Preference of cis-Thioamide Structure in N-Thioacyl- N-methylanilines

Article abstract of DOI:10.1021/acs.orglett.0c03512

The thioamide group represents a highly attractive isostere of the amide bond. We report a combined structural and computational study on cis-thioamide conformation of N-thioacyl-N-methylanilines. Amide to thioamide replacement in a class of anilides that

Full text of DOI:10.1021/acs.orglett.0c03512

pubs.acs.org/OrgLett
Letter
Preference of cis-Thioamide Structure in
N‑Thioacyl‑N‑methylanilines
Jin Zhang,* Zhulin Liu, Zheng Yin, Xiufang Yang, Yangmin Ma, Roman Szostak, and Michal Szostak*
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ABSTRACT: The thioamide group represents a highly attractive isostere of the amide bond. We report a combined structural and
computational study on cis-thioamide conformation of N-thioacyl-N-methylanilines. Amide to thioamide replacement in a class of
anilides that are highly valuable as conformational locks results in a higher preference for cis conformation in a unique compacted
template intrinsic to the thioamide structure. The study strongly supports the use of N-methylthioanilides as cis-conformational locks
in various facets of chemistry.
n their classic study, Itai and co-workers demonstrated the
cis-preference of the amide bond in N-methylbenzanilides
As part of our program on amide bonds,19,20 herein we
report a combined structural and computational study on cis-
thioamide conformation of N-thioacyl-N-methylanilines. Most
importantly, we demonstrate that amide to thioamide
replacement results in a higher preference for cis conformation
in a unique compacted template intrinsic to the thioamide
structure. The present study strongly supports the use of N-
methylthioanilides as highly valuable cis-conformational
locks8−11 in various facets of chemistry.
Guided by the study by Itai and our own studies in amide
bond chemistry, we selected six thioamides shown in Figure 2
(1−6). These thioamides are readily synthesized from the
corresponding amides using Lawesson’s reagent (see the
Supporting Information, SI). The selected compounds mirror
the amide counterparts used by Itai (Figure 2, 7−12).
We commenced by obtaining X-ray structures of N-
methylthioanilides (Figure 3). All thioamides 1−5 feature cis
conformation in the crystal. Selected structural parameters
relevant to the thioamide geometry are presented in Table 1
and the SI. Compound 6 is a liquid and is not suitable for
crystallographic analysis (vide infra). There are several
instructive structural correlations between thioamides 1−5
I
(Figure 1A).1 Although acyclic amides strongly prefer trans
conformation around the N−C(O) bond,2,3 as exemplified by
closely related benzanilides, their N-methylated counterparts
undergo a conformational switch arising from avoidance of
unfavorable steric interactions4,5 while retaining substantial
double bond character of the amide bond through nN → π*C=O
conjugation.6,7 This unexpected finding opened the door for
the implementation of trans to cis conformational switch to
control substituent geometry around the amide bond in a
variety of fields utilizing amides, including medicinal chemistry,
biochemistry, molecular recognition, conformation relays,
synthetic switches, and organic synthesis.8−11
Recently, significant attention has been given to thioamides
as attractive amide bond isosteres.12 The oxygen to sulfur
replacement is particularly attractive considering (1) the
privileged role of sulfur-based functional groups in pharma-
ceuticals, wherein more than 25% of APIs contain sulfur as the
key component,13 and (2) the unique electronic properties
inherent to thioamides vs amides, including long van der Waals
radius of sulfur vs oxygen (1.85 Å vs 1.40 Å), elongated CX
bonds (1.64 Å vs 1.19 Å, HCXNH2), and significantly lower
polarization of the CX bond (electronegativity, S: 2.58 vs O:
3.44).14 A prominent feature of thioamides is their role in
increasing the stabilization of proteins owing to strong n → π*
interactions15 and a plethora of thioamide-containing natural
products.16 Elegant studies on macrocyclic amide to thioamide
replacement have attracted considerable interest over the last
years.17,18
Received: October 21, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03512
© XXXX American Chemical Society
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A

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Figure 3. Crystal structures of 1−5. See SI for expanded structures.
50% ellipsoids. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Center.
Table 1. Selected Crystallographic Structural Parameters of
a
Thioamides 1−5
thioamide
(R)
N−C
CS
C−C(S)
N−Ph
N−Me
no.
(Å)
(Å)
(Å)
(Å)
(Å)
1
2
Ph
C(CH3)
=CH2
1.342
1.333
1.658
1.655
1.485
1.490
1.440
1.447
1.463
1.466
3
4
5
Cy
i-Pr
t-Bu
1.332
1.338
1.341
1.664
1.659
1.662
1.481
1.519
1.546
1.441
1.442
1.444
1.467
1.469
1.476
Figure 1. (a) Classical study on cis-preference of anilides, selected
applications. (b) This work: conformational preference of thioani-
lides.
a
This study. For X-ray structures, see the SI for details.
X-ray structures for geometry optimization. Geometry
optimization was performed at the B3LYP/6-311++G(d,p)
level. Extensive studies have shown that this level is accurate in
predicting structural and energetic properties of amides.19
Computations closely parallel the experimental properties of
the amide to thioamide bond substitution and allow us to
include noncrystalline compounds 6 and 12 in the correlation
(Figure 4 and SI). Thus, amide to thioamide replacement is
accompanied by a reinforced nN to π*C=X conjugation as
evidenced by a shortening of the N−C(X) bond. This effect is
accompanied by C = X bond elongation as well as C−C(X)
bond shortening and C−C(Ph) bond elongation, consistent
with a weakened nN → Ar conjugation. Overall, these effects
lead to a compacted cis amide bond geometry in the thioanilide
template.
Next, resonance energies of the thioamide bond in 1−6 were
calculated using the COSNAR method.22 Resonance energy in
1−6 ranges between 9.6 and 19.9 kcal/mol and is higher than
in the corresponding oxygen counterparts 7−12 (9.8−15.4
kcal/mol) (Figure 5A and SI). Remarkably, there is an
excellent inverse linear correlation between a plot of log(ΔRE)
of the sulfur and oxygen analogues and the steric Charton (ν)
value (Figure 5B, R2 = 0.91). Overall, the energetic parameters
in 1−6 vs 7−12 indicate a reinforced bond resonance upon O
to S replacement. The resonance manifests as a function of the
R substituent converging at the sterically demanding
substitution. This unexpected effect likely arises from the
increased van der Waals radius of sulfur vs oxygen atoms
minimizing steric interactions.
Figure 2. Structures of thioamides used in the present study.
and their amide counterparts 7−11 obtained from crystallo-
graphic studies, including (1) a significant decrease of the N−
C(X) bond length (avg 1.337 Å, X = S; avg 1.352 Å, X = O);
(2) a significant increase of the CX bond length (avg 1.660
Å, X = S; avg 1.228 Å, X = O); (3) an increase in C−C(Ph)
bond length (avg 1.443 Å, X = S; avg 1.439 Å, X = O); and (4)
an excellent linear correlation between the C−C(S) and C−
C(O) bond lengths (R2 = 0.92, see the SI for correlation
plots).21
Next, we performed computational studies to gain insight
into the structures of thioamides 1−6 and compare them with
their oxygen counterparts 7−12. As shown by our previous
studies,19 computed data provide vastly improved correlations
vs solid state structures, and this approach is particularly
effective when considering multiple series of compounds using
To gain further insight into the effect of O to S replacement,
we obtained a detailed rotational profile of the parent
thioamide 1 by systematic rotation along the X−C−N−C
dihedral angle (Figure 5C). The rotation was performed in
B
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Figure 4. (a) Plot of N−C bond length (Å) in thioamides 1−6 vs amides 7−12. (b) Plot of N−Ph bond length (Å) in thioamides 1−6 vs amides
7−12. (c) Correlation of C−C(S) bond length (Å) to C−C(O) bond length (Å)SI for additional details.
Figure 5. (a) Resonance energies for thioamides 1−6 (kcal/mol). (b) Plot of log(ΔRE) vs Charton parameter in thioamides 1−6 vs amides 7−12.
Note that the ν value for C(CH3)CH2 is not available. (c) Correlation of ΔE [kcal/mol] to X−C−C−C (deg) in 1 and 7 (B3LYP/6-311+
+G(d,p)). See the SI for additional details.
both directions using the X-ray structure of 1 as the starting
geometry. Figure 5C shows rotational profile of 1 (X = S) in
comparison with 7 (X = O). The rotational profile in 1
confirms a significantly higher barrier to rotation than in the
oxygen counterpart with a planar thioamide bond conforma-
tion (the energy minimum at ca. 0° S−C−N−C angle; the
energy maximum at ca. 90° S−C−N−C angle). The rotational
barrier was determined to be 14.02 kcal/mol (90° S−C−N−C
angle) and 10.84 kcal/mol (70° O−C−N−C angle). It is
worth noting that as suggested by the resonance energies
thioamide 6 shows one conformer in the NMR spectrum. This
effect is driven by minimization of steric interactions between
the R substituent and the sulfur atom. Both steric and
electronic effects of the substituents play a key role in adopting
the cis conformation.
Several additional studies were conducted (Scheme 1 and
see SI). (1) To further confirm the intrinsic preference of N-
methylthioanilides to exist in the cis conformation, the relative
stabilities of the trans isomers for both sulfur and oxygen
analogues were determined at the B3LYP/6-311++G(d,p)
level, showing that cis isomers are more stable in all cases (S:
avg 3.1 kcal/mol; O: avg 2.7 kcal/mol, see SI). (2) The
difference in proton affinities (ΔPA) in representative
thioamide 1 indicates that these thioanilides strongly favor
protonation at sulfur19 (ΔPA = 17.0 kcal/mol, SPA vs NPA),
which can be compared with the oxygen analogue 7 (ΔPA =
11.0 kcal/mol, OPA vs NPA)19e and is in agreement with the
findings on the enhanced nN → π*CX conjugation in
thioamides (Scheme 1A). (3) To push the prospects of
resonance alteration, RE of derivatives 13−16 varying by a
Scheme 1. Protonation Aptitude and Resonance Energies
single substituent on each aromatic ring were determined
(Scheme 1B) (13: R = 4-NMe2/R′ = 4-NO2; 14: R = 4-MeO/
R′ = 4-CN; 15: R = 4-CN/R′ = 4-MeO; 16: R = 4-NO2/R′ =
4-NMe2). The RE in 13−16 of 8.7, 11.1 19.6, 20.6 kcal/mol
spans the range of 11.9 kcal/mol, which supersedes the effects
observed in the oxygen counterparts of 9.5 kcal/mol
determined earlier.19e Overall, these studies strongly support
significantly enhanced conformational buttressing effects upon
O to S substitution.
In summary, amide bond architecture represents one of the
most vital motifs in organic chemistry and biology. Although
typical acyclic amides exist in the trans conformation, N-
methylanilides undergo a conformation switch to the cis
geometry, an effect that has been engaged as a conformational
anchor in many systems across chemical disciplines.8−11 The
present study demonstrates and quantifies that the amide to
C
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thioamide replacement in these systems results in a higher
preference for cis conformation in a unique compacted
template intrinsic to the thioamide structure. The effect of
sterics, substitution, resonance effects, barriers to rotation, and
proton affinities have been discussed and quantified. The
attractive properties of thioamides, including photoisomeriza-
tion, should facilitate the widespread use of N-methylthioani-
lides as cis-conformational locks in various facets of chemistry.
Future studies will focus on further determination of
conformational preferences of amides and thioamides by
spectroscopic and computational methods.
https://pubs.acs.org/10.1021/acs.orglett.0c03512
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.Z. thanks the CSC (No. 201808610096). Support was
provided by the Foundation for Young Scholars of SUST (No.
BJ12-26). M.S. thanks Rutgers University and the NSF (CHE-
1650766). We thank the Wroclaw Center for Networking and
Supercomputing (Grant No. WCSS159, R.S.).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03512.
■
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AUTHOR INFORMATION
Corresponding Authors
■
Jin Zhang − College of Chemistry and Chemical Engineering,
Key Laboratory of Chemical Additives for China National
Light Industry, Shaanxi University of Science and
Technology, Xi’an 710021, China; orcid.org/0000-0002-
6616-7087; Email: zhangjin@sust.edu.cn
Michal Szostak − Department of Chemistry, Rutgers
University, Newark, New Jersey 07102, United States;
orcid.org/0000-0002-9650-9690;
Email: michal.szostak@rutgers.edu
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Authors
Zhulin Liu − College of Chemistry and Chemical Engineering,
Key Laboratory of Chemical Additives for China National
Light Industry, Shaanxi University of Science and
Technology, Xi’an 710021, China
Zheng Yin − College of Chemistry and Chemical Engineering,
Key Laboratory of Chemical Additives for China National
Light Industry, Shaanxi University of Science and
Technology, Xi’an 710021, China
Xiufang Yang − College of Chemistry and Chemical
Engineering, Key Laboratory of Chemical Additives for China
National Light Industry, Shaanxi University of Science and
Technology, Xi’an 710021, China
Yangmin Ma − College of Chemistry and Chemical
Engineering, Key Laboratory of Chemical Additives for China
National Light Industry, Shaanxi University of Science and
Technology, Xi’an 710021, China
Roman Szostak − Department of Chemistry, Wroclaw
University, Wroclaw 50-383, Poland
Complete contact information is available at:
D
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