 3c (p-Me) were obtained in
the continuum solvent model (PCM) (Figure 3). We found
that the minimum thioamide structure of 3a has a twisted
thioamide plane with respect to the N-benzene ring,
independently of the solvent (in CHCl3: 56.8° (3a-DFT-
E
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Figure 4. Distribution of Z/E isomers of NH-thioamide 3a obtained by REST simulations at 300 K in various solvents. Horizontal axis is the
dihedral angle of the thioamide rotation: conformers between −50° and +50°are regarded as the Z conformer and conformers between −150° to
−180° and 150° to 180° are regarded as the E conformer. The vertical axis is the frequency of the conformer.
CHCl3);in methanol: 59.6° (3a-DFT-methanol) (Figure 3).
These calculated rotation angles are in good agreement with
the experimental value in the crystal structure (3a, 59.6°,
Figure 3). A similar rotation of the N-phenyl group is also
found in the case of thioamide 5a (p-F) (X-ray: 57.9°) and the
present DFT calculation (5a-DFT-CHCl3: 57.4°) is consistent
with the experimental value. In sharp contrast, the DFT
minimum structure of the corresponding amide 3a has a
coplanar relationship of the amide with the benzene ring (in
CHCl3: 0.3° (3c-DFT-CHCl3)), which is also consistent with
the X-ray crystal structure (3c, 18.1°) (Figure 3). The
experimentally observed planarity of other acetamides (1c
(17.5°) and 2c (20.0°)) is consistent with the DFT calculation
(1c-DFT-CHCl3: 0.4°; 2c-DFT-CHCl3: 6.9°) (Figure 3).
Therefore, the present experimental crystal structural data and
our calculation results shown herein are all consistent with
previous computational studies,16,17 particularly for the
corresponding amides, N-phenylacetamides. Our present X-
ray crystal structure studies experimentally verify for the first
time the prediction that NH-N-phenylacetamides tend to take
a coplanar structure of the N-aromatic ring with respect to the
amide, in contrast to NH-N-phenylthioacetamides, which take
a rotated structure with respect to the N-phenyl group.
On the other hand, N-Me N-phenylthioacetamide 7b (p-
NO2) takes Z-thioamide structure in the crystal (Figure 3),
which is consistent with the Z-preference in solution (Table
2). The N−Ar bond of 7b is more twisted (65.1°) than that
(18.1°) of NH-N-phenylthioacetamide 3a. This means that the
N−Ar conjugate system and the thioamide N−C(S)
conjugate system are almost orthogonal in the N-Me N-
phenyl thioacetamide; that is, the thioamide N−C(S)
F
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Figure 5. Distribution of Z/E isomers of NMe-thioamide 3b obtained by REST simulations at 300 K in various solvents. Horizontal axis is the
dihedral angle of the thioamide rotation: conformers between −50° and +50° are regarded as the Z conformer and conformers between −150° to
−180° and 150° to 180° are regarded as the E conformer. The vertical axis is the frequency of the conformer (%).
conjugation will be enhanced (see Bond Model Analysis
below).
MD based simulations clearly reproduce the experimental
solvent effects on the Z/E ratio of the NH-thioacetamide.
On the other hand, similar REST simulations reproduced
the lack of a significant solvent effect on the Z/E ratio in the
case of the N-Me-thioacetamide, as well as the Z biases (Figure
5). The calculations reproduced the experimental bias of Z/E
distribution of the N-Me thioamide 3b: in CHCl3: simulated
value (Z/E): 99.3:0.7; experiment: >99:<1; in DMSO:
simulated value(Z/E): 98.3:1.7; experiment: > 99:<1.
Radial Distribution Function (g(r)). The interactions
between the thioamides and the solvent can be analyzed
from the trajectories of MD simulations obtained at 300 K for
40 ns (force field: OPSL3e) by means of the radial distribution
function (g(r)) (Figures 6 and 7),20 which expresses the
probability distribution of the distance between the two
molecules in solution. The target atom in one molecule is
placed at the origin, and the density of the target atom in the
other molecule at the distance r is divided by the density of the
bulk system. The horizontal axis is the distance between the
atoms (Å), the left vertical axis is the radial distribution
function g(r) (blue line) with the ratio of the bulk solvent with
solvent structure set to 1.0, and the right vertical axis (Figures
6 and 7) is the integrated number of solvents (red curve,
coordination number), indicating how many molecules are
found in the range of each coordination sphere.
1. Polar and Hydrogen-Bond-Donating Solvents Such as
DMSO, Acetone, and MeOH. In polar and hydrogen-bond-
donating solvents such DMSO, acetone, and protic MeOH, the
oxygen atom of the solvent molecule can coordinate to the
acidic NH proton of the NH-thioamide 3a,21 giving a
distribution starting at 1.8 Å with a peak at approximately
2.1 Å for both Z and E thioamides ((3a)NH---O(DMSO or
acetone or CH3OH) in Figure 6a−c). From the volume
integration of g(r) in the range of 1.8−3.5 Å, approximately
one molecule of the solvent interacts with the thioamide NH
atom. The values of the radial distribution function (g(r)) and
the coordination number of solvents at the first peak are
smaller in the case of Z thioamide than those in the E
thioamide (Figure 6). This is probably due to steric hindrance
around the NH group of the Z thioamide conformer, such as
the sulfur atom of the thioamide, which hampers access of
solvent molecules to the NH moiety. This difference in solvent
coordination between Z and E thioamide conformers may be
attributed at least in part to the solvent dependency of the
stability of these conformers: these three solvents, DMSO,
4. Computational Study Based on Molecular Dynam-
ics. In order to understand the roles of solvents, acetyl alkyl
substituents, and N-methylation, we carried out molecular
dynamics (MD) calculations, including explicit solvent
molecules. Based on the behaviors of solvents found in the
MD simulations, we carried out DFT calculations that included
one or two explict solvent molecules in an implicit solvent
model, which can mimic the more realistic solvation
environment found in the MD calculations. These calculations
revealed hydrogen bonding mainly between the thioamide NH
proton and the solvent heteroatom(s) in polar solvents, and
also identified a weak interaction of halogenated solvents
(CHCl3 and CH2Cl2) with the thioamide (NH−CS)
functionality.
Replica Exchange with Solute Tempering (REST) Simu-
lations. To investigate the solvent dependence of thioamide
isomerization, we performed accelerated molecular dynamics
simulations of 3a (p-Me) using the replica exchange with
solute tempering (REST) method18 with the OPSL3e force
field in various solvent systems (Figure 4; details of simulation:
see the Experimental Section). The OPSL3e force field is
improved by additional parametrization and becomes appli-
cable to many organic compounds.19 The Z/E ratio of NH-
thioamide 3a was simulated in various solvents at 966 K. The
populations of Z and E conformations were calculated by using
1,000 snapshot structures in the trajectories at 300 K, obtained
in the REST calculations in a different solvent, over the range
of 300 to 966 K. In CHCl3, the Z/E ratio was simulated to be
40:60 [experiment: 49:51] at 300 K. In the case of DMSO, the
Z/E ratio was simulated to be 4:96 [experiment: 8:92]. Other
solvent systems gave the following simulated values: CH2Cl2:
35:65 [experiment: 36:64] (Z/E); acetone: 12:88 [experiment:
11:89] (Z/E); methanol: 12:88 [experiment: 9:91] (Z/E).
Therefore, the REST calculations are in good agreement with
the experimental trend in the Z/E ratio of the thioamide 3a.
The reduction of the Z isomer ratio in polar solvent from
that in nonpolar solvent was also reproduced in the REST
calculations for another NH-thioamides 1a (p-H): in CHCl3:
simulated value (Z/E): 37:63; experiment: 45:55; in CH2Cl2:
simulated value (Z/E): 25:75; experiment: 33:67; in acetone:
simulated value(Z/E): 21:79; experiment: 9:91; in methanol:
simulated value (Z/E): 14:86; experiment: 9:91; in DMSO:
simulated value(Z/E): 8:92; experiment: 8:92. Therefore, the
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Figure 6. Radial distribution functions (g(r)) of NH-thioamide 3a in polar solvents. Horizontal axis is the distance between the atoms (Å). The left
vertical axis is the radial distribution function g(r) (blue line): the ratio of the bulk solvent with solvent intrinsic structure is set to 1.0, and the right
vertical axis is the integrated number of solvents (red curve, coordination number).
acetone and MeOH, favor NH-E-thioamide conformation
(Table 2).
S11d,e). Even in the case of protic methanol, methanol
molecules show only weak hydrogen bonding at 2.7 Å through
the interaction of the sulfur atom of N-Me Z-thioacetamide 3b
with the H-(OMe) atom of methanol (Figure S11b).
2. Halogenated Solvents Such as CHCl3 and CH2Cl2.
Although halogenated solvents such as CHCl3 and CH2Cl2 can
be regarded as nonpolar, they might also interact with NH-
thioamide (3a) through hydrogen bonding between the acidic
NH hydrogen atom of the thioamide and the chlorine atom(s)
of the solvent (CHCl3 and CH2Cl2) ((3a)NH---Cl(CHCl3) or
(3a)NH---Cl(CH2Cl2)), in a manner similar to that of the
Furthermore, N-Me thioamides cannot form N−H (thio-
amide)---O (solvent) hydrogen bonding, as seen in NH-
thioamide (3a (p-Me)). The RDFs of the solvent with respect
to N-Me Z-thioacetamide (3b (p-Me))) were obtained from
the MD calculations and were compared with those of NH-
thioamide (3a (p-Me)): in polar solvents, the RDFs of solvents
around the N atom of the thioamide 3b show no peaks at 2.1 Å
(Figures S11b,c), and no significant association of solvent
molecules around the N-Me moiety was observed (Figures
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Figure 7. Radial distribution functions (g(r)) of NH-thioamide 3a in halogenated solvent: (a) CHCl3; (b) CH2Cl2. For details, see the caption of
Figure 6.
aforementioned polar solvents. However, the radial distribu-
tion function analysis (Figure 7a,b) did not support the idea
that such hydrogen bonding through H−Cl interaction of the
NH-thioamide 3a in CH2Cl2 or CHCl3 is a significant
contributor (Figure 7a,b):20 there are multiple peaks from 2
to 4 Å in the radial distribution functions (Figure 7a,b), but the
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Figure 8. DFT-optimized structures of an arbitrary complex of a single polar solvent molecule and NH-thioamide 3a and bond paths obtained by
QTAIM calculations. In the ball-and-stick model, the dashed line indicates interaction, supported by the formation of a bond path in the QTAIM
calculations. The colors have the following meaning: red: oxygen; blue: nitrogen; dark gray: carbon; white: hydrogen. In the molecular graph
(QTAIM), the colors have the following meaning: a color-gradation line: accumulation of electron density (bond path for covalent bonding; red
line: through-space weak bond path (with a purple arrow); red small ball: bond critical point, green small ball: ring critical point, blue small ball:
cage critical point. Values in parentheses are the energy difference, based on the calculations with M062X/6-311++G(d) with the PCM solvent
model, after zero-point energy correction and thermal correction to the energy at 300 K.
value of g(r) is smaller than 1.0. Instead, hydrogen bonding
between the sulfur atom of the thioamide and the solvent
acidic hydrogen atom (H2CCl2 or HCCl3), i.e., (3a)S---
H(CHCl3)) and CH2Cl2 ((3a)S---H(CH2Cl2), contributes to
the radial distribution function (Figure 7a,b). This putative
hydrogen bonding is slightly more marked in the Z conformer
than in the E conformer in terms of g(r) value and
coordination number at 4.0 Å. Intriguingly, integration of the
g(r) function in the range of 3.5−5 Å suggested there are
multiple solvent molecules, perhaps five or six molecules, of
CHCl3 or CH2Cl2, around the S atom of the thioamide 3a.
Furthermore, in the case of N-Me Z-thioacetamide (3b) in
CHCl3, the (3a)S---H(CHCl3))-type interaction is maintained
(Figure S11(a)).
DFT Calculations of Thioamide−solvent Complex. In
order to gain more structural insight into solvent effects on the
Z/E equilibrium of NH-N-phenylthioacetamides, we generated
a solvent-coordinated thioamide model and conducted DFT
calculations. The complex of thioamide 3a hydrogen-bonded
to a single molecule of solvent (also two molecules in the case
of CH2Cl2) was selected as an arbitrary structure in the MD
trajectory at 300 K, and the distance and angle of the solvent
with respect to the thioamide were fully scanned. The resultant
energy minimum candidate structure was fully optimized with
M062X/6-311++G(d) in the PCM solvent model. We choose
M062X because the standard B3LYP functional typically
underestimates weak intermolecular interactions, which can be
important for the solvent-stabilized complexes mentioned here.
The interaction of the solvent molecule with thioamide NH
is visualized as a bond path (or a set of bond paths in a
molecule (molecular graph); see the Experimental section),
i.e., an accumulation of electron density between two atoms,
obtained by means of Bader’s quantum theory of atoms in
molecules (QTAIM) calculations (Figure 8).22 A similar
hydrogen bond can be detected by QTAIM analysis in the
cases of acetone and MeOH. Notably, in the case of a protic
solvent, methanol, the Z conformation of thioamide 3a forms
two hydrogen bonds with one methanol molecule: there are
hydrogen bonds between the thioamide NH and the oxygen
atom of methanol and between the sulfur atom of the
thioamide 3a and the hydroxyl hydrogen atom of the same
methanol molecule (Figure 8). In the case of halogenated
solvents, the S(thioamide)−-H(solvent) bond path is present
in CHCl3 and CH2Cl2 (Figure S12), and this interaction is
consistent with S−H(solvent) hydrogen bonding. In both
CHCl3 and CH2Cl2, the Z conformer can form two hydrogen
bonds with the same halogenated solvent molecule, i.e.,
(thioamide)S−H(solvent) and (thioamide)NH---Cl(solvent)
(Figure 9), which may contribution to stabilization of the Z
conformation over the E conformation in CHCl3 and CH2Cl2.
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Figure 9. DFT-optimized structures of an arbitrary complex of one or two halogenated solvent molecules and NH-thioamide 3a. For details, see
the caption of Figure 8. Bond paths obtained in the QTAIM calculations; see Figure S13.
The energies of the Z and E structures complexed with a
solvent molecule were calculated in polar solvents (Figure 8).
In all of the polar solvents, the E isomer is more stable than the
Z isomer (the energy differences are 0.78 kcal/mol (DMSO),
1.28 kcal/mol (acetone) and 2.29 kcal/mol (CH3OH))
(M062X/6-311++G(d) with the PCM solvent model).
These differences in stability correspond well to the shorter
hydrogen bond length between the NH group of thioamide 3a
and the oxygen atom of the solvent in the E isomers.
Therefore, polar solvents favor the E conformer over the Z
conformer of the NH-thioamides 3a.
On the other hand, in less polar halogenated solvents such
CHCl3 and CH2Cl2, S-hydrogen bonding may favor the Z
conformation over the E conformation. In particular, as already
mentioned, the Z conformer of thioamide (3a) can form two
hydrogen bonds in CHCl3 and in CH2Cl2. In CHCl3, the Z
form is more stable than the E form by 0.63 kcal/mol (Figure
9), while in CH2Cl2, the E conformer is more stable than the Z
conformer by 1.16 kcal/mol (M062X/6-311++G(d) with the
PCM solvent model). Because a cluster of halogenated solvent
molecules surrounds the S atom of the thioamide, as indicated
by the radial distribution function (Figure 7b, we made a
minimal complex model of the thioamide with two molecules
of CH2Cl2. The initial arbitrary structure was selected from a
snapshot of the MD simulation at 300 K for 40 ns. Among
several CH2Cl2 molecules, two CH2Cl2 molecules with a
minimal distance between the S atom of the thioamide and H
atom of CH2Cl2 were selected, followed by DFT structure
optimization with the PCM solvent model. In this solvent
dimer model, the Z form of the thioamide 3a is more stable
than the E form by 0.92 kcal/mol (Figure 9). The QTAIM
molecular graph shows the presence of NH---Cl bonding and
S−H (CH2Cl2) bonding, the interaction of two CH2Cl2
molecules, and also the double hydrogen bonding of the
thioamide S atom with two H atoms of two CH2Cl2 molecules,
together with the interaction of two CH2Cl2 molecules (Figure
S13). The hydrogen bond distances are shorter in the Z
conformer than the E conformer (Figure 9).
In halogenated solvents (CHCl3 and CH2Cl2), hydrogen
bonding between the thioamide sulfur atom and acidic H atom
of the solvent favors Z conformation, probably due to
enhancement of the thioamide resonance, while the N-phenyl
π plane is twisted out of the thioamide π plane in the Z
conformation. This Z preference of the thioamides is present
but is not sufficiently strong to bias the equilibrium fully to Z,
and a mixture of Z and E conformers is obtained.
The DFT calculations with only the implicit solvent model
always resulted in the assessment that in the case of NH-
thioacetamides the E isomer is more stable than the Z isomer
in all the solvents studied herein (data not shown). Therefore,
the present thioamide structures complexed with (a) solvent
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molecule(s) can mimic the more realistic solvation environ-
ment found in the MD calculations.
aromatic ring. Structures of NH-thioamides 1a and 3a,
optimized with a single molecule of CHCl3 solvent at
M062X/6-311++G(d) in the SMD solvent mode (Figure
10), were used after elimination of the solvent molecule, and
single point calculations at the level of HF/6-31G(d) were
used for the bond orbital analysis. Structures of NMe-
thioamides 1b and 3b were also optimized at the same level
(M062X/6-311++G(d) in the SMD solvent mode) in CHCl3,
and single point calculations at the level of HF/6-31G(d) were
used for the bond orbital analysis (Figure 12). The details are
described in the Supporting Information.
In the case of NH-thioacetamides 1a/3a (Figures 10), while
the Z/E ratio varies depending on the solvent, the E isomer is
more stable than the Z isomer. On the other hand, N-Me
thioacetamides 1b/3b exists solely as a Z rotamer (Figures 12).
We analyzed the Z and E isomers of NH-thioacetamides 1a
and 3a and those of the corresponding N-Me-thioacetamides
1b and 3b, respectively.
Bond Model Analysis. To elucidate the origin of the effect
of N-methylation on Z/E thioamide preference (Table 2), we
analyzed the electronic structures of the molecules in terms of
the orbital interactions of thioacetamides (1a/3a and 1b/3b)
by means of bond model analysis (BMA) (Tables S2−S4).23,24
The interbond energies (IBEs), including both occupied-
occupied orbitals and occupied-vacant orbitals, were used to
evaluate the bond interactions in the molecules. The IBEs were
calculated for (1) vicinal bond interactions with respect to the
thioamide N−C(S) bond, that is, between σ(C1−C2)/σ(C1−
S) and σ(N−H)/σ(N−C(Ar)) (they are in a vicinal relation;
see Figure 10), (2) conjugation between n(N) and CS,
n(N) and Ar, and CS and Ar, and (3) repulsive interaction
between two substituents attached to the thioamide bond,
including all C−C and C−H σ bonds and π orbitals of the
In the case of NH-thioacetamide 1a, the total IBE is smaller
in the E form by 0.237 au (ΔIBEZ‑E = +0.237 au) (Figure 10
(1)), showing an E preference. The sum of repulsive
interactions is lower in the E form (0.500 au) than in the Z
form (0.736 au), contributing to the E predominance (Figure
10 (1)). The repulsion energy between Me and Ph in the Z
conformation is +0.356 au, whereas that of Me-H(N) in the E
form is +0.162 au (see Table S2 (1) and Figure 11). Notably,
the repulsion energy of n(S)-H(N) in the Z conformation
(+0.380 au) is as large as that of n(S)-Ph (+0.389 au) in the E
conformation (Table S2 (1) and Figure 11). NH-Thioaceta-
mide 3a (p-Me) shows similar trends (Figures 10 (2) and 11):
the repulsion term is larger than the conjugation term in
magnitude and sign and the repulsion in the Z conformation is
significant: the repulsion IBE values are different between the
Z and E conformers of 3a: (Z-3a) Me-Ph: +0.365 au; (E-3a)
Me-H(N): +0.161 au (Table S2 (2)). Thus, in the cases of
NH-thioacetamides, the preference for E over Z conformation
can be attributed to the repulsion effect in the Z conformation
(Figure 11).
Furthermore, in the case of N-Me thioamide 1b (Figures 12
(1)), the total IBE of the Z conformer (0.005 au) is smaller
than that of the E conformer (0.251 au) by 0.246 au (ΔIBEZ‑E
= −0.246), which is consistent with the experimentally
observed Z preference. Among the vicinal, conjugation, and
repulsion terms, the difference of conjugation interaction
between Z and E (ΔIBEZ‑E = −0.332 au) is the main
contributor to the total IBE difference for 1b (Figures 12 (1)).
In fact, the IBEs of the n(N)−π(CS) conjugation are
−2.120 au and −1.897 au in the Z and E conformations,
respectively (Table S3 (1)), indicating significant stabilization
of the Z conformer (Figure 12 (1)). The IBEs of n(N)-Ph
conjugation are +0.414 au and +0.397 au in the Z and E
conformers, respectively (Table S3 (1)), meaning that the
n(N)-Ph conjugation interaction is repulsive, rather than
stabilizing. Furthermore, the conjugation energy of C(S)
and Ph is +0.044 au in the Z conformer and +0.171 au in the E
conformer, showing significant destabilization in the E
conformation. This probably reflects a lower degree of
conjugation between n(N) and π(Ph) in both of the Z and
E structures, due to the lower degree of orbital overlap. With
respect to the repulsion energy, the values of the sum of steric
repulsion between two substituents that are syn along the
thioamide bonds are similar in the Z and E conformations: Me-
Ph (+0.414 au) and n(S)-Me (+0.457 au) in the Z conformer
Figure 10. Sum of interbond energies of NH-thioacetamides 1a (1)
and 3a (2) in atomic units. (a) In au. For each term, a positive value
indicates destabilization and a negative value indicates stabilization.
For definitions of vicinal, conjugation, and repulsion, see the text. (b)
The energy difference in interbond energies (IBE) (Z form − E form)
is shown for each term. For each term, positive values indicate the E
form is more stable, and negative values indicate the Z form is more
stable. (c) “Total” is the sum of vicinal, conjugation, and repulsion
terms for each conformer. (d) The energy difference in total
interbond energies (IBE) (Z form − E form) is shown. A positive
value indicates the E form is more stable, and a negative value
indicates the Z form is more stable. In the graphics, the energy
difference between the Z and E conformers, obtained at single-point
calculation at HF/6-31G (d), is shown in parentheses.
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Figure 11. Summary of repulsive interactions in NH-thioamides 1a and 3a (see Supporting Information Table S2).
au) in magnitude and sign when we compare the Z and E
conformers. Intriguingly, in the case of 3b, the difference in the
repulsion term (−0.475 au) between the Z and E conformers is
also significant, both repulsion and conjugation terms favoring
the Z conformer. The increase of the magnitude of the
repulsion term (−0.475 au) arises from increased repulsion
between Me(C1) and Me(N) (0.959 au) in the E
conformation, probably due to the electron-donating nature
of the aromatic p-methyl substituent (Table S3 (2)). Thus, in
the cases of NMe-thioacetamides, the preference for Z over E
conformation can be attributed to the conjugation effect in the
Z conformation (Figure 12).
Based on the present orbital interaction analysis (BMA) and
other calculations, we also consider that the solvent contributes
to the Z/E isomer preference of NH-thioacetamides by means
of hydrogen-bond formation between thioamide NH and the
solvent molecule’s heteroatom: hydrogen bonding of solvents
to the NH proton of thioacetamides may increase steric
repulsion with the sulfur atom in the Z conformation, making
the Z thioamide conformation unfavorable in hydrogen-bond
acceptor solvents. Thus, the equilibrium is biased to E
preference, depending on the H-bond-forming ability of the
solvent. Such a steric effect is absent in the case of N-
methylated derivatives due to the intrinsically perpendicular
arrangement of the N-benzene ring in the Z thioamide
conformation. In the case of N-Me acetamide, steric repulsions
have been attributed to cis predominance.16 Therefore,
counterintuitively, steric repulsion is the major factor
influencing the Z/E preference of less sterically hindered
NH-thioacetamides, while thioamide conjugation is the major
factor influencing that of more sterically hindered N-methyl-
thioacetamides.
Solvent Independency and Steric Effect in the Z/E
Preference of Nonaromatic Thioacetamide 11a. As
described above, the solvent dependency of the Z/E ratio of
thioacetamides 1a−10a can be attributed to hydrogen bonding
of a solvent molecule to the NH proton of thioacetamides 1a−
10a, which partially enforces conjugation of the benzene ring
of the aniline part (i.e., N-benzene) with the thioamide system
in the Z/E conformations. In the Z conformers, this structural
Figure 12. Sum of interbond energies of N-methyl N-phenyl
thioacetamides 1b (1) and 3b (2) in atomic units. (a−d) See the
footnotes of Figure 11.
and Me-Me (+0.380 au) and n(S)-Ph (+0.429 au) in the E
conformer (Table S3(1)).
NMe-Thioacetamide 3b (p-Me) shows similar trends to 1b
(Figure 12 (2)): the difference in the conjugation term
(−0.482 au) is larger than the vicinal interaction term (0.029
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change results in increased steric repulsion. Therefore, the
solvent effect on the Z/E isomers of thioacetamides appears to
depend on the presence of the N-benzene moiety, which is
affected by solvent NH-hydrogen bonding. To test this idea,
we replaced the N-benzene ring with an N-methyl group,
obtaining the nonaromatic thioacetamide 11a. As expected,
experimental examination showed that the solvent effect on the
Z/E preference of NH-thioacetamide 11a was greatly
decreased (Table 2).
We also conducted REST simulations of 11a in explicit
solvent of CHCl3, CH2Cl2, acetone, methanol, and DMSO
(OPSL3e, 20 ns). The simulation also showed that the E
isomer is favored over the Z isomer, accounting for more than
99% at 300 K (Figure S12), which accords well with the
experimentally observed E preference (Table 2). Furthermore,
bond model analysis showed that this nonaromatic NH-
thioamide favors the E conformer due to strong repulsion
between the two syn vicinal substituents in the Z isomer (the
IBE difference in repulsion in total is 0.192 au): Me(C1)-Me3
(repulsion IBE: 0.296 au); n(S)-H(N) (repulsion IBE: 0.274
au) (Figure 13 and Table S4).
EXPERIMENTAL SECTION
■
General Procedure. Unless stated otherwise, commercial grade
reagents were used without further purification. Open column
chromatography was carried out using Kanto chemical silica gel
(silica gel 60 N (100−210 μm)). One- and two-dimensional 1H NMR
(400 MHz) spectra and 13C NMR (100 MHz) spectra were recorded
on a Bruker Avance 400 NMR spectrometer running Topspin. The
spectra were recorded at 20 °C, unless otherwise noted. 1H NMR and
13C NMR chemical shifts (δ) are given in parts per million (ppm) and
coupling constants are given in hertz (Hz). s = singlet, brs = broad
1
singlet, d = doublet, t = triplet, m = multiplet. H NMR spectra are
reported relative to residual solvent signals (CDCl3: 7.26 ppm,
DMSO-d6: 2.50 ppm). Data for 13C NMR spectra are reported in
terms of chemical shift (ppm) relative to residual solvent peak
(CDCl3: 77.0 ppm, DMSO-d6: 39.52 ppm). The 1H NMR integrals of
a mixture of thioamide rotamers are described as defining the methyl
signal of the major rotamer as 3H. Electron spray ionization time-of-
flight mass spectra (ESI-TOF MS) were recorded on a Bruker
micrOTOF-05. The combustion analysis was carried out in the
microanalytical laboratory of the University of Tokyo. All of the
melting points were measured with a Yanaco Micro Melting Point
Apparatus without correction.
Synthesis of Compounds. Thioanilides with various kinds of
substituents (1a−10a, 1b−10b) were synthesized by thionation of
parent amides with Lawesson’s reagent in toluene at 100 °C in oil
bath.25 First, theparent anilides were obtained by the reaction of acyl
chloride (formyl chloride, acetyl chloride, propanoyl chloride, or
cyclohexanoyl chloride) and para-substituted aniline in dimethylace-
tamide (DMAC) without addition of a base.26 In the cases of N-
methylanilides, para-substituted N-methylaniline was used. N-
Methylation of p-methoxy N-phenylacetamide was performed with
dimethyl sulfate in argon-bubbled DMSO in the presence of NaH,
giving in 90% N-methylated amide.
Synthesis of Thioamides. 1a.
Acetanilide (301.0 mg, 2.23 mmol) was dried in vacuo in a round-
bottom flask for 2 h. Lawesson’s reagent (540.5 mg, 1.34 mmol) and
toluene (10 mL) were added into the flask, and the mixture was
stirred at 100−110 °C in oil bath for 2 h under Ar atmosphere. The
mixture was evaporated. The crude was column chromatographed
(hexane/EtOAc = 6:1) to give 1a (208.3 mg, 62%, colorless plates).
Mp = 120−121 °C. 1H NMR (400 MHz, CDCl3) (mixture of
rotamers) δ: 9.59 (0.8H, brs), 8.75 (1H, brs), 7.66 (2H, m), 7.45−
7.33 (4.5H, m), 7.29−7.25 (1H, m), 7.17 (1.6H, d, J = 7.6 Hz), 2.74
(3H, s), 2.51 (3H, s). 13C{1H} NMR (100 MHz, CDCl3) (mixture of
rotamers) δ: 204.9, 200.6, 138.8, 138.1, 129.8, 129.1, 128.1, 127.1,
125.3, 124.0, 36.4, 30.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C8H10NS+, 152.0528, Found: 152.0535.
Figure 13. Sum of interbond energies of nonaromatic 11a in atomic
units. (a−d) See the footnotes of Figure 11.
Therefore, the E thioamide preference of NH-thioacetamide
11a is consistent with a key role of steric repulsion, as in the
case of aromatic NH-thioacetamides.
CONCLUSION
■
2a.
We found that the Z/E isomer preference of NH-N-
phenylthioacetamides shows significant solvent dependence
due to hydrogen (H)-bond formation between thioamide NH
and a solvent molecule: this hydrogen bonding forces the
benzene ring of the aniline moiety (N-benzene) to adopt a
coplanar arrangement with respect to the thioamide plane in
the Z thioamide conformation, resulting in increased steric
repulsion. Thus, the equilibrium is biased to the E conformer
to an extent that depends on the H-bond-forming ability of the
solvent. This steric effect is absent in the case of N-methylated
derivatives due to the intrinsically perpendicular arrangement
of the N-benzene ring in the Z thioamide conformation. This
leads to the counterintuitive situation that the Z/E preference
of NH-N-phenyl thioacetamides is determined by steric
repulsion, while that of N-methyl-N-phenyl thioacetamides is
determined by thioamide conjugation.
p-Acetanisidide (151.5 mg, 0.92 mmol) was dried in vacuo in a round-
bottom flask for 2 h. Lawesson’s reagent (222.6 mg, 0.55 mmol) and
toluene (10 mL) were added into the flask, and the mixture was
stirred at 100−110 °C in oil bath for 2 h under Ar atmosphere. The
mixture was evaporated. The crude was column chromatographed
(hexane/EtOAc = 4:1) to give 2a (101.0 mg, 61%), which was
recrystallized by hexane and CH2Cl2 to afford colorless plates. Mp =
1
114−115 °C. H NMR (400 MHz, CDCl3) (a mixture of rotamers)
δ: 9.46 (0.9H, brs), 8.70 (1H, brs), 7.50 (2H, d, J = 9.2 Hz), 7.09
(2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 2.8 Hz), 6.90 (2H, d, J = 2.8 Hz),
3.82 (3H, s), 3.81 (3H, s), 2.72 (3H, s), 2.44 (3H, s). 13C{1H} NMR
(100 MHz, CDCl3) (a mixture of rotamers) δ: 205.2, 200.6, 159.3,
158.4, 131.8, 131.1, 126.9, 125.9, 114.9, 114.6, 55.7, 55.6, 35.9, 29.9.
N
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Anal. Calcd for C9H11NOS: C, 59.64; H, 6.12; N, 7.73. Found: C,
59.29; H, 6.08; N, 7.46. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C9H11NOSNa+, 204.0454, Found: 204.0471.
3a.
6a.
4-Cyanoacetanilide (300.0 mg, 1.99 mmol) was dried in vacuo in a
round-bottom flask for 2 h. The Lawesson’s reagent (483.1 mg, 1.19
mmol) and toluene (6 mL) were added into the flask, and the mixture
was stirred at 100−110 °C in oil bath for 2 h under Ar atmosphere.
The mixture was evaporated. The crude was purified by flash column
chromatographed (hexane/EtOAc = 8:1) to give 6a (178.3 mg, 60%,
yellow solid). Mp = 197−198 °C. 1H NMR (400 MHz, DMSO-d6) δ:
11.87 (1H, brs), 8.13 (2H, d, J = 6.8 Hz), 7.87 (2H, d, J = 6.8 Hz),
2.65 (3H, s). 13C{1H} NMR (100 MHz, DMSO-d6) δ: 200.9, 143.5,
132.8, 122.7, 118.7, 107.6, 35.9. Anal. Calcd for C9H8N2S+ 0.1H2O:
C, 60.72; H, 4.64; N, 15.73. Found: C, 60.58; H, 4.68; N, 15.55.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H9N2S+, 177.0481.
Found: 170.0483.
N-(4-Chlorophenyl)acetamide (304.9 mg, 2.01 mmol) was dried in
vacuo in a round-bottom flask for 2 h. Lawesson’s reagent (488.8 mg,
1.21 mmol) and toluene (10 mL) were added into the flask, and the
mixture was stirred at 100−110 °C in oil bath for 2 h under Ar
atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 6:1) to give 3a (203.4 mg, 61%),
which was recrystallized with hexane and EtOAc to afford colorless
needles). Mp = 126−128 °C. 1H NMR (400 MHz, CDCl3) (mixture
of rotamers) δ: 9.54 (0.9H, brs), 8.73 (1H, brs), 7.50 (2H, d, J = 8.4
Hz), 7.22−7.18 (4H, m), 7.04 (2H, d, J = 8.4 Hz), 2.72 (3H, s), 2.48
(3H, s), 2.37 (3H, s), 2.34 (3H, s). 13C{1H} NMR (100 MHz,
CDCl3) (mixture of rotamers) δ: 204.7, 200.5, 138.2, 137.1, 136.2,
135.6, 130.2, 129.6, 125.1, 124.1, 36.0, 30.0, 21.2, 21.1. Anal. Calcd
for C9H11NS: C, 65.41; H, 6.71; N, 8.48. Found: C, 65.23; H, 6.75;
N, 8.48. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H11NNaS+,
188.0504, Found: 188.0531.
7a.
p-Nitroacetanilide (300.4 mg, 1.67 mmol) was dried in vacuo in a
round-bottom flask for 2 h. Lawesson’s reagent (404.7 mg, 1.00
mmol) and toluene (10 mL) were added into the flask. and the
mixture was stirred at 100−110 °C in oil bath for 2 h under Ar
atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 10:1 to 4:1) to afford 7a (246.5
4a.
1
mg, 75%, yellow powder). Mp = 173−174 °C. H NMR (400 MHz,
N-(4-Chlorophenyl)acetamide (101.3 mg, 0.60 mmol) was dried in
vacuo in a round-bottom flask for 2 h. Lawesson’s reagent (146.2 mg,
0.36 mmol) and toluene (5 mL) were added into the flask, and the
mixture was stirred in 100−110 °C in oil bath oil bath for 2 h under
Ar atmosphere. The temperature was then changed to 90 °C and 3
drops water was added into the mixture and stirred for another 30
min. The mixture was dissolved in EtOAc, washed with saturated
aqueous solution of NaHCO3 and evaporated. The crude was column
chromatographed (hexane/EtOAc = 8:1) to give 4a (84.6 mg, 76%,
white solid). Mp = 139−140 °C. 1H NMR (400 MHz, CDCl3)
(mixture of rotamers) δ: 9.52 (0.4H, brs), 8.71 (1H, brs), 7.62 (2H,
d, J = 8.8 Hz), 7.42−7.38 (1 H, m), 7.37−7.34 (2H, m), 7.11 (1H, d,
J = 8.4 Hz), 2.73 (3H, s), 2.50 (1.4H, s). 13C{1H} NMR (100 MHz,
CDCl3) (mixture of rotamers) δ: 205.0, 200.9, 137.2, 136.6, 133.9,
132.3, 130.0, 129.2, 126.6, 125.3, 36.3, 30.2. Anal. Calcd for
C8H8ClNS: C, 51.75; H, 4.34; N, 7.54. Found: C, 51.61; H, 4.48;
N, 7.43. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C8H9ClNS+,
186.0139, Found: 186.0148.
DMSO-d6) δ: 12.00 (1H, brs), 8.28 (2H, d, J = 9.2 Hz), 8.22 (2H, d, J
= 9.2 Hz), 2.66 (3H, s). 13C{1H} NMR (100 MHz, DMSO-d6) δ:
201.4, 145.2, 143.9, 124.3, 122.5, 36.0. Anal. Calcd for C8H8O2N2S:
C, 48.98; H, 4.08; N, 14.28. Found: C, 48.97; H, 4.28; N, 14.15.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C8H9O2N2S+, 197.0379.
Found: 197.0383.
8a.
N-Phenylpropionamide (100.7 mg, 0.74 mmol) was dried in vacuo in
a round-bottom flask for 2 h. Lawesson’s reagent (180.0 mg, 0.45
mmol) and toluene (5 mL) were added into the flask, and the mixture
was stirred at 100−110 °C in oil bath for 260 min under Ar
atmosphere. The mixture was evaporated. The crude was flash
chromatographed (hexane/EtOAc = 8:1) to give 8a (45.3 mg, 37%,
1
yellow oil). H NMR (400 MHz, CDCl3) (mixture of rotamers) δ:
5a.
9.41 (1H, brs), 8.67 (1H, brs), 7.53 (2H, d, J = 7.6 Hz), 7.32−7.24
(3H,m), 7.15−7.11 (1H, m), 7.03 (0.6H, d, J = 7.2 Hz), 2.69 (2H, q,
J = 7.6 Hz), 2.48 (0.7H, q, J = 7.6 Hz), 1.26 (3H, t, d, J = 7.6 Hz),
1.13 (1H, t, d, J = 7.4 Hz). 13C{1H} NMR (100 MHz, CDCl3)
(mixture of rotamers) δ: 138.7, 137,7, 129.7, 129.0, 128.1, 127.0,
125.6, 124.0, 41.7, 33.7, 13.9, 13.8. Anal. Calcd for C9H11NS: C,
65.41; H, 6.71; N, 8.48. Found: C, 65.30; H, 6.44; N, 8.15. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C9H11NNaS+, 188.0504,
Found: 188.0530.
4′-Fluoroacetanilide (304.9 mg, 1.99 mmol) was dried in vacuo in a
round-bottom flask for 2 h. Lawesson’s reagent (483.1 mg, 1.19
mmol) and toluene (6 mL) were added into the flask, and the mixture
was stirred at 100−110 °C in oil bath for 2 h under Ar atmosphere.
The mixture was evaporated. The crude was column chromato-
graphed (hexane/EtOAc = 4:1) to give 5a (113.8 mg, 34%, colorless
9a.
1
plates). Mp = 80−81 °C. H NMR (400 MHz, CDCl3) (mixture of
rotamers) δ: 9.36 (0.5H, brs), 8.63 (1H, brs), 7.62- 7.58 (2H, m),
7.18−7.07 (4H, m), 7.49−7.47 (0.1H, m), 2.74 (3H, s), 2.47 (1.7H,
s). 13C{1H} NMR (100 MHz, DMSO-d6) (mixture of rotamers) δ:
199.4, 159.5 (d, J = 241 Hz),135.9, 132.4, 127.2, 125.4, 115.9 (d, J =
23 Hz), 115.2 (d, J = 13 Hz), 115.0, 34.9, 30.7. Anal. Calcd for
C8H8FNS: C, 56.19; H, 4.83; N, 8.19. Found: C, 56.26; H, 5.10; N,
7.89. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C8H9FNS+,
170.0434. Found: 170.0436.
N-Phenylcyclohexanecarboxamide (101.1 mg, 0.50 mmol) was dried
in vacuo in a round-bottom flask for 2 h. Lawesson’s reagent (120.7
mg, 0.30 mmol) and toluene (5 mL) were added into the flask, and
the mixture was stirred at 100−110 °C in oil bath for 3 h under Ar
atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 2:1) to give 9a (76.2 mg, 70%),
O
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which was recrystallized with hexane and CHCl3 to afford coloreless
needles). Mp = 132−133 °C. 1H NMR (400 MHz, CDCl3) (mixture
of rotamers) δ: 9.20 (0.1H, brs), 8.58 (1H, brs), 7.67 (2H, d, J = 7.2
Hz), 7.46−7.42 (0.2H, m), 7.42−7.37 (2H, m), 7.28−7.24 (2H, m),
7.16 (0.3H, d, J = 7.6 Hz), 2.76- 2.71 (0.1H, m), 2.68−2.60 (1H, m),
2.03−2.00 (2H, m), 1.90−1.86 (2H, m), 1.84−1.57 (4H, m), 1.43−
1.22 (3H, m), 1.13−1.06 (0.3H, m). 13C{1H} NMR (100 MHz,
CDCl3) (mixture of rotamers) δ: 210.0, 138.7, 129.8, 129.0, 128.2,
126.9, 125.7, 124.1, 56.7, 46.5, 33.5, 33.2, 26.1, 25.7, 25.7, 25.5. Anal.
Calcd for C13H17NS+ 0.3H2O: C, 69.47; H, 7.89; N, 6.23. Found: C,
69.79; H, 7.69; N, 6.30. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H18NS+, 220.1154, Found: 220.1156.
1b.
N-Methylacetanilide (300.9 mg, 2.02 mmol) was dried in vacuo in a
round-bottom flask for 2 h. Lawesson’s reagent (489.5 mg, 1.21
mmol) and toluene (10 mL) were added into the flask, and the
mixture was stirred at 100−110 °C in oil bath for 2 h under Ar
atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 4:1) to give 1b (272.9 mg, 82%,
1
coloreless plates). Mp = 49−50 °C. H NMR (400 MHz, CDCl3) δ:
7.48−7.44 (2H, m), 7.41−7.37 (1H, m), 7.18 (2H, d, J = 7.2 Hz),
3.74 (3H, s), 2.40 (3H, s). 13C{1H} NMR (100 MHz, CDCl3) δ:
201.3, 145.9, 130.0, 128.5, 125.4, 45.8, 33.9. Anal. Calcd for
C9H11NS: C, 65.41; H, 6.71; N, 8.48. Found: C, 65.40; H, 6.75; N,
8.43. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H12NS+,
166.0685, Found: 166.0690.
10a.
THF (10 mL) was added into the mixture of formanilide (303.1 mg,
2.50 mmol) and Lawesson’s reagent (607.4 mg, 1.50 mmol) at water
bath (20 °C), and the solution was stirred at this temperature for 24
h. The mixture was evaporated. The crude was column chromato-
graphed (hexane/EtOAc = 4:1) to give 10a (123.7 mg, 36%, dark
yellow oil). 1H NMR (400 MHz, CDCl3) δ: 9.77(1H, d, J= 14.8 Hz),
9.38 (1H, brs), 7.39−7.34 (2H, m), 7.24−7.20 (1H, m), 7.11 (2H, d,
J = 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ: 187.4, 138.4,
130.0, 126.3, 117.4. Anal. Calcd for C7H7NS + 0.1H2O: C, 60.49; H,
5.22; N, 10.08. Found: C, 60.63; H, 5.26; N, 9.74. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C7H8NS+, 138.0372, Found: 138.0369.
11a.
2b.
N-(4-Methoxyphenyl)-N-methylacetamide ((204.4 mg, 1.14 mmol)
was dried in vacuo in a round-bottom flask for 2 h. Lawesson’s reagent
(278.3 mg, 0.68 mmol) and toluene (5 mL) were added into the flask,
and the mixture was stirred at 100−110 °C in oil bath for 2 h under
Ar atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 6:1) to give 2b (189.3 mg, 85%,
yellow oil). 1H NMR (400 MHz, CDCl3) δ: 7.09 (2H, d, J = 8.8 Hz),
6.94 (2H, d, J = 9.2 Hz), 3.84 (3H, s), 3.72 (3H, s), 2.39 (3H, s).
13C{1H} NMR (100 MHz, CDCl3) δ: 201.7, 159.23, 138.8, 126.3,
115.0, 55.6, 45.9, 33.8. Anal. Calcd for C10H13NOS: C, 61.51; H, 6.71;
N, 7.17. Found: C, 61.73; H, 6.70; N, 7.17. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C10H14NOS+, 180.0841, Found, 180.0839.
3b.
N-Methylacetamide (306.1 mg, 4.2 mmol) was dried in vacuo in a
round-bottom flask for 2 h. Lawesson’s reagent (1953.5 mg, 4.83
mmol) and toluene (8 mL) were added into the flask, and the mixture
was stirred at room temperature (25 °C) for 19 h under Ar
atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 7:3) to give 11a (recrystallized
by hexane and CH2Cl2 to afford 58.7 mg, 17%, white solid). Mp =
N-Methyl-N-(p-tolyl)acetamide (175.8 mg, 1.08 mmol) was dried in
vacuo in a round-bottom flask for 2 h. Lawesson’s reagent (261.4 mg,
0.65 mmol) and toluene (3 mL) were added into the flask, and the
mixture was stirred at 80 °C in oil bath for 24 h under Ar atmosphere.
The mixture was evaporated. The crude was column chromato-
graphed (hexane/EtOAc = 6:1) to give 3b (175.4 mg, 98%, yellow
1
52−53 °C. H NMR (400 MHz, CDCl3) (a mixture of rotamers) δ:
7.38 (1H, brs), 3.17 (3H, d, J = 4.8 Hz), 3.02 (0.1H, d, J = 5.6 Hz),
2.56 (3H, t, J = 0.4 Hz), 2.50 (0.1H, s). 13C{1H} NMR (100 MHz,
CDCl3) δ: 201.8, 33.9, 33.2. Anal. Calcd for C3H7NS: C, 40.42; H,
7.91; N, 15.71. Found: C, 40.25; H, 7.74; N, 15.43. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C3H7NNaS+, 112.0191, Found:
112.0193.
1
oil). H NMR (400 MHz, CDCl3) δ: 7.25−7.22 (2H, m), 7.06−7.03
(2H, m), 3.72 (3H, d, J= 0.4 Hz), 2.39 (6H, t, J= 1.2 Hz). 13C{1H}
NMR (100 MHz, CDCl3) δ: 201.7, 143.7, 138.9, 130.9, 125.3, 46.1,
34.2, 21.4. Anal. Calcd for C10H13NS+ 0.1H2O: C, 66.33; H, 7.35; N,
7.74. Found: C, 66.63; H, 7.07; N, 7.66. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C10H14NS+, 180.0841, Found, 180.0839.
4b.
12a.
tert-Butyl (2-methyl-1-oxo-1-(phenylamino)propan-2-yl)carbamate
(301.2 mg, 1.09 mmol) was dried in vacuo in a round-bottom flask
for 2 h. Lawesson’s reagent (262.59 mg, 0.65 mmol) and toluene (8
mL) were added into the flask, and the mixture was stirred at 100−
110 °C in oil bath for 2 h under Ar atmosphere. The mixture was
evaporated. The crude was column chromatographed (hexane/EtOAc
= 4:1) to give 12a (114.6 mg, 36%, pale yellow powder). Mp = 116−
N-(4-Chloro-phenyl)-N-methylacetamide (300.4 mg, 1.64 mmol) was
dried in vacuo in a round-bottom flask for 2 h. Lawesson’s reagent
396.94 mg, 0.98 mmol) and toluene (6 mL) were added into the flask,
and the mixture was stirred at 100−110 °C in oil bath for 2 h under
Ar atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 2:1) to give 4b (156.6 mg,
70.1%, white solid). Mp = 94−95 °C. 1H NMR (400 MHz, CDCl3) δ:
7.43 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 3.70 (3H, d, J = 0.4
Hz), 2.39 (3H, s). 13C{1H} NMR (100 MHz, CDCl3) δ: 201.7, 144.3,
134.5, 130.3, 126.9, 45.7, 34.0. Anal. Calcd for C9H10ClNS: C, 54.13;
H, 5.05; N, 7.01. Found: C, 53.94; H, 5.06; N, 6.96. HRMS (ESI-
1
117 °C. H NMR (400 MHz, CDCl3) δ: 10.41 (1H, brs), 7.68 (2H,
d, J = 7.2 Hz), 7.44−7.37 (2H, m), 7.27−7.23 (1H, m), 1.74 (6H, s),
1.46 (9H, s). 13C{1H} NMR (100 MHz, CDCl3) δ: 206.3, 155.6,
139.3, 129.0, 126.8, 123.8, 63.2, 29.1, 28.4. Anal. Calcd for
C15H22N2O2S: C, 60.82; H, 7.55; N, 9.46. Found: C, 60.80; H,
7.40; N, 9.42. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
C15H22N2O2SNa , 317.1294, Found: 317.1297.
P
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1
TOF) m/z: [M + H]+ Calcd for C9H11ClNS+, 200.0295, Found,
yellow oil). H NMR (400 MHz, CDCl3) δ: 7.48−7.43 (2H, m),
7.41−7.37 (1H, m), 7.18−7.15 (2H, m), 3.72 (3H, s), 2.49 (2H, q, J=
7.2 Hz), 1.18 (3H, t, J= 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3)
δ: 207.8, 145.8, 130.1, 128.6, 125.6, 46.0, 37.2, 14.6. Anal. Calcd for
C10H13NS+ 0.1H2O: C, 66.33; H, 7.35; N, 7.74. Found: C, 66.32; H,
7.15; N, 7.50. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C10H14NS+, 180.0845, Found: 180.0841.
200.0316.
5b.
9b.
4-Fluoro-N-methylaniline (120.1 mg, 0.72 mmol) was dried in vacuo
in a round-bottom flask for 2 h. Lawesson’s reagent 174.56 mg, 0.43
mmol) and toluene (5 mL) were added into the flask, and the mixture
was stirred at 100−110 °C in oil bath for 4 h under Ar atmosphere.
The mixture was evaporated. The crude was column chromato-
graphed (hexane/EtOAc = 2:1) to give 5b (101.6 mg, yellow oil,
77%). 1H NMR (400 MHz, CDCl3) δ: 7.19−7.12 (4H, m), 3.71 (3H,
d, J = 0.4 Hz), 2.38 (3H, d, J = 0.4 Hz). 13C{1H} NMR (100 MHz,
CDCl3) δ: 201.7, 162.0 (J = 274 Hz), 142.0 (J = 3 Hz), 127.2 (J = 9
Hz), 117.0 (J = 22 Hz), 45.8, 33.9. Anal. Calcd for C9H10FNS: C,
58.99; H, 5.50; N, 7.64. Found: C, 58.86; H, 5.61; N, 7.64. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C9H11FNS+, 184.0591, Found,
184.0593.
N-Methyl-N-phenylcyclohexanecarboxamide (124.4 mg, 0.57 mmol)
was dried in vacuo in a round-bottom flask for 2 h. Lawesson’s reagent
(138.9 mg, 0.34 mmol) and toluene (5 mL) were added into the flask,
and the mixture was stirred at 100−110 °C in oil bath for 3 h under
Ar atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 2:1) to give 9b (88.1 mg, 66%,
white solid). Mp = 85−86 °C. 1H NMR (400 MHz, CDCl3) δ: 7.48−
7.44 (2H, m), 7.43−7.38 (1H, m), 7.15−7.12 (2H, m), 3.70 (3H, s),
2.51−2.17 (1H, m), 1.84−1.74 (2H, m), 1.68−1.51 (5H, m), 1.21−
1.14 (1H, m), 0.98−0.87 (2H, m). 13C{1H} NMR (100 MHz,
CDCl3) δ: 211.5, 145.9, 130.1, 128.5, 125.6, 49.5, 45.6, 33.7, 25.6,
25.5. Anal. Calcd for C14H19NS+ 0.2H2O: C, 70.96; H, 8.25; N, 5.91.
Found: C, 70.93; H, 8.03; N, 5.79. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C14H20NS+, 234.1311, Found: 234.1327.
6b.
N-(4-Cyanophenyl)-N-methylacetamide (150.1 mg, 0.89 mmol) was
dried in vacuo in a round-bottom flask for 2 h. Lawesson’s reagent
216.3 mg, 0.53 mmol) and toluene (6 mL) were added into the flask,
and the mixture was stirred at 100−110 °C in oil bath for 14 h under
Ar atmosphere. The mixture was evaporated. The crude was flash
column chromatographed (hexane/EtOAc = 10:1) and open column
chromatographed (hexane/EtOAc = 2:1) to give 6b (37.6 mg, 22%,
white solid). Mp = 112−113 °C. 1H NMR (400 MHz, DMSO-d6) δ:
8.00 (2H, d, J = 8.0 Hz), 7.66 (2H, d, J = 8.4 Hz), 3.63 (3H, brs),
2.30(3H, brs). 13C{1H} NMR (100 MHz, CDCl3) δ: 201.6, 149.4,
134.1, 126.9, 117.7, 112.7, 45.6, 34.0. Anal. Calcd for C10H10N2S+
0.1H2O: C, 62.54; H, 5.35; N, 14.59. Found: C, 62.76; H, 5.49; N,
14.47. HRMS (ESI-TOF) m/z: [M + H]+ C10H11N2S+, 191.0637,
Found, 191.0640.
10b.
THF (10 mL) was added into the mixture of formanilide (303.1 mg,
2.50 mmol) and Lawesson’s reagent (607.4 mg, 1.50 mmol) in water
bath (20 °C), and the solution was stirred at this temperature for 24
h. The mixture was evaporated. The crude was column chromato-
graphed (hexane/EtOAc = 2:1) to give 10b (123.7 mg, 36%, dark
1
yellow oil). H NMR (400 MHz, CDCl3): 9.63(1H, d, J= 0.4 Hz),
7.45−7.41 (2H, m), 7.35−7.31 (1H, m), 7.26−7.21 (2H, m), 3.71
(3H, d, J= 0.4 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ: 189.3,
146.2, 129.9, 127.6, 122.0, 38.5. Anal. Calcd for C8H9NS + 0.2H2O:
C, 62.06; H, 6.12; N, 9.05. Found: C, 62.16; H, 6.03; N, 9.09. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C8H10NS+, 152.0528, Found:
152.0524.
7b.
N-Methyl-N-(4-nitrophenyl)acetamide (176.1 mg, 0.90 mmol) was
dried in vacuo in a round-bottom flask for 2 h. Lawesson’s reagent
(219.0 mg, 0.54 mmol) and toluene (3 mL) were added into the flask,
and the mixture was stirred at 100−110 °C in oil bath for 2 h under
Ar atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 4:1) to give 7a (113.1 mg, 54%,
Synthesis of Amides. 1c.
1
A solution of acetyl chloride (790.5 mg, 10.07 mmol) in DMAC (5.0
mL) was made at room temperature and stirred at 0 °C for 5 min. A
solution of aniline (935.2 mg, 10.04 mmol) in DMAC (5.0 mL) was
added to the above solution slowly, and the mixture was stirred at 0
°C for another 5 min. The ice−water bath was removed, and the
reaction went on for 170 min in water bath (20 °C). Water (30 mL)
was added, and the mixture was stirred for 19 h. The mixture was
extracted with ethyl acetate (20 mL) twice, and the organic fraction
was washed with brine (40 mL). The organic layer was dried over
Na2SO4 and filtered. The solvent was evaporated, and the residue was
recrystallized with hexane and CH2Cl2 to afford 1c (1023.5 mg, 76%,
colorless plates). Mp = 105−108 °C. 1H NMR (400 MHz, CDCl3) δ:
7.89 (H, brs), 7.65 (2H, d, J = 7.6 Hz), 7.46 (2H, t, J = 7.8 Hz), 7.25
(1H, t, J = 7.4 Hz), 2.31 (3H, s). 13C{1H} NMR (100 MHz, CDCl3)
δ: 168.8, 138.0, 129.0, 124.4, 120.1, 24.6. Anal. Calcd for C8H9NO: C,
71.11; H, 6.67; N, 10.37. Found: C, 70.81; H, 6.79; N,10.32. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C8H10NO+, 136.0757, Found:
136.0766.
yellow plates). Mp = 159−160 °C. H NMR (400 MHz, CDCl3) δ:
8.34 (2H, d, J= 8.8 Hz), 7.41 (2H, d, J= 8.8 Hz), 3.74 (3H, brs), 2.43
(3H, brs). 13C{1H} NMR (100 MHz, CDCl3) δ: 201.7, 151.1, 147.3,
127.0, 125.6, 45.6, 34.1. Anal. Calcd for C9H10O2N2S: C, 51.41; H,
4.79; N, 13.32. Found: C, 51.41; H, 4.79; N, 13.32. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C9H11O2N2S+, 211.0536, Found:
211.0540.
8b.
N-methyl-N-phenylpropionamide (94.5 mg, 0.58 mmol) was dried in
vacuo in a round-bottom flask for 2 h. Lawesson’s reagent (140.5 mg,
0.35 mmol) and toluene (5 mL) were added into the flask, and the
mixture was stirred at 100−110 °C in oil bath for 200 min under Ar
atmosphere. The mixture was evaporated. The crude was column
chromatographed (hexane/EtOAc = 2:1) to give 8b (81.6 mg, 78%,
Q
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2c.
X-ray Crystallographic Analysis. The details of X-ray crystallo-
graphic analyses of 3a, 3c, 5a, and 7b are given in Supporting
Information.
Calculations of Solvation Model. To investigate the conforma-
tional preference and the distribution of conformations in solution, an
accelerated molecular dynamics (MD) simulation, that is, replica
exchange with solute tempering (REST) simulation,18 was performed
in the presence of explicit solvent molecules. Replica exchange with
solute tempering (REST) simulation was performed with Desmond.
The OPLS3e force field19 was used for a thioamide and predefined
model was used for each solvent. The custom solvent model box was
created for chloroform. The systems initially contained solvents in
orthorhombic boxes with at least 10.0 Å gap between the solute and
the periodic boundaries. Using REST, we simulated thioamide
isomerization with the OPLS3e force field in Desmond implemented
A solution of acetyl chloride (789.8 mg, 10.12 mmol) in DMAC (5.0
mL) was made at room temperature and stirred at 0 °C for 5 min. A
solution of p-anisidine (1232.1 mg, 10.00 mmol) in DMAC (5.0 mL)
was added to the above solution slowly, and the mixture was stirred at
0 °C for another 5 min. The ice−water bath was removed and the
reaction went on for 90 min in water bath (20 °C). Water (30 mL)
was added, and the mixture was stirred for 18 h. The mixture was
extracted with ethyl acetate (20 mL) twice, and the organic fraction
was washed with brine (40 mL). The organic layer was dried over
Na2SO4 and filtered. The solvent was evaporated and the residue was
recrystallized with ethanol to afford 2c (1152.5 mg, 70%, pink plates).
̈
in the Schrodinger software suite Maestro 2018−4. Simulations were
1
performed for 40 ns using 8 replicas with an effective temperature of
the solute from 300 K through about 965 K with NPT ensemble. The
exchange rate was more than 30% for each simulation. The trajectory
structures were saved every 4 ps (total 1000 frames) from the replica
at 300 K. The conformations were classified into Z and E thioamides
according to the following criteria: the horizontal axis is the dihedral
angle of the thioamide rotation: conformers between −90° to +90°
are regarded as Z and conformers between −180° to −90° and 90° to
180° are regarded as E. The vertical axis is the frequency (%) of the
conformer.
Mp = 120−121 °C. H NMR (400 MHz, CDCl3) δ: 7.66 (1H, brs),
7.38 (2H, d, J = 9.2 Hz), 6.82 (2H, d, J= 8.8 Hz), 3.767 (3H, s), 2.120
(3H, s). 13C{1H} NMR (100 MHz, CDCl3) δ: 168.7, 156.4, 131.1,
122.1, 114.0, 55.4, 24.2. Anal. Calcd for C9H11NO2: C, 65.45; H, 6.67;
N, 8.48. Found: C, 64.92; H, 6.64; N, 8.44. HRMS (ESI-TOF) m/z:
+
[M + H]+ Calcd for C9H12NO2 , 166.0863, Found: 166.0868.
3c.
Radial Distribution Function (g(r)). The interactions between
the thioamides and the solvent can be analyzed for the trajectories of
MD simulations obtained at 300 K for 40 ns (force field: OPSL3e) by
use of the radial distribution function (g(r)),20 which expresses the
probability distribution of the distance between two molecules in a
solution.
A solution of acetyl chloride (782.0 mg, 10.04 mmol) in DMAC (5.0
mL) was made at room temperature and stirred at 0 °C for 5 min. A
solution of p-toluidine (1072.8 mg, 10.01 mmol) in DMAC (5.0 mL)
was added to the above solution slowly, and the mixture was stirred at
0 °C for another 5 min. The ice−water bath was removed, and the
reaction went on for 70 min in water bath (16 °C). Water (30 mL)
was added, the mixture was extracted with ethyl acetate (20 mL)
twice, and the organic fraction was washed with brine (40 mL). The
organic layer was dried over Na2SO4 and filtered. The solvent was
evaporated, and the residue was recrystallized with hexane and EtOAc
DFT Calculations of Thioamide and Solvent Complex. A complex
of 3a and a single molecule of the solvent (also two molecules in the
case of CH2Cl2) hydrogen bonding to the thioamide 3a was selected
as an arbitrary structure in the MD trajectory at 300 K in the REST
calculations, and the distance and angle of the solvent with respect to
the thioamide were fully scanned. The resultant energy minimum
candidate structure was fully optimized (default: SCF = tight) with
M062X/6-311++G(d) in the IEFPCM solvent model with the
Gaussian 16 program.27 All the structures are energy minima in terms
of the absence of negative frequency. Total energy of the molecules in
the DFT calculations was subjected to zero-point corrections and
thermal corrections without scaling, if not otherwise specified.
QTAIM Calculations. Bond-path analysis was performed at the
Slater-type triple-ζ-polarization (TZP) level with ADF (SCM,
Netherlands).28 A polarization function is added for H through Ar
and for Ga through Kr. Details of optimization of Slater-type basis sets
were reported previously.28 The QTAIM analysis was applied on the
basis of the DFT-optimized energy-minimum structures.
1
to afford 3c (1118.3 mg, 79%, colorless plates). Mp = 78−79 °C. H
NMR (400 MHz, CDCl3) δ: 7.44 (H, brs), 7.37 (2H, d, J = 8.4 Hz),
7.10 (2H, d, J= 8.0 Hz), 2.30 (3H, s), 2.14 (3H, s). 13C{1H} NMR
(100 MHz, CDCl3) δ: 168.4, 135.4, 134.0, 129.5, 120.1, 24.5, 20.9.
Anal. Calcd for C9H11NO: C, 72.48; H, 7.38; N, 9.40. Found: C,
+
72.50; H, 7.38; N, 9.32. HRMS (ESI-TOF, [M + Na] ): Calcd for
C9H11NONa+, 172.0733, Found: 172.0730.
Synthesis of N-(4-Methoxyphenyl)-N-methylacetamide.
N-Methylation of p-methoxy-N-phenylacetamide was performed with
dimethyl sulfate in argon-bubbled DMSO in the presence of NaH,
giving in 90% N-methylated amide. To argon gas-bubbled DMSO (20
mL), NaH (60%, 562.7 mg, 1.4 equiv) was added by portions in a
water−ice bath (15 °C) over 5 min. After 15 min, a solution of p-
methoxy-N-phenylacetamide (1.6527g, 10 mmol) in 6 mL of argon
gas-bubbled DMSO was added over 5 min at 15 °C. After the mixture
was stirred for 80 min at 15 °C, 100 mL of water was added. The
whole was extracted with dichloromethane (60 mL × 3), and the
organic layer was washed with water and dried over MgSO4. The
organic solvent was evaporated to give a colorless viscous oil, which
was open column-chromatographed (with ethyl acetate/n-hexane 3:2)
to give the target N-methyl amide 2d (1.6620g, 93% yield) as
What Is the Bond Path? The concepts of bond paths and bond
critical points have been criticized and a rebuttal published.22 There
has also been controversy regarding the presence/absence of a bond
path between unusual sets of atoms in different systems (see ref 17).
A bond path is often misidentified with a chemical bond, but bond
paths have been regarded as indicative of bonded interactions, not
chemical bonds, and may encompass all kinds of interactions. Usually,
covalent bonding corresponds well to the bond path. One of the
different interpretations of a bond path involving weak interactions is
that “simply allowing two atoms to approach each other should often
cause electron density to flow to the interatomic space, depending on
the balance between nucleus-electron attraction and electron-electron
repulsion, both coulomb and exchange”. QTAIM atoms are not
simple spheres, and thus, their neighborhood can be influenced by
their complex topology. This can lead to a bond path with a bond
critical point, even in the purely classical case in which exchange is not
considered. This analysis suggests that the occurrence of a bond
critical point should depend on the interatomic distance (see ref 22e).
Bond Analysis of Thioamides. The electronic structures of the
molecules were analyzed using bond model analysis,23,24 which is able
1
colorless plates. Mp = 54−55 °C. H NMR (400 MHz, CDCl3) δ:
7.08 (2H, d, J = 9.2 Hz), 6.90 (2H, d, J = 9.2 Hz), 3.81 (3H, s), 3.21
(3H, s), 1.83 (3H, s). 13C{1H} NMR (100 MHz, CDCl3) δ: 170.9,
158.8, 137.4, 128.1, 114.8, 55.4, 37.2, 22.2. Anal. Calcd for
C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.99; H, 7.25;
N, 7.70. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C10H13NO2Na+, 202.0838, Found, 202.0835.
R
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to evaluate the bond orbital interactions in molecules. The interbond
energies (IBEs), including both occupied-occupied orbitals and
occupied-vacant orbitals, were used to evaluate the bond interactions
in the molecules. The IBEs were calculated for: (1) vicinal
interaction term (vicinal): vicinal bond interactions with respect to
the thioamide N−C(S) bond, that is, between σ(C1−C2)/σ(C1−S),
and σ(N−H) or σ(N−C(Ar)) (they all are in a vicinal relation) (2)
conjugation interaction term (conjugation): conjugation between
n(N) and CS, n(N) and Ar, and CS and Ar, and (3) repulsive
interaction term (repulsion): repulsive interaction between two
substituents attached to the thioamide bond, including all C−C and
C−H σ bonds and π orbitals of the aromatic ring.
Satoshi Inagaki − Graduate School of Pharmaceutical
Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033,
Japan
Kentaro Yamaguchi − Faculty of Pharmaceutical Sciences at
Kagawa Campus, Tokushima Bunri University, Sanuki,
Kagawa 769-2193, Japan; orcid.org/0000-0002-2629-
716X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00801
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00801.
ACKNOWLEDGMENTS
■
The computations were performed at the Research Center for
Computational Science, Okazaki, Japan. This work was
supported by Grants-in-Aid for Scientific Research (KAKEN-
HI) (TO: 18H02552) provided by Japan Society for the
Promotion of Science. K.A.L.V. is grateful to the Amgen
Scholars Program for funding a study visit at the University of
Tokyo.
NMR assignment of Z/E of thioamides (Figures S1−S3
and Table S1), X-ray crystallographic data (Figures S4−
S10), calculation data (Figures S11−S13 and Tables
S2−S4), calculation coordinates, and H and 13C{H}
1
NMR spectral spectra (PDF)
Accession Codes
REFERENCES
■
CCDC 2060674−2060677, 2072313−2072314, and 2075800
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
́
(1) (a) Jagodzinski, T. S. Thioamides as Useful Synthons in the
Synthesis of Heterocycles. Chem. Rev. 2003, 103 (1), 197−228.
(bc) Barrett, T. M.; Chen, X. S.; Liu, C.; Giannakoulias, S.; Phan, H.
A. T.; Wang, J.; Keenan, E. K.; Karpowicz, R. J., Jr; Petersson, J. E.
Studies of Thioamide Effects on Serine Protease Activity Enable Two-
Site Stabilization of Cancer Imaging Peptides. ACS Chem. Biol. 2020,
15, 774−779. (d) Yang, J.; Wang, C.; Yao, C.; Chen, C.; Hu, Y.; He,
G.; Zhao, J. Site-Specific Incorporation of Multiple Thioamide
Substitutions into a Peptide Backbone via Solid Phase Peptide
Synthesis. J. Org. Chem. 2020, 85, 1484−1494. (e) Maini, R.; Kimura,
H.; Takatsuji, R.; Katoh, T.; Goto, Y.; Suga, H. Ribosomal Formation
of Thioamide Bonds in Polypeptide Synthesis. J. Am. Chem. Soc. 2019,
141, 20004−20008. (f) Camacho, L. A., III; Nguyen, Y. H.; Turner, J.;
VanVeller, D. Deprotection Strategies for Thioimidates during Fmoc
Solid-Phase Peptide Synthesis: A Safe Route to Thioamides. J. Org.
Chem. 2019, 84, 15309−15314. (h) Goldberg, J. M.; Batjargal, S.;
Petersson, E. J. Thioamides as Fluorescence Quenching Probes:
Minimalist Chromophores to Monitor Protein Dynamics. J. Am.
Chem. Soc. 2010, 132 (42), 14718−14720.
AUTHOR INFORMATION
■
Corresponding Author
Tomohiko Ohwada − Graduate School of Pharmaceutical
Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033,
Japan; orcid.org/0000-0001-5390-0203;
Email: ohwada@mol.f.u-tokyo.ac.jp
Authors
Shuyi Song − Graduate School of Pharmaceutical Sciences,
University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Tadashi Hyodo − Faculty of Pharmaceutical Sciences at
Kagawa Campus, Tokushima Bunri University, Sanuki,
Kagawa 769-2193, Japan
Hirotaka Ikeda − Graduate School of Pharmaceutical Sciences,
University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Kim Anh L. Vu − Graduate School of Pharmaceutical
Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033,
Japan; NUS Graduate School for Integrative Sciences and
Engineering, National University of Singapore, Singapore
119077; Cancer Science Institute of Singapore, National
University of Singapore, Singapore 117599
Yulan Tang − Graduate School of Pharmaceutical Sciences,
University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Erika S. Chan − Graduate School of Pharmaceutical Sciences,
University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
Ernest Mario School of Pharmacy, Rutgers, The State
University of New Jersey, Piscataway, New Jersey 08854,
United States
Yuko Otani − Graduate School of Pharmaceutical Sciences,
University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan;
orcid.org/0000-0002-8104-283X
(2) (a) Gorske, B. C.; Nelson, R. C.; Bowden, Z. S.; Kufe, T. A.;
Childs, A. M. Bridged n→π* interactions can stabilize peptoid helices.
J. Org. Chem. 2013, 78, 11172−11183. (b) Laursen, J. S.; Engel-
Andreasen, J.; Fristrup, P.; Harris, P.; Olsen, C. A. Cis−trans-amide
bond rotamers in β-peptoids and peptoids: Evaluation of stereo-
electronic effects in backbone and side chains. J. Am. Chem. Soc. 2013,
135, 2835−2844. (c) Camacho, L. A., III; Lampkin, B. J.; VanVeller,
B. A Bottom-Up Approach To Preserve Thioamide Residue
Stereochemistry during Fmoc Solid-Phase Peptide Synthesis. Org.
Lett. 2019, 21, 7015−7018. (d) Dunbar, K. L.; Dell, M.; Molloy, E.
M.; Kloss, F.; Hertweck, C. Reconstitution of Iterative Thioamidation
in Closthioamide Biosynthesis Reveals Tailoring Strategy for
Nonribosomal Peptide Backbones. Angew. Chem., Int. Ed. 2019, 58,
13014−13018. (e) Saito, M.; Murakami, S.; Nanjo, T.; Kobayashi, Y.;
Takemoto, Y. Mild and Chemoselective Thioacylation of Amines
Enabled by the Nucleophilic Activation of Elemental Sulfur. J. Am.
Chem. Soc. 2020, 142, 8130−8135. (f) Newberry, R. W.; VanVeller,
B.; Raines, R. T. Thioamides in the collagen triple helix. Chem.
Commun. 2015, 51, 9624−9627.
(3) Stewart, W. E.; Siddall, T. H. Nuclear magnetic resonance
studies of amides. Chem. Rev. 1970, 70, 517−551.
(4) Sandström, J.; Uppström, B. NMR spectra and conformations of
some simple N-methyl thioamides. Acta Chem. Scand. 1967, 21,
2254−2260.
S
https://doi.org/10.1021/acs.joc.1c00801
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(5) (a) Wiberg, K. B.; Rush, D. J. Solvent effects on the thioamide
rotational barrier: An experimental and theoretical study. J. Am. Chem.
Soc. 2001, 123, 2038−2046. (b) Wiberg, K. B.; Rablen, P. R. Why
Does Thioformamide have a larger rotational barrier than formamide?
J. Am. Chem. Soc. 1995, 117, 2201−2209.
Two-Electron Systems. Origin of the Tilting of Their Substituents. J.
Am. Chem. Soc. 1996, 118, 7247−7254.
(23) (a) Naruse, Y.; Ma, J.; Takeuchi, K.; Nohara, T.; Inagaki, S. π-
Relaxation of the ring strain: design of polycyclic unsaturated silicon
molecules. Tetrahedron 2006, 62, 4491−4497. See also references
cited therein. (b) Inagaki, S. Orbital in Chemistry; Springer:
Heidelberg, 2009.
(24) Takahashi, Y.; Ikeda, H.; Kanase, Y.; Makino, K.; Tabata, H.;
Oshitari, T.; Inagaki, S.; Otani, Y.; Natsugari, H.; Takahashi, H.;
Ohwada, T. Elucidation of the E-Amide Preference of N-Acyl Azoles.
J. Org. Chem. 2017, 82, 11370−11382.
(25) Charette, A. B.; Grenon, M. Mild Method for the Conversion
of Amides to Thioamides. J. Org. Chem. 2003, 68, 5792−579.
(26) Otsuka, R.; Maruhashi, K.; Ohwada, T. Latent Bronsted Base
Solvent-Assisted Amide Formation from Amines and Acid Chlorides.
Synthesis 2018, 50, 2041−2057.
(27) Gaussian 16, Revision C.01; Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.;
Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts,
R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.;
Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi,
F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.;
Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov,
V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.
Gaussian, Inc., Wallingford, CT, 2016.
(6) Zhang, J.; Liu, Z.; Yin, Z.; Yang, X.; Ma, Y.; Szostak, R.; Szostak,
M. Preference of Z-Thioamide Structure in N-Thioacyl-N-methylani-
lines. Org. Lett. 2020, 22, 9500−9505.
(7) Ruud, K.; Helgaker, T.; Bak, K. L.; Jørgensen, H. J. A. Jensen,
Hartree-Fock Limit Magnetizabilities from London Orbitals. J. Chem.
Phys. 1993, 99, 3847−59.
(8) Bordwell, F. G.; Ji, G. Z. Effects of structural changes on acidities
and homolytic bond dissociation energies of the hydrogen-nitrogen
bonds in amidines, carboxamides, and thiocarboxamides. J. Am. Chem.
Soc. 1991, 113 (22), 8398−8401.
(9) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. Acidities of water
and simple alcohols in dimethyl sulfoxide solution. J. Org. Chem.
1980, 45, 3295−3299.
(10) Smiszek-Lindert, W.; Nowak, M.; Kusz, J. Acta Crystallogr., Sect.
E: Struct. Rep. Online 2007, 63, No. o3917.
(11) Maeda, H.; Kamijo, N.; Fukui, K. Cryst. Struct. Commun. 1976,
5, 129.
(12) Zhao, G. Acta Crystallogr., Sect. E: Cryst. Commun. 2015, 71,
No. o353.
(13) Hyodo, T.; Kawahata, M.; Hikami, Y.; Komatsu, A.; Tominaga,
M.; Yamaguchi, K. Cycloalkanes and cycloalkenes in dispersive force.
CrystEngComm 2019, 21, 1548−1554.
(14) Tominaga, M.; Hyodo, T.; Maekawa, Y.; Kawahata, M.;
Yamaguchi, K. One-Step Synthesis of Cyclophanes as Crystalline
Sponge and Their [2]Catenanes through SNAr Reactions. Chem. - Eur.
J. 2020, 26, 5157−5161.
(15) Haisa, M.; Kashino, S.; Ueno, T.; Shinozaki, N.; Matsuzaki, Y.
Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1980, 36,
2306.
(28) Baerends, E. J. et al. ADF2020. Theoretical Chemistry; Vrije
Universiteit: Amsterdam, The Netherlands, 2020, http://www.scm.
com. te Velde, G.et al.Chemistry with ADFJ. Comput. Chem. 2001, 22
931−967.
(16) Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. Theoretical Studies
on cis-Amide Preference in N-Methylanilines. J. Org. Chem. 1995, 60,
4715−4720.
(17) Pros, G. J.; Bloomfield, A. J. Why Do N-Alylated Anilides Bend
Over? The Factors Dictating the Divergent Conformational
Preferences of 2° and 3° N-Aryl Amides. J. Phys. Chem. A 2019,
123, 7609−7618.
(18) Wang, L.; Friesner, R. A.; Berne, B. J. Replica Exchange with
Solute Scaling: A More Efficient Version of Replica Exchange with
Solute Tempering (REST2). J. Phys. Chem. B 2011, 115, 9431−9438.
(19) Roos, K.; Wu, C.; Damm, W.; Reboul, M.; Stevenson, J. M.; Lu,
C.; Dahlgren, M. K.; Mondal, S.; Chen, W.; Wang, L.; Abel, R.;
Frisner, R. A.; Garder, E. D. OPLS3e: Extending Force Field
Coverage for Drug-Like Small Molecules. J. Chem. Theory Comput.
2019, 15, 1863−1874.
(20) (a) Cohn, J. Theory of the Radial Distribution Function. J.
Phys. Chem. 1968, 72, 608−616. (b) Kopera, B. A. F.; Retsch, M.
Computing the 3D Radial Distribution Function from Particle
Positions: An Advanced Analytic Approach. Anal. Chem. 2018, 90,
13909−13914.
(21) Hollosi, M.; Majer, Z.; Zewdu, M.; Ruff, F.; Kajtar, M.; Kövér,
K. E. Mixed intramolecular H-bonds of secondary thioamides.
Tetrahedron 1988, 44, 195−202.
(22) (a) Bader, R. F. W. Atoms in Molecules. A Quantum Theory;
Oxford University Press: New York, 1990. (b) Runtz, G. R.; Bader, R.
F. W.; Messer, R. R. Definition of bond paths and bond directions in
terms of the molecular charge distribution. Can. J. Chem. 1977, 55,
3040−3045. (c) Matta, C. F.; Boyd, R. J. The Quantum Theory of
Atoms in Molecules: From Solid State to DNA and Drug Design; Wiley-
VCH: New York, 2007. (d) Bader, R. F. W. Bond Paths Are Not
Chemical Bonds. J. Phys. Chem. A 2009, 113, 10391−10396. (e) Zhai,
L.; Otani, Y.; Ohwada, T. Uncovering the Networks of topological
Neighborhoods in β-strand and Amyloid β-sheet structures. Sci. Rep.
2019, 9, 10737. (f) Lammertsma, K.; Ohwada, T. Three-Center,
T
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