A new imidazoline-containing Bunte salt: Synthesis, molecular and electronic structure

Article abstract of DOI:10.1515/hc-2017-0177

S-[(4,5-dihydro-1H-imidazol-2-yl)methyl]sulfothioate, a new imidazoline-containing Bunte salt 4 was prepared by reacting 2-chloromethylimidazoline 3 with sodium thiosulfate in aqueous solution at room temperature. The mechanism of the concerted S_N2 reaction pathway was studied by means of quantum chemical calculations at the B3LYP/6-31G?? level of theory. The molecular structure of compound 4 incorporating a formal amidine moiety was confirmed by single crystal X-ray diffraction analysis, while its electronic structure was studied using quantum chemical calculations at the MP2/6-311++G?? level of theory.

Full text of DOI:10.1515/hc-2017-0177

Heterocycl. Commun. 2017; 23(5): 359–363
Preliminary Communication
Franciszek Sączewski*, Maria Gdaniec and Krzysztof Data
A new imidazoline-containing Bunte salt:
synthesis, molecular and electronic structure
https://doi.org/10.1515/hc-2017-0177
Bunte salts undergo a reaction with carbocations of iso-
benzofuranone and isoindolone [13], as well as the use of
Bunte salts as the odorless thiol surrogates for the synthe-
sis of α-sulfido carbonyl compounds via the thia-Michael
addition [14]. Worth noting are also the biological activi-
ties of Bunte salts that include antimicrobial [15], antira-
diation [16] and schistosomicidal [17] properties.
The most common methods developed for the prepara-
tion of S-alkyl thiosulfates include reactions of sodium or
thalium thiosulfate with alkyl halides, alkenes or oxiranes
Received August 10, 2017; accepted August 23, 2017
Abstract:
S-[(4,5-dihydro-1H-imidazol-2-yl)methyl]sul-
fothioate, a new imidazoline-containing Bunte salt 4
was prepared by reacting 2-chloromethylimidazoline
3
with sodium thiosulfate in aqueous solution at room
temperature. The mechanism of the concerted S 2 reac-
N
tion pathway was studied by means of quantum chemi-
cal calculations at the B3LYP/6-31G** level of theory.
The molecular structure of compound 4 incorporating a
formal amidine moiety was confirmed by single crystal
X-ray diffraction analysis, while its electronic structure
was studied using quantum chemical calculations at the
MP2/6-311ꢀ+ꢀ+ꢀG** level of theory.
[
1], while some pharmacologically relevant, amino-con-
taining analogs can be obtained by reacting aminothiols
with chlorosulfonic acid [18]. Our continuous interest
in the preparation of synthetically useful imidazolines
containing the sulfate group of type A [19–21] prompted
Keywords: Bunte salt; imidazoline; quantum chemical us to investigate the reactions of sodium thiosulfate with
calculations;
S-[(4,5-dihydro-1H-imidazol-2-yl)methyl] 2-chloro-4,5-dihydroimidazole and 2-chloromethyl-4,5-di-
sulfothioate; S 2 reaction mechanism; synthesis; X-ray hydroimidazole that were expected to provide new thio-
N
crystallographic structure.
sulfates of type B and C, respectively (Figure 1).
First, 2-chloro-4,5-dihydroimidazole hemisulfate (1)
22] was subjected to a reaction with a 2-fold excess of
[
Salts of S-alkylthiosulfuric acid (S-substituted thiosul-
fates, Bunte salts) have long been known as valuable
reagents in synthetic organic chemistry [1] and in the
industry [2]. Perspectives in the application of these sul-
furating reagents have recently been defined in a versa-
tile review article [3]. Thus, S-alkylsulfothioates are easily
transformed into the corresponding sulfhydrides and
sulfides [1, 4, 5], disulfides [6, 7], trisulfides [8, 9], as well
as isothiocyanates and mercaptals [10]. They also serve
as thiol precursors in the synthesis of 3-thioindoles [11]
and in conjugated polymer self-assemblies on gold and
silver surfaces [12]. Of special interest are alkylthiolation
reactions, in which S-nucleophiles generated in situ from
sodium thiosulfate in aqueous solution at room tempera-
ture. An exothermic nucleophilic substitution reaction
[
23–26] took place with vigorous evolution of sulfur tri-
oxide. As shown in Scheme 1, the initially formed inter-
nal Bunte salt D proved to be unstable and decomposed
with the formation of imidazolidine-2-thione (2) in quan-
titative yields. The identity of product 2 was confirmed
by comparison of its IR spectrum and melting point with
data of the commercially available imidazolidine-2-thione
(
Experimental section). The facile dehalogenation of 1
bears resemblance to the previously described reaction
of sodium thiosulfate with 2-chloro-1-methylquinolinium
tetraborate (CQMT) that can be used as a tool in medical
diagnostics for the determination of thiosulfate ion in
human urine [27, 28].
*
Corresponding author: Franciszek Sączewski, Department
of Chemical Technology of Drugs, Faculty of Pharmacy,
Medical University of Gdańsk, 80-416 Gdańsk, Poland,
e-mail: saczew@gumed.edu.pl
Next, we attempted an analogous reaction of sodium
thiosulfate with 2-chloromethyl-4,5-dihydroimidazole (3).
As shown in Scheme 2, the reaction carried out in aqueous
solution at ambient temperature led to the formation of
the expected Bunte salt that precipitated from the reaction
mixture in the form of the stable zwitterion 4. The presence
Maria Gdaniec: Faculty of Chemistry, A. Mickiewicz University,
Poznań, Poland
Krzysztof Data: Department of Chemical Technology of Drugs,
Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland
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60ꢀꢀꢀꢀꢁꢀF. Sączewski et al.: A new imidazoline-containing Bunte salt
O
O
S S O
O
H
N
H
N
S
O
Cl
Cl
Na S O /H O
2 2 3
2
N
O
A
NH
OH
N
H
–2 NaCl
N
H
N
H
Previous works
N
4
3
O
S
O
O
Internal Bunte salt
N
S
S
O
S
OH
OH
Scheme 2ꢀReaction of 2-chloromethyl-4,5-dihydroimidazole (3) with
sodium thiosulfate.
N
H
N
H
B
This work
C
Figure 1ꢀImidazoline derivatives containing a sulfate or thiosulfate
group. Imidazolines containing the sulfate group A and reactions of
sodium thiosulfate with 2-chloro 4,5-dihydroimidazole and 2-chloro-
methyl-4,5-dihydroimidazole to provide thiosulfates B and C.
−
of the S-SO group in 4 was confirmed by a strong absorp-
3
−1
tion at 1031 cm , characteristic of Bunte salts, found in
the IR spectrum. A protonated 2-methyleneimidazoline
moiety was identified by the presence of two singlets in
1
Figure 2ꢀMolecular structure of 4. Displacement ellipsoids are
the H NMR spectrum, corresponding to four protons of
shown at the 50% probability level.
the imidazoline ring and two protons of the exocyclic
CH group at 3.78 and 3.89 ppm, respectively, as well as
2
13
three signals in the C NMR spectrum at 28.8 ppm (S-CH ), (the B3LYP/6-31G** level of theory) on the concerted SN2
2
4
5.2 ppm (CH -CH grouping) and 170.2 ppm (quaternary reaction pathway. As shown in Figure 4, the displace-
2 2
C2 atom of imidazoline ring).
ment of the chloride ion with thiosulfate occurs in the
The constitution of the thiosulfate 4 was further inves- plane perpendicular to the imidazoline ring, in a nearly
tigated by single crystal X-ray diffraction analysis. The linear manner (S2-C1-Cl angleꢀ=ꢀ170.32°), and is exother-
‡
crystal unit of 4 consists of zwitterionic molecules with a mic (ΔGꢀ=ꢀ26.7 kcal/mol). The transition state TS has
proton transferred from the sulfate group to the 4,5-dihy- sufficiently low activation energy (E ꢀ=ꢀ3.5 kcal/mol) to
a
dro-1H-imidazole fragment. The molecular structure fea- undergo a substitution reaction under mild reaction con-
tures the typical characteristics of the thiosulfate group ditions (Figure 5). The geometry of the transition state
[
29], with the S-S bond length of 2.1097(6) Å (Figure 2). The shows a single imaginary frequency pertaining to the S-C
−1
crystal packing is dominated by intermolecular hydro- bond formation and C-Cl bond breakage at 409 cm .
gen bonding N-Hꢀ·ꢀ·ꢀ·ꢀO interactions, with the molecules
To identify reactive sites at compound 4, the elec-
arranged in a ‘head-to-tail’ manner within the hydrogen- tronic structure of this compound was studied using
bonded chain propagating along the z axis (Figure 3A). quantum chemical calculations at the MP2/6-311ꢀ+ꢀ+ꢀG**
There are also numerous C-Hꢀ·ꢀ·ꢀ·ꢀO interactions formed level of theory. Bunte salts are defined as a class of sul-
predominantly between the molecules forming (-102) furating reagents bearing an SO3− ‘mask’ on the sulfur
layers (Figure 3B).
atom, which serves as a steric bulky group to prevent
To gain a mechanistic insight into the reaction homocoupling and as a conjugated group to tune the
depicted in Scheme 2, we carried out DFT calculations electron effect on sulfur [3]. Shielding of the S(II) sulfur
O
O O
S O
H
N
S S O 2 Na
O
H
N
H
N
Cl
HSO4
S
S
N
H
–NaHSO , –NaCl
N
H
N
H
SO3
4
D
2
1
Unstable
Bunte salt
Imidazolidine-2-thione
Scheme 1ꢀReaction of 2-chloro-4,5-dihydroimidazole (1) with sodium thiosulfate.
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F. Sączewski et al.: A new imidazoline-containing Bunte saltꢀꢁꢀꢀꢀꢀ361
E
E = –1749.14198 a. u.
E = –1749.14765 a. u.
Ea = 3.5 kcal/mol
Transition state
TS#
Substrates
∆G = 26.7 kcal/mol
E = –1749.190335 a. u.
Products
Energy profile
Figure 5ꢀEnergy profile computed at the B3LYP/6-31G** level for the
transformation 3→4 (S 2 reaction).
N
Figure 3ꢀN-Hꢁ·ꢁ·ꢁ·ꢁO and C-Hꢁ·ꢁ·ꢁ·ꢁO interactions. (A) Hydrogen-bonded
chain in 4. (B) C-Hꢁ·ꢁ·ꢁ·ꢁO interactions between the molecules in (-102)
layers. Hydrogen bonds are shown with dashed lines.
atom is assured by a negative electrostatic potential that
Figure 6ꢀElectronic structure of thiosulfate 4: localization of HOMO
−
surrounds the SO mask (Figure 6). As shown in Figure 4,
3
3
(top left), LUMO (top right) (isovalueꢁ=ꢁ0.032 e/au ) and electrostatic
the HOMO orbital is mainly localized at the S(II) sulfur potential (bottom) (isovalueꢁ=ꢁ−83.68 kJ/mol).
‡
Figure 4ꢀStructure of the transition state TS : N1-S2, C1-Cl and C1-C2 atom distances (Å), S2-C1-Cl bond angle (°), electrostatic potential
3
3
mapped on the isodensity surface (0.002 e/au ) and localization of frontier orbitals HOMO and LUMO (isovalueꢁ=ꢁ0.032 e/au ).
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62ꢀꢀꢀꢀꢁꢀF. Sączewski et al.: A new imidazoline-containing Bunte salt
atom of the thiosulfate moiety, which should be involved Crystal data for Bunte salt 4
in the orbital-controlled reactions with electrophiles. On
the other hand, scrutiny of the calculated charges in 4 (C H N O S ;Mꢀ=ꢀ196.24g/mol):monoclinic, spacegroupP2 /c(no. 14),
4
8
2
3
2
1
aꢀ=ꢀ8.22560(12) Å, bꢀ=ꢀ9.45112(13) Å, cꢀ=ꢀ9.75528(15) Å, βꢀ=ꢀ99.6136(14)°,
suggests that electrostatically controlled reactions with
electrophilic reagents should proceed preferentially at
the C1 carbon atom. Studies of possible applications of
3
−1
Vꢀ=ꢀ747.736(19) Å , Zꢀ=ꢀ4, Tꢀ=ꢀ130.15 K, μ(CuKα)ꢀ=ꢀ6.186 mm , Dcalcꢀ=ꢀ1.743
3
g/cm , 8294 reflections measured (13.134°ꢀ≤ꢀ2Θꢀ≤ꢀ148.946°), 1526
unique (R ꢀ=ꢀ0.0824, Rsigmaꢀ=ꢀ0.0353), which were used in all calcula-
int
4
in the synthesis of new imidazoline-containing com-
tions. The final R was 0.0404 [Iꢀ>ꢀ2σ(I)] and wR was 0.1065 (all data).
1
2
pounds are in progress.
Illustrations were prepared with the OLEX2 software [34].
CDC 1550367 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
Experimental
Melting points were determined on a Boetius apparatus and are
uncorrected. FT-IR spectra were measured on a Nicolet 380 spectro-
1
13
meter. H NMR and C NMR spectra were recorded in dimethyl
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