Through-Space Polar-π Interactions in 2,6-Diarylthiophenols

Article abstract of DOI:10.1002/cphc.202000132

Molecular recognition between polar groups and aromatic molecules is fundamentally important to rational drug design. Although it has been well established that many polar functionalities interact with electron-rich aromatic residues through energetically favorable polar-π interactions, there is a limited understanding of the association between thiols and aromatic systems. Herein we report physical-organic chemistry studies on 2,6-diarylthiophenols that possess the central thiophenol ring and two flanking aromatic rings with tunable electronic properties caused by substituents at distant para position. Hammett analysis revealed that pK_a values and proton affinities correlate well with Hammett sigma values of substituents. Additional energy decomposition analysis supported the conclusion that both through-space SH-π interactions and S^?-π interactions contribute to intramolecular stabilization of 2,6-diarylthiophenols.

Full text of DOI:10.1002/cphc.202000132

Accepted Article
Title: Through-Space Polar–π Interactions in 2,6-Diarylthiophenols
Authors: Jie Jian, Jordi Poater, Roel Hammink, Paul Tinnemans,
Christine McKenzie, F. Matthias Bickelhaupt, and Jasmin
Mecinović
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemPhysChem 10.1002/cphc.202000132
Link to VoR: https://doi.org/10.1002/cphc.202000132
01/2020

10.1002/cphc.202000132
ChemPhysChem
Through-Space Polar–π Interactions in 2,6-Diarylthiophenols
Jie Jian,#[a] Jordi Poater,#[b,c] Roel Hammink,#[d,e] Paul Tinnemans,[f] Christine J. McKenzie,[a]
F. Matthias Bickelhaupt,*[f,g] and Jasmin Mecinović*[a]
[a] J. Jian, Prof. Dr. C. J. McKenzie, Prof. Dr. J. Mecinović
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense
(Denmark)
E-mail: mecinovic@sdu.dk
[b] Dr. J. Poater
ICREA, Passeig Lluís Companys 23, 08010 Barcelona (Spain)
[c] Dr. J. Poater
Departament de Química Inorgànica i Orgànica & IQTCUB, Universitat de Barcelona, Martí i Franquès 1-11,
08028 Barcelona (Spain)
[d] Dr. R. Hammink
Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen (The Netherlands)
[e] Dr. R. Hammink
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical
Center, Geert Grooteplein 26, 6525 GA Nijmegen (The Netherlands)
[f] Dr. P. Tinnemans, Prof. Dr. F. M. Bickelhaupt
Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen (The
Netherlands)
E-mail: f.m.bickelhaupt@vu.nl
[g] Prof. Dr. F. M. Bickelhaupt
Department of Theoretical Chemistry, Amsterdam Center for Multiscale Modeling, Vrije Universiteit Amsterdam,
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
# These authors contributed equally to this work.
Abstract: Molecular recognition between polar groups and aromatic molecules is
fundamentally important to rational drug design. Although it has been well established that
many polar functionalities interact with electron-rich aromatic residues via energetically
favorable polar–π interactions, there is a limited understanding of the association between
thiols and aromatic systems. Here we report physical-organic chemistry studies on 2,6-
diarylthiophenols that possess the central thiophenol ring and two flanking aromatic rings with
tunable electronic properties caused by substituents at distant para position. Hammett analysis
revealed that pKa values and proton affinities correlate well with Hammett sigma values of
substituents. Additional energy decomposition analysis supported the conclusion that both
through-space SH–π interactions and S––π interactions contribute to intramolecular
stabilization of 2,6-diarylthiophenols.
1
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10.1002/cphc.202000132
ChemPhysChem
1. Introduction
Thiols represent an important class of molecules that play essential roles in molecular and
biological systems.[1,2] The nucleophilic sulfhydryl group (-SH) typically reacts with various
electrophiles, thus enabling a preparation of well-defined biomolecules and biomaterials with
novel structure and function.[3,4] Cysteine, the only thiol in the panel of 22 proteinogenic amino
acids, has commonly been used for site-specific chemoselective modification of peptides and
proteins.[5] Although the chemical reactivity of cysteine and other thiols has been extensively
studied,[3-5] the involvement of thiols in molecular recognition has been less understood.[2,6]
The polar SH group, for example, can act both as a hydrogen bond donor and acceptor in the
presence of the amide backbone in proteins and small molecules.[7] Structural analyses of
proteins demonstrated that cysteine can form three type of interactions with aromatic rings,
namely SH−π interactions (i.e. interactions between H and the π face), HS−π interactions (i.e
interactions between S and the π face), and HS–HC interactions (i.e. interactions between S
and the HC face of the aromatic ring), with the second one being the most common.[2,8]
Computational analyses, however, showed that energetically favorable SH−π interactions with
the π system of aromatic rings appear to be preferred.[9] In comparison with other types of
polar−π interactions (e.g. OH−π, NH−π, cation−π and π−π interactions), direct SH−π
interactions appear to be less studied and established.[2]
Simple small molecular systems have emerged as good models for studies of through-
space polar−π interactions. For instance, substituted 2,6-diaryl aromatic systems enabled
detailed physical-organic investigations on carboxylic acids, pyridines, anilines and phenols
(Figure 1).[10-13] The molecular architecture of the 2,6-diaryl aromatic system is particularly
suitable for examinations of intramolecular polar−π interactions between a polar group located
at the central aromatic ring and the two flanking aromatic rings whose electronic properties can
be fine-tuned by substituents at the distant para position. Measurements of pKa values,
structural analyses, and computational studies revealed the presence of COOH−π interactions
in 2,6-diarylcarboxylic acids,[11] NH−π interactions in 2,6-diarylpyridines,[12] cation−π
interactions in 2,6-diarylanilines,[13] and OH−π interactions in 2,6-diarylphenols.[10] Inspired
by these precedents, here we report experimental and computational investigations of through-
space SH−π interactions in 2,6-diarylthiophenols. We hypothesized that there is a linear
correlation between the pKa values and Hammett σ values in para-substituted 2,6-
diarylthiophenols, leading to stabilization by through-space, and not by through-bond, polar−π
interactions.
2
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10.1002/cphc.202000132
ChemPhysChem
Figure 1. 2,6-Diaryl aromatic systems for examinations of through-space polar–π interactions.
2. Results and Discussion
Substituted 2,6-diarylthiophenols 1–7 were synthesized in several steps from 2,6-
dibromophenol (Scheme 1). Based on our previous protocol,[10] 2,6-diarylphenols 1a−7a were
prepared through palladium-catalyzed Suzuki cross-coupling between 2,6-dibromophenol and
para/meta-substituted phenylboronic acids in good yields. The resulting 2,6-diarylphenols
1a−7a reacted with dimethylthiocarbamoyl chloride in the presence of NaH in N-methyl
pyrrolidone (NMP) to give O-thiocarbamates 1b−7b, which underwent the microwave-
mediated Newman-Kwart rearrangement at 300 ℃ to produce corresponding S-carbamates
1c−7c. Reduction of S-carbamates 1c−7c by lithium aluminum hydride (LiAlH4) refluxed in
tetrahydrofuran (THF) afforded 2,6-diarylthiophenols 1−7.
Scheme 1. Synthesis of 2,6-Diarylthiophenols 1–7.
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10.1002/cphc.202000132
ChemPhysChem
The acidity of 2,6-diarylthiophenols 1−7 in aqueous solutions (with 10% DMSO to
obtain fully soluble compounds) was measured by UV-Vis spectroscopy in the range of pH 3–
12, similarly as used previously for related 2,6-diarylphenols (Table 1 and Figure S1).[10] The
experimentally obtained pKa values for 1–6 were then plotted against the Hammett sigma
values for para-substituents (2σ was used because two flanking rings are present) (Figure 2).
We observed a strong linear correlation with R2 = 0.95, and the ρ value of +0.42. These results
indicate that the acidity constant for 2,6-diarylthiophenols is affected by the presence of
substituents at distant para position of the flanking aromatic rings; electron-donating
substituents (e.g. OMe) make thiols weaker acids, whereas electron-withdrawing substituents
(e.g. CF3) make thiols stronger acids. The meta-substituted F, having a significantly different
σ value than the para-substituted F (0.34 vs 0.06), was found to have quite similar pKa value
to its para analog. Through-bond effects appear to play a minor role in the acidity of 2,6-
diarylthiophenols; the inductive effect diminishes with the number of bonds (there are five C-
C bonds between the SH and para-X), whereas the resonance effect is excluded due to the
nonplanarity of the entire system. Collectively, these results suggest that 2,6-diarylthiophenols
could not be stabilized via through-bond interactions (through resonance and/or inductive
effects), but via through-space polar–π interactions.
Table 1. pKa Values for Thiophenols 1–7.
a
compd
X
H
σ
pKa
1
2
3
4
5
6
7
0.00
5.52
5.81
5.66
5.44
5.45
5.07
5.30
p
p
p
p
p
-OMe
–0.27
–0.17
0.06
-Me
-F
-Cl
0.46
-CF3
0.54
m
-F
0.34
a Determined in H2O:DMSO = 9:1.
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10.1002/cphc.202000132
ChemPhysChem
Figure 2. Correlation between pKa values of phenols 1−6 and the Hammett sigma values
(2σ).
To provide a structural insight into the position of the SH group and the neighboring
aromatic rings, we then determined X-ray structures of thiols 4 and 6 (Figure 3, Figures S2–
S6, Tables S1–S5). The X-ray crystal structure of para-F possessing 2,6-diphenylthiophenol 4
shows that the three aromatic rings in 4 are not coplanar (Figure 3). The flanking rings are 26°
from eclipsing each other when viewed parallel to the central ring (Figure S2). Dihedral angles
between the mean planes of the central thiophenol ring and the ortho para-fluorobenzene rings
are 89.5° (φ1) and 63.7° (φ2). The presence of ortho aryl groups apparently prevents association
between adjacent molecules which, by comparison, are otherwise orientated in head-to-head
dimers through a combination of H bonding and thiophilic interactions in the X-ray crystal
structure of unsubstituted thiophenol. This arrangement allows for the emergence of the strong
SH–p interaction between the neighboring ring and the thiophenol moiety in a close to
perpendicular orientation. The thiol H atom, which was located in the electron density map, is
associated with this aromatic ring with distances of SH−Ca 2.4 Å, SH−Cβ 2.9 Å, SH−Cγ 3.6 Å
and SH−Cδ 3.9 Å (Figure S3). Similarly, the structure elucidation of para-CF3 containing 2,6-
diphenylthiophenol 6 showed that the dihedral angles between the central thiophenol ring and
the adjacent aromatic rings were 52.0° (φ1) and 58.1° (φ2), and that the shortest distances
between the hydrogen of SH and carbon of flanking rings were SH−Ca 2.6 Å, SH−Cβ 2.5 Å,
SH−Cγ 3.4 Å and SH−Cδ 4.1 Å.
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10.1002/cphc.202000132
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Figure 3. X-ray crystal structures of 4 (top) and 6 (bottom).
Following our previous computational analyses that constituted an essential part in
physical-organic studies on 2,6-diarylanilines,[13] 2,6-diarylpyridines,[12] and 2,6-
diarylphenols,[10] we carried out detailed quantum chemical analyses on the role of through-
space polar–π interactions in 2,6-diarylthiophenols. Our objectives were to examine: (1)
dependence of the para/meta substituent on the energy (enthalpy) change for ArSH à ArS– +
H+; (2) for X = H, rotational barrier for internal rotation around the C-C bond linking the central
thiophenol ring and the adjacent flanking aromatic rings (i.e. the lowest energy of X = H is
computed, followed by calculation of the rotational barrier around C-C for one ring while
keeping the other at the lowest energy conformation); and (3) the foundation of the para-
substituent effect by means of an energy decomposition analysis. This computational analysis
was done using the ADF program at the BLYP-D3BJ/TZ2P level of dispersion-corrected DFT
in aqueous solvation simulated using COSMO (Tables S6–S13).[14]
The optimization of the 2,6-diarylthiophenols 1–7 drives to two almost isoenergetic
conformations with respect to the dihedral angle with the two aryl rings: eclipsed (also
described as parallel) and staggered (also described as antiparallel) (Figure 4a). In agreement
with structural analyses (see above), the eclipsed conformation is slightly more stable than the
staggered conformation, both in the gas phase and in water, by up to 0.41 kcal mol-1 (Table 2
and Tables S14 and S15). In addition, the rotational barrier was calculated for 2,6-
diarylthiophenol (1, X = H) in the range 0–180º (Figure 4b). Only the HSC-C2-Cα-Cß dihedral
angle was varied, whereas the other angle was kept at either 117.5º (water) or 116.9º (gas). The
6
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10.1002/cphc.202000132
ChemPhysChem
conformers in the range 50–150º differ by less than 2 kcal mol-1, thus confirming again the
almost isoenergetic eclipsed and staggered conformations, whereas those close to either 0º or
180º appear to be energetically unfavorable.
Figure 4. (a) Structures of eclipsed and staggered conformations for 2,6-diarylthiophenol 1.
(b) Dependence of the relative energy ∆E (in kcal mol-1) of 2,6-diarylthiophenol 1 with the
rotation of the HSC-C2-Cα-Cβ dihedral angle (j, in degrees) in water and in vacuo.
Table 2. Energy difference between eclipsed and staggered conformations and proton affinities
for both conformations in water and in vacuo of the series of 2,6-diarylthiophenols 1–7 (values
in kcal mol-1).
water
vacuo
compd X
∆∆Eecli-stag ∆EPA
∆EPA
∆∆Eecli-stag ∆EPA
∆EPA
ecli
stag
ecli
stag
1
2
3
4
5
6
7
H
–0.30
–0.41
–0.36
–0.32
–0.35
–0.38
–0.25
174.6
175.8
175.3
174.2
174.0
173.3
173.6
174.6
175.6
175.2
174.2
174.0
173.2
173.7
–0.26
–0.36
–0.31
–0.28
–0.29
–0.27
–0.15
341.5
343.1
342.7
336.4
334.4
328.9
336.3
341.3
342.8
342.4
336.1
334.1
328.9
336.3
p-OMe
p-Me
p-F
p-Cl
p-CF3
m-F
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Table 2 also contains the calculated proton affinities (∆EPA) of the set of substituted 2,6-
diarylthiophenols 1–7. Both conformations appear to have indistinguishable ∆EPA. Next, we
have plotted the ∆EPA for eclipsed conformations against twice the Hammett constant (2s), and
it can be observed that good correlations are obtained both in water (slope = –1.55, R2 = 0.95)
and in the gas phase (slope = –9.36, R2 = 0.94) (Figure 5 and Figure S7). The larger slope in
the gas phase correlates with the larger ∆EPA in the gas phase than in water. The reduced ∆EPA
in aqueous solution is due to the much stronger solvation of the proton than of the protonated
thiophenol in which the net positive charge is distributed over a larger volume. In addition, the
fact that meta- and para-substituted F have similar ∆EPA further supports the presence of
through-space interaction in the series of 2,6-diarylthiophenols.
Figure 5. Dependence of calculated proton affinities ∆E on the Hammett sigma values (2s) of
2,6-diarylthiophenols 1-6 in an eclipsed conformation in (a) water and (b) gas phase.
Next, further insight into the molecular origin of the para-substituent effect was obtained
by means of an energy decomposition analysis (EDA) on all seven systems, and particularly
8
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10.1002/cphc.202000132
ChemPhysChem
on 2 (∆EPAecli = 175.8 kcal mol-1) and 6 (∆EPAecli = 173.3 kcal mol-1), which present the largest
and the smallest PA, respectively (Table 3). In particular, the EDA has been performed on the
interaction between one aryl and either H2S (to mimic thiol) or HS- (to mimic thiolate) (results
in Table 3, and methodology in Experimental Section).[10,13] From the interaction energies of
p-OMe (–0.3 kcal mol-1) and p-CF3 (–0.6 kcal mol-1), it is evident that SH–π interactions are
quite weak. In addition, their close ∆Eint values cannot justify the difference in PA values. This
-
is at variance with the unprotonated systems, for which the ∆Eint for p-CF3 is clearly more
attractive (–9.7 kcal mol-1) than for p-OMe- (–2.0 kcal mol-1). The EDA proves that this
-
difference is a result of the reduction of electrostatic interaction from p-CF3 to p-OMe- from –
9.5 to –3.0 kcal mol-1, respectively, whereas ∆EPauli, ∆Eoi and ∆Edisp are very similar for both
substituents (Table 3). The calculation of the VDD charges for both charged systems (Figure
-
6) shows that the more attractive ∆Velstat for p-CF3 than for p-OMe- is due to less negatively
charged carbon atoms in the former, in line with the electron-donating character of OMe and
the electron-withdrawing character of CF3. In particular, the closest H and C atoms of the aryl
-
ring to the HS– in p-CF3 are more positively and less negatively charged, respectively, than in
p-OMe-, which causes more favorable interaction with the negatively charged HS– group (the
distance between the fragments is almost the same in both systems, although slightly shorter
-
for p-CF3 , so also in line with the better interaction). Finally, S–H stretching frequency shifts
of the substituted 2,6-diarylthiophenols (1–7) have been tabulated in Table S16. Electron-
donating substituents drive to frequency lowering, whereas electron-withdrawing ones cause
an increase of the frequency.
9
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ChemPhysChem
Table 3. Through-space interaction analyses in simplified models of para-substituted 2,6-
diarylthiophenols and their conjugate bases.a
System Interaction
∆Eint ∆EPauli ∆Velstat ∆Eoi ∆Edisp
-0.46 11.35 -5.07 -2.88 -3.87
p-OMe H2S···Aryl(OMe) −0.59 11.67 −5.41 −2.98 −3.87
R
H
H2S···Aryl(CF3)
H2S
Aryl
p-Me
p-F
H2S···Aryl(Me)
H2S···Aryl(F)
H2S···Aryl(Cl)
-0.50 11.55
-0.38 11.34
-0.38 11.18
-5.22 -2.94 -3.89
-5.00 -2.85 -3.86
-4.88 -2.81 -3.87
p-Cl
p-CF3
m-F
H-
H2S···Aryl(CF3) −0.28 10.91 −4.61 −2.69 −3.90
H2S···Aryl(F)
-0.39 10.88
-4.69 -2.72 -3.86
HS-···Aryl(CF3)
-2.96 12.44
-4.03 -8.45 -2.93
R
p-OMe- HS-···Aryl(OMe) −1.97 12.66 −2.98 −8.71 −2.94
HS-
Aryl
p-Me-
p-F-
HS-···Aryl(Me)
HS-···Aryl(F)
HS-···Aryl(Cl)
HS-···Aryl(CF3)
HS-···Aryl(F)
-2.44 12.60
-5.51 12.55
-6.76 12.47
-3.25 -8.84 -2.95
-6.51 -8.61 -2.93
-6.98 -9.31 -2.94
p-Cl-
p-CF3
m-F-
-
−9.69 12.57 −9.47 −9.82 −2.97
-5.45 12.31 -6.27 -8.55 -2.93
a Values in kcal mol-1. Calculated at the ZORA-BLYP-D3BJ/TZ2P level of theory. Values correspond to the
eclipsed conformation in water.
Figure 6. VDD charges (in milli-electrons) for fragments in model systems used in through-
-
space interaction analysis for p-CF3 and p-OMe-. Shortest S···C and S···H bond lengths (in
Å) are also included for both systems (values in italics).
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3. Conclusions
In conclusion, our physical-organic chemistry approach enabled the probing of polar–π
interactions in the series of 2,6-diarylthiophenols. Hammett analyses, based on measurements
of acidity constants and calculations of proton affinity energies, demonstrated that electron-
donating groups at the distant para position of the flanking rings in 2,6-diarylthiophenols lead
to weaker acidic character, whereas the presence of electron-withdrawing groups at the same
position results in stronger acids. Our quantum chemical bonding analyses reveal that these
trends are the result of predominant intramolecular through-space polar–π interactions,
whereas the through-bond effect (resonance and/or inductive) appears to play a minor role in
acidity trends. Our bonding analyses of the 2,6-diarylthiophenols furthermore show that both,
S––π interactions and, to a lesser extent SH–π interactions, contribute to the overall polar–π
interactions that stabilize 2,6-diarylthiophenols. This work suggests that the -SH as well as -S–
moieties, both representing the existing protonation states of biologically relevant thiols under
physiological conditions, can form energetically favorable interactions with electron-rich
aromatic rings that constitute the active/recognition sites in proteins. Thiols may therefore be
considered not only as reactive moieties in (bio)molecules, but also as important functional
groups that contribute to the stabilization of (bio)molecular structures.
4. Experimental Section
Synthesis of 2,6-diarylphenols. To a mixture of 2,6-dibromophenol acetate and Pd(PPh3)4 (0.1
equiv) in toluene (4 mL) were added a solution of arylboronic acid (2.5 equiv) in THF (5 mL)
and an aqueous solution of Na2CO3 (2 M, 3 equiv). After it was refluxed at 80 °C under Argon
atmosphere for 3 days, the reaction mixture was poured into 20 mL of water and extracted with
ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over
MgSO4 and concentrated to give the acetylated 2,6-diarylphenols. To a solution of acetylated
2,6-diarylphenols in THF/MeOH/H2O was added an aqueous solution of NaOH (5 M, 3 equiv),
and the mixture was stirred at room temperature for 15 minutes. The mixture was acidified
with 5 % aq. HCl, organic solvent was evaporated, and the aqueous phase extracted with ethyl
acetate (3×30 mL). The combined layers were washed with brine (50 mL), dried over Mg2SO4
and concentrated. The crude product was purified by flash column chromatography on silica
gel (petroleum ether (PE)/EA) to give the 2,6-diarylphenols 2a−7a.
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2,6-Di(4-methoxy)phenylphenol (2a). White solid (340 mg, 43%); 1H NMR (400 MHz, CDCl3)
δ 7.51–7.46 (m, 4H), 7.23 (d, J = 7.6 Hz, 2H), 7.05–6.98 (m, 5H), 5.37 (s, 1H), 3.86 (s, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 159.3, 149.6, 130.7, 130.0, 129.7, 128.5, 120.7, 114.5,
55.5.
2,6-Di(4-methyl)phenylphenol (3a). White solid (150 mg, 34%); 1H NMR (400 MHz, CDCl3)
δ 7.51−7.38 (m, 4H), 7.33−7.18 (m, 6H), 7.06−7.00 (m, 1H), 5.40 (s, 1H), 2.41 (s, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 148.4, 136.4, 133.7, 128.7, 128.5, 128.2, 127.7, 119.6,
20.2.
2,6-Di(4-fluoro)phenylphenol (4a). White solid (124 mg, 32%); 1H NMR (400 MHz, CDCl3)
δ 7.55–7.48 (m, 4H), 7.24 (d, J = 7.6 Hz, 2H), 7.21–7.12 (m, 4H), 7.05 (t, J = 7.6 Hz, 1H), 5.23
(s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.6 (d, J = 247.3 Hz), 149.4, 133.5(d, J = 3.4
Hz), 131.2 (d, J = 8.1 Hz), 130.2, 128.1, 121.0, 116.0 (d, J = 21.5 Hz); 19F NMR (376 MHz,
CDCl3) δ -114.4.
2,6-Di(4-chloro)phenylphenol (5a). White solid (363 mg, 79%); 1H NMR (400 MHz, CDCl3)
δ 7.54 –7.40 (m, 8H), 7.24 (d, J = 7.6 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 5.22 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 149.3, 135.9, 134.0, 130.8, 130.3, 129.2, 127.9, 121.1.
2,6-Di(4-trifluoromethyl)phenylphenol (6a). White solid (410 mg, 77%); 1H NMR (400 MHz,
CDCl3) δ 7.79–7.72 (m, 4H), 7.72–7.65 (m, 4H), 7.32 (d, J = 7.6 Hz, 2H), 7.13 (t, J = 7.6 Hz,
1H), 5.23 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.4, 141.2, 130.8, 130.1 (q, J = 32.6
Hz), 130.0, 128.0, 126.0 (q, J = 3.8 Hz), 124.3 (q, J = 272.2 Hz), 121.4; 19F NMR (376 MHz,
CDCl3) δ -62.6.
2,6-Di(3-fluoro)phenylphenol (7a). White solid (246 mg, 41%); 1H NMR (400 MHz, CDCl3)
δ 7.48–7.41 (m, 2H), 7.35–7.31 (m, 2H), 7.30–7.26 (m, 4H), 7.13–7.05 (m, 3H), 5.37 (s, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 163.0 (d, J = 246.8 Hz), 149.2, 139.6 (d, J = 8.2 Hz), 130.4
(d, J = 8.5 Hz), 130.3, 127.8, 124.9 (d, J = 2.9 Hz), 121.0, 116.5 (d, J = 21.8 Hz), 114.7 (d, J =
21.1 Hz); 19F NMR (376 MHz, CDCl3) δ -112.3.
Synthesis of O-(2,6-diaryl)phenyl N,N-dimethylthiocarbamates. To a solution of 2,6-
diarylphenol in anhydrous NMP (0.1 M) at 0 °C under Argon atmosphere was added NaH (2
equiv) in 3 portions every 15 minutes. Then the mixture was stirred for another 30 minutes at
0 °C before dimethylthiocarbamoyl chloride (1.5 equiv) in NMP was added. The mixture was
then stirred at 80 °C for 2 hours, quenched with water (15 mL), and extracted with ethyl acetate
(3×15 mL). The combined layers were washed with brine, dried over Mg2SO4 and
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concentrated. The crude material was purified by flash column chromatography on silica gel
(PE/EA) to afford O-(2,6-diaryl)phenyl N,N-dimethyl thiocarbamates 1b−7b.
1
O-(2,6-diphenyl)phenyl N,N-dimethylthiolcarbamate (1b). White solid (330 mg, 49%); H
NMR (400 MHz, CDCl3) δ 7.53–7.46 (m, 4H), 7.40–7.31 (m, 7H), 7.33–7.25 (m, 2H), 2.99 (s,
13
3H), 2.94 (s, 3H); C NMR (101 MHz, CDCl3) δ 186.2, 148.1, 138.1, 136.5, 130.1, 129.5,
127.9, 127.3, 126.3, 42.9, 38.3; HRMS (ESI): m/z calcd for C21H19NNaOS [M + Na]+:
356.1080, found 356.1093.
O-[2,6-di(4-methoxylphenyl)phenyl] N,N-dimethylthiolcarbamate (2b). White solid (230 mg,
1
53%); H NMR (400 MHz, CDCl3) δ 7.47–7.41 (m, 4H), 7.39–7.30 (m, 3H), 6.96–6.89 (m,
4H), 3.84 (s, 6H), 3.09 (s, 3H), 3.03 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 186.4, 159.0,
136.2, 130.7, 130.6, 129.8, 126.4, 113.5, 55.4, 43.1, 38.4; HRMS (ESI): m/z calcd for
C23H24NO3S [M + H]+: 394.1471, found 394.1453.
O-[2,6-di(4-methylphenyl)phenyl] N,N-dimethylthiolcarbamate (3b). White solid (110 mg,
56%); 1H NMR (400 MHz, CDCl3) δ 7.43–7.33 (m, 7H), 7.23–7.13 (m, 4H), 3.08 (s, 3H), 3.02
13
(s, 3H), 2.38 (s, 6H); C{1H} NMR (101 MHz, CDCl3) 186.5, 148.2, 137.0, 136.5, 135.4,
130.0, 129.4, 128.8, 126.4, 43.0, 38.4, 21.3; HRMS (ESI): m/z calcd for C23H23NNaOS [M +
Na]+: 384.1393, found 384.1388.
O-[2,6-di(4-fluorophenyl)phenyl] N,N-dimethylthiolcarbamate (4b). White solid (96 mg,
1
59%); H NMR (400 MHz, CDCl3) δ 7.43–7.35 (m, 4H), 7.34–7.25 (m, 3H), 7.03–6.95 (m,
4H), 3.01 (s, 3H), 2.92 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 186.2, 162.4 (d, J = 246.4
Hz), 148.2, 135.8, 134.1 (d, J = 3.4 Hz), 131.2 (d, J = 8.0 Hz), 130.3, 126.5, 115.0 (d, J = 21.4
Hz), 43.1, 38.4; 19F NMR (376 MHz, CDCl3) δ -115.1; HRMS (ESI): m/z calcd for
C21H18F2NOS [M + H]+: 370.1072, found 370.1067.
O-[2,6-di(4-chlorophenyl)phenyl] N,N-dimethylthiolcarbamate (5b). White solid (216 mg,
47%); 1H NMR (400 MHz, CDCl3) δ 7.44–7.32 (m, 11H), 3.09 (s, 3H), 3.01 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 186.02, 148.0, 136.5, 135.6, 133.6, 130.7, 130.4, 128.3, 126.6, 43.2,
38.4; HRMS (ESI): m/z calcd for C21H18Cl2NOS [M + H]+: 402.0481, found 402.0467.
O-[2,6-di(4-trifluoromethylphenyl)phenyl] N,N-dimethylthiolcarbamate (6b). White solid
(170 mg, 36%); 1H NMR (400 MHz, CDCl3) δ 7.69–7.58 (m, 8H), 7.49–7.37 (m, 3H), 3.05 (s,
3H), 2.99 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 185.9, 148.0, 141.6, 135.6, 130.8, 129.9,
129.4 (q, J = 32.4 Hz), 126.8, 125.1 (q, J = 3.7 Hz), 124.4 (q, 272.1 Hz), 43.2, 38.4; 19F NMR
(376 MHz, CDCl3) δ -62.4; HRMS (ESI): m/z calcd for C23H18F6NOS [M + H]+: 470.1008,
found 470.1024.
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O-[2,6-di(3-fluorophenyl)phenyl] N,N-dimethylthiolcarbamate (7b). White solid (180 mg,
56%); 1H NMR (400 MHz, CDCl3) δ 7.42–7.38 (m, 3H), 7.37–7.31 (m, 2H), 7.27 (dt, J = 7.7,
1.3 Hz, 2H), 7.23 (ddd, J = 10.0, 2.6, 1.5 Hz, 2H), 7.03 (tdd, J = 8.3, 2.6, 1.1 Hz, 2H), 3.09 (s,
3H), 3.04 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 186.0, 162.5 (d, J = 245.3 Hz), 148.0,
140.1 (d, J = 8.1 Hz), 130. 5, 129.6 (d, J = 8.5 Hz), 126.6, 125.4 (d, J = 2.9 Hz), 116.5 (d, J =
19
22.3 Hz), 114.4 (d, J = 21.0 Hz), 43.2, 38.4; F NMR (376 MHz, CDCl3) δ -113.7; HRMS
(ESI): m/z calcd for C21H18F2NOS [M + H]+: 370.1072, found 370.1054.
Synthesis of S-(2,6-diaryl)phenyl N,N-dimethylthiolcarbamates. The O-(2,6-diaryl)phenyl
N,N-dimethylthiocarbamates were dissolved in NMP (0.1 M) and heated at 300 °C under
microwave for 3 hours. After cooling to room temperature, the solvent was evaporated to give
a dark brown oil. The crude product was purified by flash column chromatography on silica
gel (PE/EA) to afford S-(2,6-diaryl)phenyl N,N-dimethylthiolcarbamates 1c−7c.
1
S-(2,6-diphenyl)phenyl N,N-dimethylthiolcarbamate (1c). Colorless oil (250 mg, 76%); H
13
NMR (400 MHz, CDCl3) δ 7.50–7.26 (m, 13H), 2.65 (brs, 6H); C{1H} NMR (101 MHz,
CDCl3) δ 166.8, 148.7, 142.2, 129.8, 129.7, 129.6, 129.3, 127.5, 127.0, 126.7, 37.0; HRMS
(ESI): m/z calcd for C21H19NNaOS [M + Na]+: 356.1080, found 356.1074.
S-[2,6-di(4-methoxylphenyl)phenyl] N,N-dimethylthiolcarbamate (2c). White solid (182 mg,
79%); 1H NMR (400 MHz, CDCl3) δ 7.47–7.42 (dd, J = 8.2, 6.9 Hz, 1H), 7.36–7.31 (m, 6H),
13
6.94–6.87 (m, 4H), 3.85 (s, 6H), 2.73 (brs, 6H); C{1H} NMR (101 MHz, CDCl3) δ 167.0,
158.7, 148.3, 134.8, 130.7, 129.8, 129.2, 127.0, 112.9, 55.3, 36.9; HRMS (ESI): m/z calcd for
C23H23NNaO3S [M + Na]+: 416.1291, found 416.1300.
S-[2,6-di(4-methylphenyl)phenyl] N,N-dimethylthiolcarbamate (3c). Colorless oil (70 mg,
1
64%); H NMR (400 MHz, CDCl3) δ 7.49–7.43 (m, 1H), 7.37–7.28 (m, 6H), 7.22–7.16 (m,
13
4H), 2.71 (brs, 6H), 2.40 (s, 6H); C{1H} NMR (101 MHz, CDCl3) δ 167.2, 148.8, 139.5,
136.7, 129.9, 129.6, 129.3, 128.3, 126.9, 37.1, 21.4; HRMS (ESI): m/z calcd for C23H24NOS
[M + H]+: 362.1573, found 362.1573.
S-[2,6-di(4-fluorophenyl)phenyl] N,N-dimethylthiolcarbamate (4c). Colorless oil (28 mg, 63
%); 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H), 7.39–7.32 (m, 6H), 7.10–7.02 (m, 4H), 2.73
(brs, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.6, 162.3 (d, J = 245.9 Hz), 147.9, 138.1 (d,
J = 3.4 Hz), 131.3 (d, J = 8.0 Hz), 130.1, 129.5, 127.0, 114.5 (d, J = 21.4 Hz), 37.1; HRMS
(ESI): m/z calcd for C21H17F2NNaOS [M + Na]+: 392.0891, found 392.0891.
S-[2,6-di(4-chlorophenyl)phenyl] N,N-dimethylthiolcarbamate (5c). Colorless oil (170 mg,
47%); 1H NMR (400 MHz, CDCl3) δ 7.52–7.46 (m, 1H), 7.38–7.30 (m, 10H), 2.74 (brs, 6H);
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13C{1H} NMR (101 MHz, CDCl3) δ 166.5, 147.8, 140.5, 133.3, 131.0, 130.1, 129.7, 127.8,
126.6, 37.1; HRMS (ESI): m/z calcd for C21H17Cl2NNaOS [M + Na]+: 424.0300, found
424.0301.
S-[2,6-di(4-trifluoromethylphenyl] N,N-dimethylthiolcarbamate (6c). Colorless oil (80 mg,
1
47%); H NMR (400 MHz, CDCl3) δ 7.68–7.61 (m, 4H), 7.59–7.48 (m, 5H), 7.42–7.37 (m,
2H), 2.73 (s, 3H), 2.69 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 147.7, 145.5, 130.3,
130.1, 129.8, 129.6 (q, J = 32.1 Hz) 124.6 (q, J = 3.8 Hz), 124.5 (q, J = 272.1 Hz), 37.0; 19F
NMR (376 MHz, CDCl3) δ -62.4; HRMS (ESI): m/z calcd for C23H17F6NNaOS [M + Na]+:
492.0827, found 492.0855.
S-[2,6-di(3-fluorophenyl)phenyl] N,N-dimethylthiolcarbamate (7c). White foam (49 mg,
27%); 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 8.2, 7.0 Hz, 1H), 7.41–7.30 (m, 4H), 7.21–
13
7.11 (m, 4H), 7.05 (tdd, J = 8.6, 2.6, 1.0 Hz, 2H), 2.75 (s, 6H); C{1H} NMR (101 MHz,
CDCl3) δ 166.5, 162.2 (d, J = 245.4 Hz), 147.7 (d, J = 1.9 Hz), 144.1 (d, J = 8.1 Hz), 130.1,
129.6, 129.1 (d, J = 8.3 Hz), 126.6, 125.5 (d, J = 2.9 Hz), 116.7 (d, J = 22.0 Hz), 114.1 (d, J =
21.0 Hz), 37.0; 19F NMR (376 MHz, CDCl3) δ -114.1; HRMS (ESI): m/z calcd for
C21H17F2NNaOS [M + Na]+: 392.0891, found 392.0891.
Synthesis of 2,6-diarylthiophenols. To a flask filled of LiAlH4 (10 equiv), a solution of S-
(2,6-diaryl)phenyl N,N-dimethylthiolcarbamates in anhydrous THF (0.1 M) was added
dropwise at 0 ℃ under Argon atmosphere. Then the mixture was heated under reflux for 2
hours. The reaction was cooled to 0 °C, and methanol (1 mL) was added slowly to quench the
reaction. Then H2SO4 (6 M, 3 mL) was added and the mixture was stirred at room temperature
for 30 minutes. The mixture was filtered, and filtrate was extracted with ethyl acetate. The
combined layers were washed with brine, dried over Mg2SO4 and concentrated. The crude
product was purified by flash column chromatography on silica gel (PE/DCM) to yield 2,6-
diaryl(thiophenol)s 1−7.
2,6-diphenyl(thiophenol) (1). White solid (64 mg, 81%); mp 67−68 °C; 1H NMR (400 MHz,
13
CDCl3) δ 7.44 (m, 8H), 7.41−7.35 (m, 2H), 7.21−7.18 (m, 3H), 3.41 (s, 1H); C{1H} NMR
(101 MHz, CDCl3) δ 141.5, 140.9, 130.8, 129.4, 129.4, 128.6, 127.8, 124.5; HRMS (GC-TOF)
[M+] m/z calcd for C18H14S 262.0816; found, 262.1639.
2,6-di(4-methoxyphenyl)benzenethiol (2). White solid (53 mg, 73%); mp 98−99 °C; 1H NMR
(400 MHz, CDCl3) δ 7.42–7.34 (m, 4H), 7.19–7.16 (m, 3H), 7.04–6.94 (m, 4H), 3.86 (s, 6H),
13
3.47 (s, 1H); C{1H} NMR (101 MHz, CDCl3) δ 159.3, 140.6, 134.1, 130.7, 129.5, 124.5,
114.1, 55.5; HRMS (GC-TOF) [M+] m/z calcd for C20H18O3S 322.1028; found, 322.2073.
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2,6-di(4-methylphenyl)benzenethiol (3). White solid (25 mg, 78%); mp 108−109 ℃; 1H NMR
(400 MHz, CDCl3) δ 7.37–7.30 (m, 4H), 7.31–7.23 (m, 4H), 7.22–7.15 (m, 3H), 3.46 (s, 1H),
13
2.41 (s, 6H); C{1H} NMR (101 MHz, CDCl3) δ 141.0, 138.8, 137.6, 131.1, 129.4, 129.4,
124.6, 21.4; HRMS (GC-TOF) [M+] m/z calcd for C20H18S 290.1129; found, 290.2091.
1
2,6-di(4-fluorophenyl)benzenethiol (4). White solid (16 mg, 70%); mp 73−74 °C; H NMR
(400 MHz, CDCl3) δ 7.45–7.37 (m, 4H), 7.24–7.11 (m, 7H), 3.33 (s, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 162.6 (d, J = 247.2 Hz), 140.1, 137.4 (d, J = 3.4 Hz), 131.2 (d, J = 8.1 Hz),
129.8, 124.8, 115.7 (d, J = 21.5 Hz); 19F NMR (376 MHz, CDCl3) δ -114.2; HRMS (GC-TOF)
[M+] m/z calcd for C18H12F2S 298.0628; found, 298.1617.
2,6-di(4-chlorophenyl)benzenethiol (5). White solid (13 mg, 64%); mp 165−168 °C; 1H NMR
(400 MHz, CDCl3) δ 7.46–7.41 (m, 4H), 7.40–7.35 (m, 4H), 7.25–7.16 (m, 3H), 3.33 (s, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 140.0, 139.8, 134.1, 130.9, 130.7, 129.8, 129.0, 124.9;
HRMS (GC-TOF) [M+] m/z calcd for C18H12Cl2S 330.0037; found, 330.1085.
2,6-di(4-trifluoromethylphenyl)benzenethiol (6). White solid (45 mg, 66%); mp 143−145 °C;
1H NMR (400 MHz, CDCl3) δ 7.78–7.69 (m, 4H), 7.62–7.54 (m, 4H), 7.30–7.25 (m, 1H), 7.24–
7.20 (m, 2H), 3.24 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.8, 140.0, 130.3 (q, J = 32.5
Hz), 130.3, 130.0, 130.0, 125.8 (q, J = 3.7 Hz), 125.2, 124.3 (q, J = 272.3 Hz); 19F NMR (376
MHz, CDCl3) δ -62.6; HRMS (GC-TOF) [M+] m/z calcd for C20H12F6S 398.0564; found,
398.2094.
1
2,6-di(3-fluorophenyl)benzenethiol (7). White solid (24 mg, 60%); mp 99−100 °C; H NMR
(400 MHz, CDCl3) δ 7.43 (td, J = 8.0, 5.9 Hz, 2H), 7.25–7.19 (m, 5H), 7.17 (dd, J = 2.6, 1.6
Hz, 1H), 7.14 (dd, J = 2.6, 1.6 Hz, 1H), 7.13–7.07 (m, 2H), 3.37 (s, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 162.9 (d, J = 247.1 Hz), 143.5 (d, J = 7.7 Hz), 139.9 (d, J = 2.0 Hz), 130.6,
130.3 (d, J = 8.4 Hz), 129.8, 125.3 (d, J = 3.0 Hz), 124.9, 116.6 (d, J = 21.7 Hz), 114.9 (d, J =
21.1 Hz); 19F NMR (376 MHz, CDCl3) δ -112.5; HRMS (GC-TOF) [M+] m/z calcd for
C18H12F2S 298.0628; found, 298.1594.
Quantum Chemical Analyses. All calculations were carried out with the Amsterdam Density
Functional (ADF) program using dispersion-corrected density functional theory at the BLYP-
D3BJ/TZ2P level of theory.[14,15] The effect of solvation in water was simulated by means of
the Conductor like Screening Model (COSMO) of solvation as implemented in ADF. The
approach has been benchmarked against highly correlated post-Hartree-Fock methods and
experimental data and was found to work reliably.[12,16,17] The bonding mechanism of hydrogen
sulfide (taken from thiophenol) or bisulfide anion (taken from unprotonated thiophenol) with
16
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the two substituted benzene rings (taken from aryl rings) was analyzed within the framework
of quantitative Kohn-Sham molecular orbital theory[18] in combination with a quantitative
energy decomposition analysis (EDA)[18] in the gas phase. The interaction energy ∆Eint between
these fragments is decomposed into the classical electrostatic attraction ∆Velstat, Pauli repulsion
∆EPauli between occupied orbitals, stabilizing orbital interactions ∆Eoi, and dispersion ∆Edisp.
Atomic charges were computed with the Voronoi deformation density (VDD) method.[19]
Energy decomposition analysis (EDA) methodology: To analyze the through-space
interactions between the bisulfide group and the para-substituted aryl rings in the 2,6-
diarylthiophenols, the central benzene ring was removed, and also the aryl moiety to which the
H of the SH group is not pointing to. Thus, the remaining two moieties (the bisulfide radical
and the para-substituted phenyl radical to which the SH is pointing to) were kept frozen to their
geometry and position they had in the complete thiophenol system. The two radical positions
were terminated with hydrogen atoms. It is worth noting that only the bond lengths of these
three hydrogen atoms were geometrically optimized (angles were also constrained) at the
ZORA-BLYP-D3BJ/TZ2P level; other atoms were kept frozen to keep the structure of 2,6-
diarylthiophenol system. Next, the added proton to the bisulfide radical was rotated through
the other S-H bond to be as far as possible from the aryl ring, thus avoiding spurious S-H···H-
C steric repulsion that is not present in the original compound.
X-ray crystallography: The data for compound 4 were collected at 100(1)K on a Synergy,
Dualflex, AtlasS2 diffractometer using CuKα radiation (l = 1.54184 Å) and the CrysAlis PRO
1.171.40.29a suite. Using SHELXLE and Olex2 the structure was solved by dual space
methods (SHELXT) and refined on F2 using all the reflections (SHELXL-2018/3). All the non-
hydrogen atoms were refined using anisotropic atomic displacement parameters and hydrogen
atoms bonded to carbon inserted at calculated positions using a riding model. For compound
6, reflections were measured on a Bruker D8 Quest diffractometer with sealed tube and
Triumph monochromator (λ = 0.71073Å). Software package used for the intensity integration
was Saint. Absorption correction was performed with SADABS. The structure was solved with
direct methods using SHELXT. Least-squares refinement was performed with SHELXL-2014
against |F_h^o |^2 of all reflections. Non-hydrogen atoms were refined freely with anisotropic
displacement parameters. Hydrogen atoms were placed on calculated positions or located in
difference Fourier maps. All calculated hydrogen atoms were refined with a riding model. Data,
17
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10.1002/cphc.202000132
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data collection and structure refinement details are summarised in Tables S1 and S5. CCDCs
1980288 and 1980799 contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting information: NMR spectra, pKa measurements, IR data, X-ray crystallography
data, computational studies. Crystallographic data for 4 and 6.
Acknowledgments
J.J. acknowledges the financial support from the China Scholarship Council. F.M.B.
acknowledges the Netherlands Organization for Scientific Research (NWO) for financial
support. J.P. thanks the Spanish MINECO (CTQ2016-77558-R and MDM-2017-0767) and the
Generalitat de Catalunya (2017SGR348). The Carlsberg Foundation is acknowledged for
funding for the X-ray diffractometer (grant CF15-0675).
Keywords: Aromatic compounds • Molecular recognition • Noncovalent interactions • Polar–
π interactions • Thiols
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Graphic for Table of Contents
Despite a well-established knowledge that polar–π interactions play an important role in
molecular recognition, it is currently poorly understood how do thiols interact with aromatic
systems. Our physical-organic chemistry studies, based on measurements of pKa values,
structural studies, and quantum chemical analyses, reveal that 2,6-diarylthiophenols are
stabilized by through-space SH–π interactions and S––π interactions.
19
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