Chalcogen Bonding “2S–2N Squares” versus Competing Interactions: Exploring the Recognition Properties of Sulfur

Article abstract of DOI:10.1002/chem.201804261

Chalcogen bonding (CB) is the focus of increased attention for its applications in medicinal chemistry, materials science, and crystal engineering. However, the origin of sulfur's recognition properties remains controversial, and experimental evidence for supporting theories is still emerging. Here, a comprehensive evaluation of sulfur CB interactions is presented by investigating 2,1,3-benzothiadiazole X-ray crystallographic structures gathered from the Cambridge Structure Database (CSD), Protein Data Bank (PDB), and own laboratory findings. Through the systematic analysis of substituent effects on a subset library of over thirty benzothiadiazole derivatives, the competing interactions have been categorized into four main classes, namely 2S–2N CB square, halogen bonding (XB), S???S, and hydrogen-bonding (HB). A geometric model is employed to characterize the 2S–2N CB square motifs and discuss the role of electrostatic, dipole, and orbital contributions toward the interaction.

Full text of DOI:10.1002/chem.201804261

DOI: 10.1002/chem.201804261
Full Paper
&
Chalcogen Bonding
Chalcogen Bonding “2S–2N Squares” versus Competing
Interactions: Exploring the Recognition Properties of Sulfur
[a]
[b]
[b]
[b]
[b]
Mark R. Ams,* Nils Trapp, Anatol Schwab, Jovana V. Mili c´ , and FranÅois Diederich*
Abstract: Chalcogen bonding (CB) is the focus of increased
attention for its applications in medicinal chemistry, materi-
als science, and crystal engineering. However, the origin of
sulfur’s recognition properties remains controversial, and ex-
perimental evidence for supporting theories is still emerging.
Here, a comprehensive evaluation of sulfur CB interactions is
presented by investigating 2,1,3-benzothiadiazole X-ray crys-
tallographic structures gathered from the Cambridge Struc-
ture Database (CSD), Protein Data Bank (PDB), and own labo-
ratory findings. Through the systematic analysis of substitu-
ent effects on a subset library of over thirty benzothiadiazole
derivatives, the competing interactions have been catego-
rized into four main classes, namely 2S–2N CB square, halo-
gen bonding (XB), S···S, and hydrogen-bonding (HB). A geo-
metric model is employed to characterize the 2S–2N CB
square motifs and discuss the role of electrostatic, dipole,
and orbital contributions toward the interaction.
Introduction
intermolecular organosulfur interactions with Lewis-basic
atoms remain elusive, and intramolecular association constants
[39]
Chalcogen bonding (CB), categorized as the interaction be-
have only been reported in 2017. Earlier progress was made
by the Taylor group, which obtained intermolecular binding
constants for 2,1,3-benzotelluradiazole complexes with anionic
[
1–12]
tween Group VI elements (O, S, Se, Te, Po)
and a Lewis-
has received significant attention in
the past decade, largely in response to the advances made in
[
13–19]
basic partner atom,
and neutral Lewis bases (quinuclidine) in organic solvents
[
20–27]
[28–30]
[40,41]
understanding halogen bonding (XB).
Seminal work
using UV/Vis and NMR spectroscopies.
Their results were
led to the realization that polarizable halogens can be tuned
to exploit the electron-poor regions of their surfaces, now de-
rationalized on the basis of N-nucleophile!Te s-hole attrac-
tion, which was not strong enough to produce measurable
benzoselena- and thiadiazole binding constants.
[
31–34]
fined as s-holes,
for efficient intermolecular interactions
with Lewis-basic atoms. Unlike XB, the deliberate application
of CB is still emerging. This is especially true for sulfur, which
The solution-phase challenges of unlocking the underpin-
nings of organosulfur recognition can be compensated, at
least in part, by closely analyzing interactions in the solid state,
3
retains a large degree of atomic dipole polarizability (2.90 ꢀ )
3
[20,42]
compared to oxygen (0.80 mꢀ ), but less than the heavier sele-
as had been done in the early days of halogen bonding.
3
[35]
nium or tellurium atoms (3.77 and 3.9 ꢀ ).
Dunitz, Parthasarathy, and co-workers reported the first X-ray
crystallographic investigations on the intermolecular interac-
tions of divalent sulfur and observed distinct directionality at
close proximity, as expected for intermolecular CB interac-
Recent reports have highlighted the importance of sulfur’s
role in recognition and the major aspects that still remain to
be explored. The comprehensive Review by Meanwell and co-
workers reports the wide diversity of sulfur recognition in bio-
logical systems and in protein–ligand interactions for medicinal
[43,44]
tions.
Yet, large gaps still remain in the understanding of
how the electronic environments of the interacting groups in-
fluence these interactions. For instance, it is now recognized
that factors such as the hybridization state of sulfur can alter
[
36]
chemistry applications. CB has been applied to anion trans-
[
37]
[38]
port and organocatalysis for the first time by Matile and
co-workers. Yet, solution-phase binding constants for individual
[12,15–17,19,37,38,45,46]
its interactions.
,2,5-Thiadiazoles present interesting systems,
[47,48]
1
although
the nature of their S···N interactions and the involved structural
[
a] Prof. Dr. M. R. Ams
Department of Chemistry, Allegheny College
Meadville, PA 16335 (USA)
boundaries remain largely unexplored. Most knowledge has
[49]
been derived from computational analysis.
Early density
E-mail: mams@allegheny.edu
functional theory (DFT) studies concluded that close-range
S···N orbital–orbital interactions (i.e., charge transfer) were pri-
marily responsible for the interactions between 2,1,3-thiadia-
[
b] Dr. N. Trapp, Dr. A. Schwab, Dr. J. V. Mili c´ , Prof. Dr. F. Diederich
Laboratory of Organic Chemistry, ETH Zꢀrich
Hçnggerberg, HCI, 8093 Zꢀrich (Switzerland)
E-mail: diederich@org.chem.ethz.ch
[50]
zoles. More recently, ab initio coupled-cluster single-double
and perturbative triple (CCSD(T)) calculations, which account
for dispersion, revealed that S···N orbital–orbital interactions
are repulsive and that the longer-range dispersion interaction
Supporting Information and ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/chem.201804261.
Chem. Eur. J. 2018, 24, 1 – 12
1
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[
51]
is most influential.
The primary driving force switches to
teractions and impose other intermolecular contacts, different
from the 2S–2N square interactions.
electrostatics (i.e., s-hole interactions) for the more polarizable
Se and Te diazoles. The energy gain for 2S–2N thiadiazole
ꢀ
1
squares is calculated to be ꢀ3.14 kcalmol , as compared to
ꢀ
1
ꢀ1
Results and Discussion
Se (ꢀ5.29 kcalmol ) and Te (ꢀ12.42 kcalmol ) dimers. Finally,
the influence of molecular dipoles for these systems has not
been reported.
To geometrically define the alignment of two thiadiazole
edges, we constructed a practical description for the 2S–2N
square contact shown in Figure 3. This contact involves three
critical angles q, f, and F, representing the three dimensions
of available freedom when the thiadiazole edges converge and
pair the sulfur with nitrogen through CB.
[
52]
Herein we investigate 2,1,3-benzothiadiazoles
for the
nature of their sulfur interactions, the factors controlling CB
geometry, and how these forces compete with other crystal
[
53]
packing forces.
2,1,3-Benzothiadiazole (1b; Figure 1a) and
its derivatives serve as an effective test-case because of their
[
54–56]
affinity for crystallization, relevance to medicinal chemistry
[
57–68]
and materials science.
Furthermore, many structural deriv-
[
69,70]
atives are capable of forming 2S–2N square dimeric
or
polymeric interactions within their crystalline lattices (Fig-
ures 1b,c), and the scaffold allows for the systematic substitu-
tion of positions 4–7 on the benzo ring.
Figure 3. Geometric parameters of the 2S–2N square interaction. Parameter
q is the N-S···N angle, f is the S-N···S-N torsion angle, and F is the diazole
plane C-N-*a-*b torsion angle. The point *a is the center of the NꢀS bond,
and point *b is the midpoint between point *a of one thiadiazole and point
*
of a second thiadiazole.
a
Figure 1. a) Top view of the 2,1,3-benzothiadiazole core structure and loca-
tion of lone pair electrons: N in plane, S out of plane. b) Top view showing
the in-plane position of the nitrogen lone pairs, sulfur s-holes and s* orbi-
tals. c) Square dimer interaction.
[73]
We applied the ConQuest module (v. 1.19) to the CSD (v
.38) to determine the abundance of 2,1,3-benzothiadiazole
5
square contacts by constraining the maximum and minimum
allowable CB distance to be 2.50ꢁCBꢁ4.00 ꢀ and an R factor
of ꢁ0.1. Each CSD structure hit was analyzed further using
[74]
We present an analysis of 2,1,3-benzothiadiazoles 2a–9h
Mercury software to determine (q, f, and F), and then ren-
[75]
from our synthetic work and from the Cambridge Structure Da-
dered using PyMOL software to isolate the interactions of in-
terest.
[
71,72]
tabase (CSD)
(Figure 2). They contain a diversity of small,
non-aromatic substituents, some of which can act as H-bond
donor/acceptors. These substituents may attenuate sulfur in-
The CSD search revealed 197 structurally diverse organic
and organometallic 2,1,3-benzothiadiazoles, 58 of which have
contact distances ꢁ4.0 ꢀ (Table S2 and Figure S10 in the Sup-
porting Information). Within this subgroup, 20 contain two or
more potential 2S–2N square interactions within their lattices,
which raises the total number of such squares to 84. The con-
tact S···N distance, which we define as the calculated CB aver-
age distance (CB ) between the monomers, spanned from
ave
[76]
[77]
2.89 ꢀ
to 3.95 ꢀ
with the mean being 3.42 ꢀ (see Fig-
ure S10 for structures).
An analysis of the correlation between CBave distance and
the associated angles q, f, and F for each structure shows
that those with close contacts (CB ꢁ van der Waals radii sum
ave
[78]
N+S=3.35 ꢀ)
have angular ranges of q =67.7–89.78
ave
(
mean 74.08), fave =0–36.38 (mean 1.78) and Fave =149.6–
79.58 (mean 171.68). Every structure in this category contains
1
a highly aligned square planar interaction, with angles ap-
proaching fꢂ08, qꢂ908, and Fꢂ1808. The shortest
[76]
[79]
[77]
(
2.89 ꢀ), middle (3.39 ꢀ) and longest (3.95 ꢀ) CBave dis-
tances, respectively, illustrate the marked diversity in 2S–2N
square 2,1,3-benzothiadiazole dimer structures that fall within
the 2.89–4.0 ꢀ CBave range (Figure S10). The strikingly high
Figure 2. 2,1,3-Benzothiadiazole structures investigated in the present study.
&
&
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
2
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
prevalence of diverse structures (39) containing both sub-van
der Waals S···N contacts and highly aligned square planar inter-
actions suggests that the square attraction out-competes the
myriad of other substituent interactions during packing.
The 2S–2N Square Class Assembled by Chalcogen Bonding
Of the four unsubstituted 2,1,3-benzochalcogenadiazoles (O, S,
[81–83]
Se and Te) 1a–1d, only the X-ray structure of tellurium 1d
contains highly aligned, sub-van der Waals 2Te–2N square in-
teractions (CBave =2.70 ꢀ, qave =69.18, f =2.48, Fave =178.78)
ave
[
84–86]
[87,88]
(Figure S8). Conversely, the sulfur 1b
and selenium 1c
Figure 5. Crystal structures of 5a–5b, featuring complementary interactions
with squares. Atom coloring: C green, N blue, S yellow, F cyan.
isostructures have significantly out-of-plane, distorted squares
that are nearly identical (S; Se, respectively: CBave =3.40 ꢀ;
3
.41 ꢀ, qave =76.48; 76.68, fave =20.08; 23.48, Fave =145.58;
44.48). Cozzolino et al. attributed the robust Te···N nonbond-
1
5b (Figure 5), each having 5,6-substitution, form squares
nearly identical to the dimers having asymmetric 4- or 5-substi-
tution in 2a and 4a (Figure 6).
ing interactions as outcompeting the steric demands of its
benzo- tail, while the cost remains too high for the sulfur and
[
50]
[85]
selenium derivatives.
The oxygen derivative 1a
has no
In 5a and 5b, there are also tail-tail interactions that allow
for apolar Me···Me or Teflon-like F···F ribbons to form
(Figure 5). In 5b, the squares are further stabilized by close
square interactions and aligns in head–tail columns.
Small, non-aromatic substituent additions to the benzo tail
of 1b results in significant changes to the square geometry.
Unexpectedly, 74% (23 structures) of the sulfur derivatives 1b-
[89]
F···H contacts (not shown) similar to those reported for di-
[90]
thieno-2,1,3-benzothiadiazoles.
9
h contain S···N contacts <4.0 ꢀ and have at least one square
Twelve of the fourteen asymmetric monomers align to
orient their largest substituent anti- relative to each other, re-
gardless of the substituent being electron withdrawing or do-
interaction (Figure 4). Furthermore, the most highly aligned
squares (17 structures with ranges qave =68.1–78.68, fave =0–
[91]
[92]
[92]
23.48, Fave =162.8–179.18), representing 81% of the subset,
nating (Figure 6). For instance, in 2d and 2e the 4-NH2
contain sub-van der Waals S···N contacts. This is in agreement
with the CSD population shown in Figure S9, where a strong
correlation between sub-van der Waals contacts and square
alignment exists, but the high degree of alignment does not
discriminate between substituent types.
and 4-NO groups differ dramatically in their electronic proper-
2
ties but 2d and 2e contain nearly identical squares (2d; 2e,
respectively: CBave =3.12 ꢀ; 3.09 ꢀ, qave =72.78; 74.98, fave
0.08; 0.08, Fave =177.08; 177.28).
=
The electronic characteristics of -CH versus -NO also differ
3
2
[
51]
[93]
While the calculations by Tsuzuki et al.
show that S···N
profoundly, yet the dimers of 4a and 4e are nearly equiva-
lent as well (4a; 4e, respectively: CBave =3.09 ꢀ; 3.14 ꢀ, qave
thiazole contacts stabilize the squares, the diversity of substitu-
ents (in Figure S9) indicates that they have a role in stabilizing
dimerization in other ways besides tuning sulfur’s polarization,
such as through substituent···substituent or substituent···ben-
zothiadiazole tail interactions. The substituent position on the
benzo- tail is not relevant in this regard. For instance, 5a and
=
78.68; 71.78, fave =0.08; 0.08, Fave =177.68; 173.38). The only
two asymmetric structures that display dimerization with their
[94]
substituents in syn-orientation are 2c and 8 (Figure 7). These
represent rare examples of benzothiadiazole square-ribbon
[95]
complexes that have repeating square interactions on both
[
80]
Figure 4. Compounds 1–9 having CBave ꢁ4.0 ꢀ (blue values), plotted in the order of increasing sulfur s-hole electrostatic potential. For compounds having
more than one 2S–2N square interaction, only the shortest CBave contact is plotted. Striped bars represent dimers having CBave ꢁ3.35 ꢀ. The SꢀN covalent
bond length of each monomer is presented in red (ꢀ).
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
3
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
teractions, we further organized the square class according to
the increasing molecular electrostatic potential (MESP) of the
sulfur atom. Every sulfur in the set contains some degree of
+
electropositive (d ) potential, known as the s-hole region, lo-
cated in the extension of the NꢀS bonds (Figures 1b and 4). In
[98]
the case of 2,1,3-thiadiazole, which contains divalent sulfur,
two s-holes are generated that result in two angular distribu-
tions with respect to the N-S-N bonds (N-S-s-hole angles 60–
[99,100]
908 and 150–1808, Figure 1b).
The sulfur atoms in the 5-
nitro derivative 4e and 5,6-dimethyl derivative 5a contain
among the largest and smallest s-holes, respectively. These
two extremes nevertheless have virtually identically aligned
dimers (4e; 5a, respectively: CBave =3.14 ꢀ; 3.05 ꢀ, qave =71.78;
75.28, fave =0.08; 0.08, Fave =173.38; 179.18).
While sulfur s-holes do pervade the 2S–2N square class, we
acknowledge that the extent of their influence on square inter-
+
actions would likely be limited to cases when the d charge is
very large. If they are the primary cause of dimerizations
throughout the class, the preservation of highly aligned
squares and contact distances for compounds like 5a, where
the sulfur s-hole is significantly diminished in both size and
magnitude, would not be observed (Figure S5). This is in
agreement with the recent comprehensive CSD X-ray investi-
gation of C=S···S=C interactions, where no meaningful correla-
tion could be found between sulfur s-hole magnitude and
[101]
S···S contact distance, binding energy, or trajectory angle.
[
92]
Figure 6. anti-Square orientation and crystal structures of 2a, 2d, 2e, and
a. Atom coloring: C green, N blue, O red, S yellow, Br brown.
Rather, attractive binding energies and close contacts were cal-
4
ꢀ
culated to exist even for two d charged S···S atoms in the
dimers (H CS) and [(OH) CS] . Furthermore, stabilizing contri-
2
2
2
2
butions from n!s* orbital–orbital or electrostatic interactions
of the N···S contacts could be evidenced by the lengthening
[39,102]
of the accepting SꢀN bond.
bond length of each structure does not follow this trend
Figure 4, ꢀ in red). For instance, the unsubstituted 1b
However, the accepting SꢀN
(
has poor alignment (CBave =3.40 ꢀ; qave =76.48; fave =20.08;
Fave =145.58), yet its SꢀN bond length of 1.62 ꢀ matches
that of highly aligned squares such as 4a (1.62 ꢀ) and 2c
(
1.62 ꢀ).
In addition to the interatomic electrostatic considerations
between thiadiazoles, the influence of multipole expansion of
the electrostatics within each thiadiazole structure may cause
favorable dipole–dipole alignments to play a role in forming
the 2S–2N square geometries. We estimated the dipole and
quadrupole moments of compounds 2a–9h by performing
DFT calculations at the B97D3/aug-cc-pvtz level of theory (Sup-
[103]
porting Information).
For most monomers, the dipole vector
lies within the flat plane of the benzothiadiazole scaffold. Ar-
ranging the class in accordance with the (+) and (ꢀ) poles of
each monomer‘s vector (Figure S7) reveals that, for most mon-
omers, the vector pole is unfavorably positioned toward its
Figure 7. syn-Square orientation and crystal structures of 2c and 8. Atom
coloring: C green, N blue, O red, S yellow, F cyan.
[104]
contact partner.
For instance, the top seven structures con-
taining the strongest dipole moments (m>3.0 D) position their
monomer vector poles in (+,+) or (ꢀ,ꢀ) orientations. Most
notable is compound 2e, which has among the strongest
dipole moment in the series (4.53 D), yet positions its vector
unfavorably with its contact partner to achieve highly aligned
square interactions.
thiazole edges, and may be useful for supramolecular wiring
[
50,96,97]
applications.
To determine the role these small substituents play in sul-
fur’s electronic environment and the resulting 2S–2N square in-
&
&
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
4
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
[
108]
Favorable quadrupole interactions would not result in
square contacts and would instead reveal themselves as T-
shaped dipole-quadrupole configurations between part-
tion of a 5-fluoro atom (3a)
causes the I···N distance to
shorten further to 3.11 ꢀ, far below the van der Waals radii
sum of 3.53 ꢀ. The square interactions are suppressed, and a
complementary CB-type F···S contact exists at 2.97 ꢀ with a N-
S···F angle of 164.88 (F+S sum of van der Waals radii: 3.27 ꢀ).
5,6-Halogenation: While the parent scaffold 1b shows poorly
aligned 2S–2N squares that become highly aligned in the 5,6-
difluoro derivative 5b (Figure 5), the squares cannot compete
with heavier halogens in this position. For 5c–5e, square CB
interactions are replaced by XB interactions, as shown in
Figure 9. Replacing just one fluorine in 5b with bromine (5e)
[
105,106]
ners.
A significant contribution of the quadrupole
moment is only expected in the case of small dipole moments,
which otherwise would be dominant. The calculated molecular
[
103]
quadrupole moment Qzz values
were used to interpret
stacking interactions, while the dipole values are provided in
Figure S7.
The Halogenated Class: Halogen Bonding Outcompetes
Chalcogen Bonding in the Assembly of 2,1,3-Thiadiazoles
Bearing Multiple Higher Halogens
For the halogenated compounds in Figure 2, a wide variety of
XB contacts appear to out-compete the square class, since the
thiadiazole moiety itself contains exposed nitrogen and sulfur
lone pair electrons that provide convenient acceptor points to
[
107]
halogens.
Additionally, the nonbonded electrons of halo-
gens also serve as convenient acceptors to halogen or sulfur
donors. We have summarized the XB contacts that are struc-
ture-determining into four categories, as follows.
4
-Halogenation: A halogen in the 4-position serves as a natu-
ral handle for X···N intermolecular contacts and attenuates 2S–
N square alignments. For instance, brominated 2a has closer
2
and higher-ordered 2S–2N squares (CBave =3.19 ꢀ, qave =75.58,
fave =0.08, Fave =163.18) compared to 1b, and contains a long-
range Br···N donor–acceptor contact at 4.0 ꢀ and angles of
149.5/156.08 (Figure 8). The I···N contact in 2b is closer (3.29 ꢀ)
and now has an in-plane, near ideal XB at an angle of interac-
tion at 177.88 that appears to weaken its neighboring square
dimer interactions in the lattice (CBave =3.78 ꢀ, qave =99.58,
fave =0.08, Fave =139.08). Polarizing the iodine with the addi-
Figure 9. Crystal structures of 5c–5e with XB interactions that attenuate CB.
Atom coloring: C green, N blue, S yellow, Br brown, Cl magenta, F cyan.
results in repeating close XB-type F···Br contacts that are at or
slightly below the sum of the van der Waals radii (3.32 ꢀ) and
at angles of 150.78 147.78 respectively. Brominating both 5,6-
positions (5d) results in a triangular N···Br···S XB/CB-type con-
tact (N···Br: 3.10 ꢀ, angles 154.98 and 161.58; Br···S: 3.71 ꢀ,
angle 156.48) near or slightly below the sums of the van der
Waals radii (3.40 ꢀ (N+Br) and 3.65 ꢀ (Br+S)). These are addi-
tionally stabilized by weak XB-type Br···Br contacts (3.91 ꢀ) be-
tween the monomer tails at a favorable angle of 162.98. The
tail–tail contacts are maintained in the dichloro-derivative 5c,
where the Cl···Cl distance is 3.57 ꢀ (sum of van der Waals radii
for (Cl+Cl): 3.50 ꢀ). Interestingly, the monomers further ar-
range to position the sulfur between the two chlorines of the
next monomer’s tail at 3.63/3.67 ꢀ. Sulfur can similarly interact
between two oxygen atoms at close range (3.15 ꢀ), as ob-
Figure 8. Crystal structures of 2a–2b and 3a featuring co-existing and com-
peting XB and CB interactions. Atom coloring: C green, N blue, S yellow, Br
brown, F cyan, I purple.
[109]
served in 9a (Figure S12).
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
5
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
4,7-Halogenation: Prominent XB-type X···X networks, with
and 3.96 ꢀ for (I+I). We note that the addition of polarizing
Br···Br distances below the sum of the van der Waals radii and
C-Br···Br angles between 1638 and 1728 are observed when the
nitro groups tightens the XB interactions even further, as ob-
[113]
served in 9g,
which now includes near linear Br···Br/N con-
4
,7-positions are substituted by the heavier halogens bromine
tacts at 3.47 and 3.06 ꢀ, respectively. A new O···S donor–ac-
ceptor contact at 3.21 ꢀ also emerges, which is below the sum
of the van der Waal radii of (O+S)=3.32 ꢀ.
[
110]
[111]
or iodine, as seen for 6a,
6b,
and 9 f-h (Figure 10). In
contrast the 2S–2N squares completely vanish. It becomes
clear that the doubly CB-bridged squares cannot compete with
two strong XB interactions. Past reports have noted the X···X
networks without highlighting their recognition signifi-
Fluorination: Distinct from the derivatives bearing higher halo-
gen substituents, highly aligned squares are abundant for
[109]
most of the fluoro-benzothiadiazoles (5b, 7, 8, 9b–9e).
These interactions coexist with the congregation of tightly-
[
110–113]
cance.
[114]
In each crystal shown in Figure 10, there are at least two
Br···Br or I···I contacts for each monomer that are at or below
the respective van der Waals radii sum of 3.70 ꢀ for (Br+Br)
packed F···F bands,
as described for 5b above (Figure 5),
which are often at sub-van der Waals distance (Table S5). Struc-
ture 4c is the exception, which has a 5-trifluoromethyl group
instead of benzo-fluorination, and undergoes head-tail mono-
[115]
mer orientation to gain F···F (ꢃ3.09 ꢀ), N···H (3.44 ꢀ),
F···S (3.15 ꢀ) contacts (Figure S11).
and
The S···S Interaction Class: Secondary Interactions Having
Biological Significance
The S···S interaction is rare in 1–9, but notable exceptions do
appear in the X-ray structures of 5a (Figure 5) and 3b, 4d, 5d,
and 6c (Figure 11). We classify this subset as the S···S class to
make note of the observed contact distances, near the (S+S)
sum of the van der Waals radii, of 3.60 ꢀ (3b (3.71 ꢀ), 4d
(
3.83 ꢀ), 5a (3.48 ꢀ), 5d (3.62 ꢀ), and 6c (3.48 ꢀ)). Dispersion is
presumed to be the major attractive force in these con-
[5,51,116]
tacts,
which is reflected in the varying interaction geo-
metries. Nevertheless, the case of 4d illustrates a nice example,
where one sulfur accepts a chalcogen bond from a second
thiadiazole moiety.
While the S···S contacts in Figure 11 appear attractive, they
are not expected to control their lattice interactions. For in-
stance, the CCSD(T) calculated Einteraction for the electron-rich sul-
ꢀ
1
furs in the SMe ···SMe dimer is ꢀ2.79 kcalmol , and increases
2
2
ꢀ
1
[5,6]
to ꢀ3.85 kcalmol for the heterodimer pair SMe ···MeSCN.
2
These strengths are weaker than the competing hydrogen
Figure 10. Crystal structures of 6a–6b and 9 f–9h. Atom coloring: C green,
Figure 11. S···S motif in the crystal structures of 3b, 4d, 5d and 6c. Atom
N blue, S yellow, O red, Br brown, I purple.
coloring: C green, N blue, S yellow, Br brown.
&
&
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
6
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
[
86]
bonding observed in the X-ray structures of 3b, 4d, and 6c,
the square interaction in 5a (ꢂꢀ3.14 kcalmol
mine XB contacts in 5d.
ꢀ
1[51]
), or the bro-
There are currently no published studies that use X-ray anal-
ysis to systematically evaluate substituent effects on divalent
[
92,98,101,117]
S···S contacts in small molecules.
Yet such effects are
becoming increasingly relevant in the recognition of sub-
strates, pharmaceuticals, and agrochemicals by protein recep-
[
118]
[43,119]
tors. The sulfur atoms of methionine
and cysteine
are
[120,121]
strongly involved in protein conformation and stability,
and Met frequently act as gatekeepers in kinases, controlling
ATP binding. Boeckler et al. recently published the X-ray struc-
ture showing the “gatekeeper” residue Met146 in the c-Jun N-
terminal kinase 3 (JNK3) interacting by CB with the neighbor-
ing sulfur of Met115 and by XB with an iodinated inhibitor
[
122]
(Figure 12a).
For comparison, we superimposed the X-ray
structures of 3b and 5a onto JNK3 and observed them to pos-
sess strong similarities to the I-SMET146-SMET115 contacts (Fig-
ure 12b–12c).
A similar chalcogen bonding interaction is also observed for
the 3-hydroxy-1,2,5-thiadiazoles present within the protein co-
[
123]
crystal structures with of PDB IDs 3BFT and 3BFU,
align the thiadiazole and methionine sulfur atoms at 3.91 ꢀ
angle S···S-N 159.18) and 3.53 ꢀ (angle S···S-N 142.28), respec-
which
(
tively (Figure 12d–12e).
The HB Interaction Class: Competition between 2S–2N
Square Interactions and Hydrogen Bonding
The extent to which the benzothiadiazole 2S–2N square inter-
actions may compete with HB has not been addressed. We
identified several examples within the CSD, as well as through
our synthetic contributions, that provide insight toward the in-
fluence of hydrogen bonding in this context.
Figure 12. Co-crystal structure of JNK3 bound to an iodinated ligand (PDB
[
122]
ID: 2P33) (a),
c). The protein co-crystal structure of a 3-hydroxy-1,2,5-thiadiazole ligand as
CB donor interacting with a Met S-atom as acceptor (PDB IDs 3BFT (d) and
overlaid with the crystal structures of dimer 3b (b) and 5a
(
The selected series of amine derivatives in Scheme 1 demon-
strates that highly aligned squares can in fact coexist while hy-
drogen bonding occurs directly on the thiadiazole (TDA) unit.
[123]
3BFU (e)).
Atom coloring: C green (amino acids, ligands) or cyan and ma-
genta (overlay), N blue, S yellow, O red, I purple.
Within the 2d monomer, the 4-NH group intramolecularly H-
2
[
124]
bonds to one NTDA while the remaining NTDA engages in close,
highly aligned 2S–2N squares with a second 2d partner. Re-
placing the 4-NH2 with 4-NH-pyridyl (CSD reference code
FEBYES, Scheme 1)
disrupts the square 2d·2d dimer in
favor of new intermolecular NTDA···NH networks and close
NTDA···S-N CB contacts at 3.10 ꢀ (angle N···S-N 169.68). Adding
[
124]
[124]
Scheme 1. Crystal structures 2d, FEBYES
and FEBYAO
highlighting the co-existence of HB and CB interactions. The red arrows indicate the position of
the substituent changes. Atom coloring: C green, N blue, S yellow, Br brown.
Chem. Eur. J. 2018, 24, 1 – 12 www.chemeurj.org
7
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[
126]
Scheme 2. Crystal structures of 10 and REVYAT
highlighting the propensity for co-existence of HB and CB interactions revealed after deprotection. Atom
coloring: C green, N blue, O red, S yellow.
[
124]
bromine to the 7-position (FEBYAO,
Scheme 1), or fluorine
(Figure S12), evidently prevents the inter-
molecular NTDA···NH networks and permits highly aligned
squares to compete again (CBave =2.99 ꢀ, qave =74.28, fave
.08, Fave =179.08).
To determine whether the NTDA atom participating directly in
a square interaction can concurrently H-bond to neighbors, we
ii) In the halogenated compound class, new X···X/S/N motifs
are abundant; they vary greatly depending on the halide
position on the benzo ring and the nature of X. While
squares coexist alongside 4-X interactions (2a), halogen-
bonding type X···S/N motifs dominate for 5,6-halogenated
systems (5c–5e), followed by X···X contacts for 4,7-halo-
genation (6a–6b, 9 f, 9h). Good evidence is obtained to
propose that halogen bonding interactions outcompete
the chalcogen-bonding interactions in the 2S–2N squares.
Fluorinated structures are exceptional as this hard halo-
gen does not engage in halogen-bonding interactions.
Here, close F···F contacts in unison with highly aligned
squares (5b, 7, 8, 9b–9e) dominate.
iii) In the S···S interaction class, a diversity of geometric align-
ments is observed, in agreement with the theoretically
predicted predominance of dispersion interactions in
these contacts. Five compounds (3b, 4d, 5a, 5d, 6c) con-
tain sub-van der Waals S···S, with the alignment of the S-
atoms in the structures of 3b and 5a mimicking chalco-
gen-bonding type Met···Met interactions seen in kinases
and in Metprotein-1,2,5-thiazole complexes.
[
109]
in the case of 9e
=
0
[
125]
synthesized the BOC-protected 4,7-pyrole 10
its crystal structure to the free amine REVYAT
and compared
[
126]
(Scheme 2).
Both contain highly aligned squares (10; REVYAT respectively:
CBave =3.65; 3.31 ꢀ, qave =118.08; 80.38, fave =0.08; 0.08, Fave
65.18; 176.08), but REVYAT forms closer, sub-van der Waals CB
contacts (3.65 ꢀ vs. 3.31 ꢀ) while the NTDA simultaneously H-
bonds to the flanking pyrrole (Scheme 2). This unexpected ob-
servation, which demonstrates that aligned squares can form
even without the full electron donation of the participating
NTDA, lends additional support against orbital or electrostatical-
ly driven explanations for 2S–2N square interactions.
=
1
Conclusion
A detailed crystal structure investigation of the interactions of
(iv) With NH hydrogen-bond donor substituents on the ben-
zothiadiazole, structural analysis revealed that highly
aligned 2S–2N square interactions can complete with
NH···N attractions (2d, FEBYAO, REVYAT, 9e), and even
occur simultaneously on the same NTDA (REVYAT).
2,1,3-benzothiadiazoles was performed to understand the
nature of figurative 2S–2N square interactions and the inter-/
intramolecular forces that compete with it. Our CSD study re-
vealed 2S–2N square interactions in benzothiadiazole dimers
with sub-van der Waals N···S distances for a wide array of de-
rivatives. A model for the square geometry was created to
characterize the angle variability of the dimer trajectory, show-
ing a strong correlation between sub-van der Waals N···S dis-
tances and highly aligned square dimers (angles approaching
fꢂ08, qꢂ908, and Fꢂ1808).
Though 2S–2N square dimers are the most abundant interac-
tion motif, competing forces can disrupt or coexist with them.
Though the complementary N···S dimer contacts are accepted
[51]
as being weakly attractive, we found no correlation between
purely electrostatic N···S contributions and contact distance or
orientation angle. Structural evidence of N···S orbital delocali-
zation effects (n!s*) are also not clearly observed. Sub-van
der Waals, highly aligned squares can form even when the
donor NTDA is occupied by hydrogen-bonding. Finally, no corre-
lation is observed between favorably-aligned molecular dipoles
and squares.
To investigate substituent effects, library 1b–9h containing
31 2,1,3-benzothiadiazole compounds with small, non-aromatic
substituents was assembled and analyzed systematically. Four
general interaction types were determined and are summar-
ized as follows (see also Figure S13 for a visual summary):
i)
In the 2S–2N square dimer class, 71% compounds of 1b–
h have N···S contacts <4.0 ꢀ, with 18 dimers considered
We express caution when attempting to generalize a singu-
lar, dominating attractive force for all sulfur interactions. In the
absence of a high-level energy decomposition analysis of 1–9,
9
as CBave ꢁ3.35 ꢀ and q =68.1–78.68, fave =0.0–23.48,
ave
[51]
Fave =162.8–179.18.
the chalcogenadiazole ab initio work by Tsuzuki et al. pro-
&
&
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
8
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
vides useful insights. In that study, the largest contribution
energy for dimerization varies, depending on the chalcogen,
being predominantly electrostatics for Te and Se, whereas dis-
persion for S. In all cases, the orbital-orbital contributions are
repulsive. We anticipate a similar gradient of attractive contri-
butions (E , E , E , etc.) in 1–9, depending on how substitu-
Conflict of interest
The authors declare no conflict of interest.
Keywords: 2,1,3-benzothiadiazole · 2S–2N square · chalcogen
bonding · sulfur · X-ray crystallography
es
ind
dis
ents tune the local environment of sulfur.
Despite the complex energetic origin of the interaction, the
2
S–2N square dimer presents a well-defined non-covalent in-
[1] P. Sanz, M. YꢃÇez, O. Mꢄ, J. Phys. Chem. A 2002, 106, 4661–4668.
[
2] M. Iwaoka, S. Takemoto, S. Tomoda, J. Am. Chem. Soc. 2002, 124,
0613–10620.
3] D. B. Werz, R. Gleiter, F. Rominger, J. Am. Chem. Soc. 2002, 124, 10638–
0639.
[4] P. Sanz, M. YꢃÇez, O. Mꢄ, Chem. Eur. J. 2002, 8, 3999–4007.
teraction motif in the solid state. The studied set of com-
pounds shows the scope of the interaction and can act as a
design guideline for the use of the benzothiadiazole 2S–2N
square motif in supramolecular chemistry and crystal engineer-
ing.
1
[
1
[
5] C. Bleiholder, D. B. Werz, H. Kçppel, R. Gleiter, J. Am. Chem. Soc. 2006,
28, 2666–2674.
6] C. Bleiholder, R. Gleiter, D. B. Werz, H. Kçppel, Inorg. Chem. 2007, 46,
249–2260.
1
[
2
[
[
7] S. Hayashi, W. Nakanishi, Bull. Chem. Soc. Jpn. 2008, 81, 1605–1615.
8] W. Wang, B. Ji, Y. Zhang, J. Phys. Chem. A 2009, 113, 8132–8135.
Experimental Section
General information: The crystallographic data for library 1a–9h
and compound 10 were collected from various sources. Com-
pounds 9 f, 9h, and 10 are new compounds and their synthesis,
characterization and crystallographic data are provided in the Sup-
[9] G. Sꢃnchez-Sanz, I. Alkorta, J. Elguero, Mol. Phys. 2011, 109, 2543–
552.
10] G. Sꢃnchez-Sanz, C. Trujillo, I. Alkorta, J. Elguero, ChemPhysChem 2012,
3, 496–503.
11] E. Alikhani, F. Fuster, B. Madebene, S. J. Grabowski, Phys. Chem. Chem.
Phys. 2014, 16, 2430–2442.
2
[
[
[
1
[127]
[128]
[129]
[130]
porting Information. Compounds 2a,
2b,
2c,
3b,
5e, and 7
[
131]
[132]
[133]
[134]
[64]
[60]
[68]
[135]
4
a,
4b,
4c,
4d,
5a, 5b, 5c, 5d,
12] M. D. Esrafili, F. Mohammadian-Sabet, Int. J. Quantum Chem. 2016, 116,
were obtained commercially. These compounds were reported pre-
viously (except for 5e and 7), without crystallographic characteriza-
tion. The crystals were grown or used as received, and reported for
the first time in this report (see Supporting Information). Com-
5
29–536.
[13] U. Adhikari, S. Scheiner, Chem. Phys. Lett. 2011, 514, 36–39.
[14] L. M. Azofra, I. Alkorta, S. Scheiner, Theor. Chem. Acc. 2014, 133, 1586.
[15] U. Adhikari, S. Scheiner, J. Phys. Chem. A 2014, 118, 3183–3192.
16] X. Guo, X. An, Q. Li, J. Phys. Chem. A 2015, 119, 3518–3527.
[17] R. Shukla, D. Chopra, J. Phys. Chem. B 2015, 119, 14857–14870.
[85]
[86]
[88]
[
pounds 1a (BEOXAZ),
1b (BETHAZ01),
1c (BESEAZ),
1d
4e
8
[81]
[92]
[92]
[108]
(
(
(
(
DEBHEY), 2d (KODXEI), 2e (KODXOS), 3a (IKUYUK),
[93]
[110]
[111]
[86]
[18] M. D. Esrafili, F. Mohammadian-Sabet, Chem. Phys. Lett. 2015, 634,
GINTII), 6a (ESUYEW),
6b (MOPHOO),
9b (NABROA), 9c (NABRAM), 9d
6c (XOQBEK),
2
10–215.
[94]
[109]
[94]
[94]
ZUFKIW), 9a (NABRIU),
[
[
[
19] R. Shukla, D. J. Chopra, J. Chem. Sci. 2016, 128, 1589–1596.
20] P. Metrangolo, G. Resnati, Chem. Eur. J. 2001, 7, 2511–2519.
21] P. Auffinger, F. A. Hays, E. Westhof, P. Shing Ho, Proc. Natl. Acad. Sci.
USA 2004, 101, 16789–16794.
[22] L. A. Hardegger, B. Kuhn, B. Spinnler, L. Anselm, R. Ecabert, M. Stihle, B.
Gsell, R. Thoma, J. Diez, J. Benz, J.-M. Plancher, G. Hartmann, D. W.
Banner, W. Haap, F. Diederich, Angew. Chem. Int. Ed. 2011, 50, 314–
[94]
[94]
[113]
NABREQ), 9e (NABRUG), and 9g (JUYSON01)
are previously
reported compounds and their crystallographic data are available
free of charge from the Cambridge Crystallographic Data Centre
[136]
via www.ccdc.cam.ac.uk/structures.
Computational details: Calculations were performed using Gaussi-
an 09 on the Euler Cluster of ETH Zꢂrich using the dispersion cor-
3
18; Angew. Chem. 2011, 123, 329–334.
23] P. Politzer, K. E. Riley, F. A. Bulat, J. S. Murray, Comput. Theor. Chem.
012, 998, 2–8.
24] P. Politzer, J. S. Murray, ChemPhysChem 2013, 14, 278–294.
[103,137]
rected B97D3/aug-cc-pvtz method.
On iodine atoms, the
[
LANL2DZ basis set was used. Basis sets from Gaussian internal li-
brary were used. Molecules were positioned in the XY-coordinate
plane with the sulfur pointing in the +X direction. Optimized
structures were used for the calculation of dipole, or quadrupole
moments and for visualization. Further details are provided in the
Supporting Information.
2
[
[25] P. Politzer, J. S. Murray, T. Clark, Phys. Chem. Chem. Phys. 2013, 15,
11178–11189.
[26] R. Wilcken, M. O. Zimmermann, A. Lange, A. C. Joerger, F. M. Boeckler,
J. Med. Chem. 2013, 56, 1363–1388.
[
[
[
[
27] O. Dumele, D. Wu, N. Trapp, N. Goroff, F. Diederich, Org. Lett. 2014, 16,
4
722–4725.
28] T. Clark, M. Hennemann, J. S. Murray, P. Politzer, J. Mol. Model. 2007, 13,
291–296.
29] J. S. Murray, P. Lane, P. Politzer, Int. J. Quantum Chem. 2008, 108, 2770–
Acknowledgements
2
781.
30] P. Politzer, J. S. Murray, T. Clark, Phys. Chem. Chem. Phys. 2010, 12,
748–7757.
[31] J. S. Murray, M. C. Concha, P. Lane, P. Hobza, P. Politzer, J. Mol. Model.
008, 14, 699–704.
32] A. Mohajeri, A. H. Pakiari, N. Bagheri, Chem. Phys. Lett. 2009, 467, 393–
97.
This work was supported by a grant from the Swiss National
Science Foundation SNF 200020_159802. M.R.A. gratefully ac-
knowledges the opportunity and financial support from ETH
Zꢂrich as a guest professor in the laboratory of Prof. Dr. Fran-
Åois Diederich in 2016, and Allegheny College for financial sup-
port. The authors are grateful to Michael Solar (ETH Zurich) for
X-ray crystallographic analysis and Dr. Bruno Bernet for proof-
reading the Experimental Section of the manuscript. All listed
authors contributed to this investigation.
7
2
[
[
[
3
33] J. S. Murray, K. E. Riley, P. Politzer, T. Clark, Aust. J. Chem. 2010, 63,
1598–1607.
34] M. Kolꢃr, J. Hosta sˇ , P. Hobza, Phys. Chem. Chem. Phys. 2014, 16, 9987–
9
996.
[
[
35] T. M. Miller, B. Bederson, Adv. At. Mol. Phys. 1977, 13, 1–55.
36] B. R. Beno, K.-S. Yeung, M. D. Bartberger, L. D. Pennington, N. A. Mean-
well, J. Med. Chem. 2015, 58, 4383–4438.
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
9
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[
[
[
[
[
[
[
[
37] S. Benz, M. Macchione, Q. Verolet, J. Mareda, N. Sakai, S. Matile, J. Am.
[69] A. Boudebous, E. C. Constable, C. E. Housecroft, M. Neuburger, S.
Schaffner, Aust. J. Chem. 2008, 61, 755–757.
[70] L. M. Lee, V. B. Corless, M. Tran, H. Jenkins, J. F. Britten, I. Vargas-Baca,
Dalton Trans. 2016, 45, 3285–3293.
[71] F. H. Allen, Acta Crystallogr. Sect. B 2002, 58, 380–388.
[72] C. R. Groom, I. J. Bruno, M. P. Lightfoot, S. C. Ward, Acta Crystallogr.
Sect. B 2016, 72, 171–179.
[73] I. J. Bruno, J. C. Cole, P. R. Edgington, M. Kessler, C. F. Macrae, P.
McCabe, J. Pearson, R. Taylor, Acta Crystallogr. Sect. B 2002, 58, 389–
397.
Chem. Soc. 2016, 138, 9093–9096.
38] S. Benz, J. Lꢄpez-Andarias, J. Mareda, N. Sakai, S. Matile, Angew. Chem.
Int. Ed. 2017, 56, 812–815; Angew. Chem. 2017, 129, 830–833.
39] D. J. Pascoe, K. B. Ling, S. L. Cockroft, J. Am. Chem. Soc. 2017, 139,
15160–15167.
40] G. E. Garrett, G. L. Gibson, R. N. Straus, D. S. Seferos, M. S. Taylor, J. Am.
Chem. Soc. 2015, 137, 4126–4133.
41] G. E. Garrett, E. I. Carrera, D. S. Seferos, M. S. Taylor, Chem. Commun.
2016, 52, 9881–9884.
42] G. Desiraju, Angew. Chem. Int. Ed. Engl. 1995, 34, 2311–2327; Angew.
Chem. 1995, 107, 2541–2558.
43] R. E. Rosenfield, Jr., R. Parthasarathy, J. D. Dunitz, J. Am. Chem. Soc.
[74] C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E.
Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de Streek, P. A. Wood, J.
Appl. Crystallogr. 2008, 41, 466–470.
[
75] Schrçdinger, LLC., The PyMOL Molecular Graphics System, Version 1.8,
015.
1
977, 99, 4860–4862.
44] T. N. Guru Row, R. Parthasarathy, J. Am. Chem. Soc. 1981, 103, 477–
79.
2
[
76] T. S. Sukhikh, D. A. Bashirov, N. V. Kuratieva, A. I. Smolentsev, A. S. Bo-
gomyakov, V. A. Burilov, A. R. Mustafina, A. V. Zibarev, S. N. Konchenko,
Dalton Trans. 2015, 44, 5727–5734.
4
[
[
[
45] P. Sanz, O. Mꢄ, M. YꢃÇez, Phys. Chem. Chem. Phys. 2003, 5, 2942–2947.
46] R. Shukla, D. Chopra, Phys. Chem. Chem. Phys. 2016, 18, 13820–13829.
47] B. D. Lindner, B. A. Coombs, M. Schaffroth, J. U. Engelhart, O. Tverskoy,
F. Rominger, M. Hamburger, U. H. F. Bunz, Org. Lett. 2013, 15, 666–669.
48] S. Langis-Barsetti, T. Maris, J. D. Wuest, J. Org. Chem. 2017, 82, 5034–
[
77] W.-Y. Wong, X. Wang, H.-L. Zhang, K.-Y. Cheung, M.-K. Fung, A. B. Djuri-
sˇ i c´ , W.-K. Chan, J. Organomet. Chem. 2008, 693, 3603–3612.
78] A. Bondi, J. Phys. Chem. 1964, 68, 441–451.
[
[
[
[
[
79] H. Sakurai, M. T. S. Ritonga, H. Shibatani, T. Hirao, J. Org. Chem. 2005,
5045.
7
0, 2754–2762.
49] F. De Vleeschouwer, M. Denayer, B. Pinter, P. Geerlings, F. De Proft, J.
Comput. Chem. 2018, 39, 557–572.
50] A. F. Cozzolino, I. Vargas-Baca, S. Mansour, A. H. Mahmoudkhani, J. Am.
Chem. Soc. 2005, 127, 3184–3190.
[
[
[
[
[
80] The authors’ ranking of sulfur s-hole size and magnitude are qualita-
tive and based on the visual size and color of the s-hole position.
81] A. F. Cozzolino, J. F. Britten, I. Vargas-Baca, Cryst. Growth Des. 2006, 6,
1
81–186.
82] A. F. Cozzolino, Q. Yang, I. Vargas-Baca, Cryst. Growth Des. 2010, 10,
959–4964.
83] A. F. Cozzolino, P. S. Whitfield, I. Vargas-Baca, J. Am. Chem. Soc. 2010,
32, 17265–17270.
84] The CSD reports two, nearly identical, X-ray structures for compound
b (BETHAZ (Ref 85) and BETHAZ01 (ref. [86])). Our investigation fo-
[
[
51] S. Tsuzuki, N. Sato, J. Phys. Chem. B 2013, 117, 6849–6855.
52] We use the trivial name 2,1,3-benzothiadiazole throughout the main
manuscript, and reserve the IUPAC name benzo[c][1,2,5]thiadiazole in
the Synthetic Procedures section of the Supporting Information.
53] T. Suzuki, H. Fujii, Y. Yamashita, C. Kabuto, S. Tanaka, M. Harasawa, T.
Mukai, T. Miyashi, J. Am. Chem. Soc. 1992, 114, 3034–3043.
4
1
[
[
1
2
54] Tizanidine, an a -adrenoreceptor agonist and muscle relaxant, and
cuses on the more recently reported BETHAZ01.
Timolol, a beta blocker used against ocular hypertension and glauco-
ma, are two U.S. FDA approved drugs that contain thiadiazole moiet-
ies.
[
[
85] P. V. Luzzati, Acta Crystallogr. 1951, 4, 193–200.
86] T. Suzuki, T. Tsuji, T. Okubo, A. Okada, Y. Obana, T. Fukushima, T. Miya-
shi, Y. Yamashita, J. Org. Chem. 2001, 66, 8954–8960.
[
[
[
[
55] For tizanidine, see: K. Strohmaier, E. Snyder, I. Adamsons, J. Am.
[
[
87] The CSD reports two, nearly identical, X-ray structures for compound
Optom. Assoc. 1998, 69, 441–451.
56] For timolol, see: L. Kamen, H. R. Henney III, J. D. Runyan, Curr. Med.
Res. Opin. 2008, 24, 425–439.
1
c (BESEAZ (Ref 85) and BESEAZ01 (ref. [88])). Our investigation focus-
es on the more recently reported BESEAZ01.
88] A. C. Gomes, G. Biswas, A. Banerjee, W. L. Duax, Acta Crystallogr. C
57] Md. Akhtaruzzaman, M. Tomura, J. Nishida, Y. Yamashita, J. Org. Chem.
1
989, 45, 73–75.
2004, 69, 2953–2958.
[
[
89] R. Taylor, Cryst. Growth Des. 2016, 16, 4165–4168.
90] C. B. Nielsen, A. J. P. White, I. McCulloch, J. Org. Chem. 2015, 80, 5045–
58] A. L. Appleton, S. Miao, S. M. Brombosz, N. J. Berger, S. Barlow, S. R.
Marder, B. M. Lawrence, K. I. Hardcastle, U. H. F. Bunz, Org. Lett. 2009,
5048.
11, 5222–5225.
[
[
91] A. F. Cozzolino, I. Vargas-Baca, Cryst. Growth Des. 2011, 11, 668–677.
92] D. A. Bashirov, T. S. Sukhikh, N. V. Kuratieva, E. A. Chulanova, I. V. Yushi-
na, N. P. Gritsan, S. N. Konchenko, A. V. Zibarev, RSC Adv. 2014, 4,
[
[
[
[
59] T. L. Tam, H. Li, F. Wei, K. J. Tan, C. Kloc, Y. M. Lam, S. G. Mhaisalkar, A. C.
Grimsdale, Org. Lett. 2010, 12, 3340–3343.
60] H. Zhou, L. Yang, A. C. Stuart, S. C. Price, S. Liu, W. You, Angew. Chem.
Int. Ed. 2011, 50, 2995–2998; Angew. Chem. 2011, 123, 3051–3054.
61] G. C. Welch, R. C. Bakus II, S. J. Teat, G. C. Bazan, J. Am. Chem. Soc.
28309–28316.
[
93] L. S. Konstantinova, E. A. Knyazeva, N. V. Obruchnikova, Y. V. Gatilov,
A. V. Zibarev, O. A. Rakitin, Tetrahedron Lett. 2013, 54, 3075–3078.
94] A. G. Makarov, N. Yu. Selikhova, A. Yu. Makarov, V. S. Malkov, I. Yu. Ba-
gryanskaya, Y. V. Gatilov, A. S. Knyazev, Y. G. Slizhov, A. V. Zibarev, J. Flu-
orine Chem. 2014, 165, 123–131.
2013, 135, 2298–2305.
[
62] X. Zhang, H. Bronstein, A. J. Kronemeijer, J. Smith, Y. Kim, R. J. Kline,
L. J. Richter, T. D. Anthopoulos, H. Sirringhaus, K. Song, M. Heeney, W.
Zhang, I. McCulloch, D. M. DeLongchamp, Nat. Commun. 2013, 4,
[
95] G. Berionni, B. Pꢅgot, J. Marrot, R. Goumont, CrystEngComm 2009, 11,
2238.
9
86–988.
96] A. Kremer, A. Fermi, N. Biot, J. Wouters, D. Bonifazi, Chem. Eur. J. 2016,
2, 5665–5675.
[
63] D. Venkateshvaran, M. Nikolka, A. Sadhanala, V. Lemaur, M. Zelazny, M.
Kepa, M. Hurhangee, A. J. Kronemeijer, V. Pecunia, I. Nasrallah, I. Roma-
nov, K. Broch, I. McCulloch, D. Emin, Y. Olivier, J. Cornil, D. Beljonne, H.
Sirringhaus, Nature 2014, 515, 384–388.
[
2
[
[
97] N. Biot, D. Bonifazi, Chem. Eur. J. 2018, 24, 5439–5443.
98] Divalent sulfur is defined as a sulfur atom that is bound to two sub-
stituents, neither one being a hydrogen.
[64] Z. Shi, H. T. Black, A. Dadvand, D. F. Perepichka, J. Org. Chem. 2014, 79,
5
858–5860.
[99] J. S. Murray, P. Lane, T. Clark, P. Politzer, J. Mol. Model. 2007, 13, 1033–
1038.
[
65] N. E. Jackson, K. L. Kohlstedt, B. M. Savoie, M. O. de la Cruz, G. C.
Schatz, L. X. Chen, M. A. Ratner, J. Am. Chem. Soc. 2015, 137, 6254–
[100] Y. Geboes, F. De Vleeschouwer, F. De Proft, W. A. Herrebout, Chem. Eur.
J. 2017, 23, 17384–17392.
6262.
[
[
[
66] D. Xia, X. Wang, X. Guo, M. Baumgarten, M. Li, K. Mꢂllen, Cryst. Growth
[101] R. Shukla, D. Chopra, Cryst. Growth Des. 2016, 16, 6734–6742.
[102] S. Tsuzuki, T. Uchimaru, M. Mikami, J. Phys. Chem. A 2003, 107, 10414–
10418.
[103] Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. Marenich, J. Bloino,
Des. 2016, 16, 7124–7129.
67] D. Xia, X. Guo, L. Chen, M. Baumgarten, A. Keerthi, K. Mꢂllen, Angew.
Chem. Int. Ed. 2016, 55, 941–944; Angew. Chem. 2016, 128, 953–956.
68] S. Kang, G. D. Tabi, J. Lee, G. Kim, Y. Noh, C. Yang, Macromolecules
2017, 50, 4649–4657.
&
&
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
10
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F.
Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F.
Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G.
Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peral-
ta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Star-
overov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C.
Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O.
Farkas, J. B. Foresman, D. J. Fox, Gaussian Inc., Wallingford CT, 2016.
104] A. J. Stone, The Theory of Intermolecular Forces, 2nd ed., Oxford Univer-
sity Press, Oxford 2013, p. 52.
[119] I. S. Antonijevi c´ , G. V. Janji c´ , M. K. Mil cˇ i c´ , S. D. Zari c´ , Cryst. Growth Des.
2016, 16, 632–639.
[120] R. T. Raines, Nat. Struct. Biol. 1997, 4, 424–427.
[121] R. Bhattacharyya, D. Pal, P. Chakrabarti, Protein Eng. Des. Sel. 2004, 17,
795–808.
[122] A. Lange, M. Gꢂnther, F. M. Bꢂttner, M. O. Zimmermann, J. Heidrich, S.
Hennig, S. Zahn, C. Schall, A. Sievers-Engler, F. Ansideri, P. Koch, M.
Laemmerhofer, T. Stehle, S. A. Laufer, F. M. Boeckler, J. Am. Chem. Soc.
2015, 137, 14640–14652.
[123] M. Beich-Frandsen, D. S. Pickering, O. Mirza, T. N. Johansen, J. Green-
wood, B. Vestergaard, A. Schousboe, M. Gajhede, T. Liljefors, J. S. Kastr-
up, J. Med. Chem. 2008, 51, 1459–1463.
[
[
[
[
124] B. A. D. Neto, P. H. P. R. Carvalho, D. C. B. D. Santos, C. C. Gatto, L. M.
Ramos, N. M. de Vasconcelos, J. R. CorrÞa, M. B. Costa, H. C. B. de Oli-
veira, R. G. Silva, RSC Adv. 2012, 2, 1524–1532.
125] J. Mili c´ , M. Zalibera, D. Talaat, J. Nomrowski, N. Trapp, L. Ruhlmann, C.
Boudon, O. S. Wenger, A. Savitsky, W. Lubitz, F. Diederich, Chem. Eur. J.
[
[
[
105] J. H. Williams, Acc. Chem. Res. 1993, 26, 593–598.
106] J. Hernꢃndez-Trujillo, A. Vela, J. Phys. Chem. 1996, 100, 6524–6530.
107] T. Kusamoto, H. M. Yamamoto, R. Kato, Cryst. Growth Des. 2013, 13,
4533–4541.
2
018, 24, 1431–1440.
[
108] Q. Shi, S. Zhang, J. Zhang, V. F. Oswald, A. Amassian, S. R. Marder, S. B.
Blakey, J. Am. Chem. Soc. 2016, 138, 3946–3949.
109] T. F. Mikhailovskaya, A. G. Makarov, N. Yu. Selikhova, A. Yu. Makarov,
E. A. Pritchina, I. Y. Bagryanskaya, E. V. Vorontsova, I. D. Ivanov, V. D. Ti-
khova, N. P. Gritsan, Y. G. Slizhov, A. V. Zibarev, J. Fluorine Chem. 2016,
126] H. Kooijman, A. L. Spek, R. van Mullekom, E. W. Meijer, CCDC 633303:
CSD Communication, 2007.
[
[127] K. Pilgram, M. Zupan, R. Skiles, J. Heterocycl. Chem. 1970, 7, 629–633.
[128] S. Zimdars, H. Langhals, P. Knochel, Synthesis 2011, 1302–1308.
[129] P. Vanelle, C. T. Liegeois, J. Meuche, J. Maldonado, M. P. Crozet, Hetero-
cycles 1997, 45, 955–962.
1
83, 44–58.
110] M. Tomura, Y. Yamashita, Z. Kristallogr. New Cryst. Struct. 2003, 218,
55–556.
[
[
[
[
[
[
130] V. G. Pesin, V. A. Sergeev, Zh. Org. Khim. 1989, 25, 1799–1801.
131] S. Mataka, K. Takahashi, S. Shiwaku, M. Tashiro, J. Chem. Res. 1985, 11,
5
111] M. Tomura, Md. Akhtaruzzaman, K. Suzuki, Y. Yamashita, Acta Crystal-
logr. Sect. C 2002, 58, o373–o375.
112] K. Ono, S. Tanaka, Y. Yamashita, Angew. Chem. Int. Ed. Engl. 1994, 33,
346–347.
[132] V. G. Pesin, A. M. Khaletskii, Zh. Obshch. Khim. 1957, 27, 2599–2604.
[133] H. Koopman, J. J. Van Daalen, J. Daams, Weed. Res. 1967, 7, 200–207.
[134] I. A. Belen’kaya, G. P. Krokhina, S. A. Sirik, S. A. Andronati, Khim. Geterot-
sikl. Soedin. 1987, 12, 1683–1687.
1
977–1979; Angew. Chem. 1994, 106, 2030–2032.
113] The CSD reports two independent X-ray structures for compound 9g
JUYSON and JUYSON01) from the reference: M. S. Pavan, A. K. Jana, S.
(
[
[
135] K. Pilgram, R. D. Skiles, J. Heterocycl. Chem. 1974, 11, 777–780.
136] Based on the insight gained in this comprehensive investigation of
Natarajan, T. N. Guru Row, J. Phys. Chem. B 2015, 119, 11382–11390.
JUYSON01 contains two symmetry-independent moieties that engage
in square interactions (Figure 4). JUYSON is dominated by XB interac-
tions and does not contain squares (Figure 10).
2S–2N square interactions in the solid state, supramolecular capsules
formed solely by these interactions have been prepared and their as-
sociation strength in solution and their structures in the solid-state (X-
ray) elucidated. See: L.-J. Riwar, N. Trapp, K. Root, R. Zenobi, F. Dieder-
ich, Angew. Chem. Int. Ed. 2018, 57, DOI: 10.1002/anie.201812095.
[
[
114] M. R. Ams, M. Fields, T. Grabnic, B. G. Janesko, M. Zeller, R. Sheridan, A.
Shay, J. Org. Chem. 2015, 80, 7764–7769.
115] The N···H contact was identified by measuring the N···CH contact dis-
tance.
116] S. Tsuzuki, H. Orita, N. Sato, J. Chem. Phys. 2016, 145, 174503.
117] M. Pyziak, J. Pyziak, M. Hoffmann, M. Kubicki, Cryst. Growth Des. 2015,
[
137] S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem. 2011, 32, 1456–
1465.
[
[
15, 5223–5232.
Manuscript received: August 21, 2018
[118] R. Silaghi-Dumitrescu, A. Lupan, Cent. Eur. J. Chem. 2013, 11, 457–463.
Version of record online: && &&, 0000
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
11
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
Sulfur square interactions predominate
the crystal lattices of diverse 2,1,3-ben-
zothiadiazole structures, yet the origin
and robustness of these close contacts
has not been experimentally examined.
A comprehensive X-ray evaluation
sheds light on the nature of these inter-
actions and their implications for chalc-
ogen bonding.
&
Chalcogen Bonding
M. R. Ams,* N. Trapp, A. Schwab,
J. V. Mili c´ , F. Diederich*
&
& – &&
Chalcogen Bonding “2S–2N Squares”
versus Competing Interactions:
Exploring the Recognition Properties
of Sulfur
&
&
Chem. Eur. J. 2018, 24, 1 – 12
www.chemeurj.org
12
ꢁ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!