Programmed Formation of HCN Oligomers through Organosulfur Catalysis

Article abstract of DOI:10.1021/acs.joc.1c01023

An efficient, inexpensive, and reliable synthesis of diaminomaleonitrile (DAMN, 1) is described starting from readily available acetone cyanohydrin as the source of hydrogen cyanide (HCN). Diaminomaleonitrile (DAMN) is known to be an important intermediate in heterocyclic and medicinal chemistry as well as being a possible precursor for the origin of life's hypothesis within prebiotic chemistry. The mechanism of its formation through organosulfur catalysis has been investigated by electrospray ionization mass spectrometry (ESI-MS) using two newly synthesized cationic "marker"molecules as a tool that allows for sensitive detection. As a result, the proposed mechanism of a thiocyanate-mediated synthesis of the HCN tetramer DAMN starting from organic disulfides was confirmed.

Full text of DOI:10.1021/acs.joc.1c01023

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Article
Programmed Formation of HCN Oligomers through Organosulfur
Catalysis
Caroline Grundke, Caleb Kong, Christopher J. Kampf, B. Frank Gupton, D. Tyler McQuade,*
and Till Opatz*
Cite This: J. Org. Chem. 2021, 86, 10320−10329
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Supporting Information
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ABSTRACT: An efficient, inexpensive, and reliable synthesis of diaminomaleonitrile (DAMN, 1) is described starting from readily
available acetone cyanohydrin as the source of hydrogen cyanide (HCN). Diaminomaleonitrile (DAMN) is known to be an
important intermediate in heterocyclic and medicinal chemistry as well as being a possible precursor for the origin of life’s hypothesis
within prebiotic chemistry. The mechanism of its formation through organosulfur catalysis has been investigated by electrospray
ionization mass spectrometry (ESI-MS) using two newly synthesized cationic “marker” molecules as a tool that allows for sensitive
detection. As a result, the proposed mechanism of a thiocyanate-mediated synthesis of the HCN tetramer DAMN starting from
organic disulfides was confirmed.
aminonitrile hydrolysis.11 Disulfides and related sulfur species
INTRODUCTION
■
have been widely studied for their catalytic activity in
Diaminomaleonitrile (DAMN, 1), an interesting product
organosynthetic12 as well as biochemical pathways,12a,b,13 as
formed during HCN oligomerization, has been heavily studied
one major impact is the (reversible) scission of sulfur−sulfur
as a common precursor to a variety of biologically relevant and
bonds that can occur through several mechanisms.14 A large
commercially useful heterocycles (e.g., imidazoles,1 pyrroles,2
number of nucleophiles have been identified, which allow
pyrazines,3 amino acids,4 see Scheme 1) during the past
nucleophilic displacement at one of the sulfur atoms of a
decades.5 For instance, DAMN is a key element in the abiotic
disulfide and the process has been subjected to several studies
formation of purines and pyrimidines (nucleobases)6 as well as
over the 20th century.14b,15 Cyanide, a typical pseudohalide
in the prebiotic formation of more complex organic molecules.7
nucleophile with high affinity for electrophilic sulfur (thio-
Its symmetrical cis-arrangement of four C−N-units, which
philicity), was applied in a considerable number of such
bears two electron donor (−NH2) and two electron acceptor
reactions yielding either thioethers through desulfurization of
groups (−CN) attached to a central CC unit, makes DAMN a
disulfides in dipolar aprotic solvents or thiocyanates through
unique π-conjugated organic molecule (Figure 1).8 The
simple substitution as possible products.16 To the best of our
resulting remarkable electronic properties, e.g., render 1 a useful
knowledge, no detailed investigation of (organo)catalytically
building block in the synthesis of organic chemosensors for the
active sulfur species in the oligomerization of HCN has been
detection of ionic and reactive oxygen species.9
We became interested in the role sulfur species such as thiols
and disulfides can play in the chemistry of HCN and its
Received: April 30, 2021
Published: July 12, 2021
oligomers based on initial (photo)chemical investigations of the
oligomerization of HCN by Orgel and Ferris,10 as well as by
̈
̈
some findings from Wachtershauser and co-workers, who
described several (mineral) sulfide species as potential catalysts
for the formation of amino acids and peptides through
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Scheme 1. Structures of HCN-derived Products4,17
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Table 1. Investigation of the Solvent-Dependent Formation
of DAMN (1) According to a Patent by the Nippon Soda
Company18f
Figure 1. Structure of diaminomaleonitrile DAMN (1).
performed so far and its implications for prebiotic chemistry
remain unknown. Therefore, we sought to study the formation
of the metastable key intermediate DAMN (1) starting from
acetone cyanohydrin as a source of HCN under the action of
different organic sulfur species.
85 min (%)
240 min (%)
DMF
EtSH
PhSH
EtSH
PhSH
8.5
38.2
11.4
53.0
13.8
39.6
15.9
68.4
DMSO
RESULTS AND DISCUSSION
■
Though numerous methods have been reported in the literature
concerning the synthesis of 1,18 only a few of them describe
protocols yielding a high concentration of the desired HCN
tetramer or a HCN surrogate. Interestingly, one promising
procedure from the patent literature reports the use of
organosulfur compounds as catalysts for the synthesis of 1
(Scheme 2, vide infra).
In further investigations, we found that the addition of thiols
provided higher yields of tetramer 1, and these results were
solvent-dependent. Evaluating different solvents and screening
additives, it turned out that in solvents like MeCN, where the
thiol did not lead to the significant promotion of DAMN
formation, the addition of disulfides would indeed yield
significant amounts of product 1 (Scheme 3).
Scheme 2. Formation of DAMN (1) from Acetone
Cyanohydrin as Described in Patents by Arkema (a)18e and
Nippon Soda Company (b)18f
Scheme 3. Formation of DAMN (1) in MeCN as a Function of
the Sulfur Species Applied. Isolated Yields Following a
Crystallization Procedure (see the Supporting Information
(SI))
We found the disparate outcomes between different polar
aprotic solvents incongruous where DMSO and DMF provided
about 70% yield of DAMN in the presence of thiophenol
whereas very little DAMN was produced in MeCN. The
observation that diphenyl disulfide provided some recovery of
DAMN formation in MeCN seemed to be an important clue.
We speculated that redox chemistry might be important and
attempted to improve the yield in MeCN by adding thiophenol
once the reaction reached equilibrium. This experiment did not
provide enhanced yields but did provide some new information
that spurred further studies.20
For example, in a reproduction of a patent by Arkema,18e
which describes a commercial method to produce 1 using
acetone cyanohydrin (2) as a HCN source in combination with
triethylamine, the high yields reported could not be reproduced
in our hands. Instead, mixtures of the starting material with the
desired product and other HCN-derived materials were
produced (Scheme 2a).
1
Analysis of the reaction mixture by H NMR spectroscopy
An older patent filed by the Nippon Soda Company described
a high-yielding synthesis of DAMN (1) in the presence of thiols
and disulfides as catalysts (Scheme 2b).18f Owing to the fact that
other groups previously showed the necessity of sulfur-
containing minerals for the activation of HCN,19 we sought to
further investigate the role of organic sulfur compounds in HCN
oligomerization reactions. Initial reproduction of the reaction
described in the patent led to the formation of DAMN (1) using
both NaCN as a base and ethanethiol or thiophenol as catalysts
in either dimethylformamide (DMF) or dimethyl sulfoxide
(DMSO) as solvents. It was found that these additives indeed
led to higher yields of DAMN relative to the uncatalyzed
reaction and that thiophenol is superior to ethanethiol in its
catalytic activity (Table 1).
revealed the emergence of a new chemical species (see Table
S2), which could be identified as the thiocyanate derivative from
the thiol or disulfide. This was not entirely unexpected given the
precedence of preparative methods for producing thiocyanates
from a variety of thiols and disulfides with nucleophilic and
electrophilic cyanide sources.21 We then investigated whether
the thiocyanate may be a critical intermediate in the catalytic
activity of thiols and disulfides for the selective tetramerization
of HCN to DAMN.
To this end, the thiophenol/diphenyl disulfide catalytic
system could be replaced by phenyl thiocyanate resulting in a
similar catalytic activity (see Table 2). When probing the
1
reaction with phenyl thiocyanate as a catalyst via H NMR
spectroscopy, we also found the emergence of diphenyl disulfide
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the reaction conditions, together with either thiophenol or
diphenyl disulfide. When probing both reaction mixtures after 4
h of reaction time, no depletion of 1 could be observed via 1H
NMR, suggesting it to be a thermodynamic sink in this HCN
oligomerization sequence.
Table 2. Comparison of Different Sulfur Species for the
Formation of DAMN (1)
a
Although sulfur-containing compounds have been proposed
in the literature as necessary components for the emergence of
biological molecules,13a,23 the role that thiocyanate intermedi-
ates may have had in controlling the oligomerization of HCN
toward such chemical fossils like nucleobases or amino acids has
not been proposed in detail yet. As an initial test of this
hypothesis, an experiment was set up to survey the
concentration of 1 produced while varying the amount of
diphenyl disulfide (Figure 2). Higher loadings of the disulfide
sulfur species
yield DAMN [%] after4 h
PhSSPh
PhSH
PhSCN
57
18
65
a
Yields determined from concentrated, crude product mixture by
high-performance liquid chromatography (HPLC) assay before
crystallization (see the SI for more details).
(see T2) so that a reversible reaction between the two can be
assumed.
As a result of the described experiments, a first picture of the
role these additives could play in the oligomerization of cyanide
emerged. The addition of disulfides could activate HCN through
intermediate formation of a thiocyanate monomeric unit, the
reactivity of which favors terminating the oligomerization as the
tetramer, e.g., by the acceleration of the first three addition steps
(Scheme 4). The thiocyanate’s sulfur prevents the electrophilic
reaction partner in the addition of cyanide from being
deprotonated and seems to accelerate the addition step. The
mechanistic proposal was supported by exposing DAMN (1) to
Figure 2. Yield of DAMN (1) while varying the amount of diphenyl
disulfide. Reaction conditions: diphenyl disulfide, acetone cyanohydrin
(500.0 mg, 5.87 mmol, 4.0 equiv), triethylamine (164 μL, 1.18 mmol,
0.8 equiv), and acetonitrile to get to a total reaction volume of 2 mL (for
more detailed information, see the Supporting Information).
Scheme 4. Proposed Mechanism for the Disulfide-Catalyzed
Synthesis of DAMN (1) Using Diphenyl Disulfide: Step 1:
Heterolytic Cleavage of the Disulfide Bond and Formation of
Thiocyanate 6 Using Acetone Cyanohydrin (2) as a Cyanide
Source under the Formation of Acetone (4) and Thiophenol
(5). Steps 2−4: Oligomerization of HCN.22 Step 5: Release of
DAMN (1) and Recovery of Diphenyl Disulfide (3)
did increase the yield of 1 until a catalyst loading of about 40
mol% was reached. At considerably higher loadings, a significant
decrease in yield was found instead. This provides further
indication that the additive was acting as a chain transfer catalyst,
while at higher concentrations it could instead behave like a
chain terminator, inhibiting the desired tetramer formation.
An analytical tool was required that would provide detailed
insight into the reaction at a level of sensitivity sufficient to
detect the postulated sulfur-containing oligomers while not
influencing the reaction of these unstable transient intermedi-
ates. Electrospray ionization mass spectrometry (ESI-MS) could
effectively record the formation of the intermediates proposed
even at low levels but permanent ionization would be required to
obtain at least semiquantitative data on the relative concen-
trations of individual components. Thus, two new cationic
disulfides 10 and 11 were prepared, which carry a quaternary
nitrogen atom as an “ionization marker” for MS detection.24
Aliphatic disulfide 10 was synthesized in four steps starting
from commercial 8-bromo-1-octene (12) via quaternization of
trimethylamine (13) in the first step. After radical thiolation
with thioacetic acid and AIBN, the acetyl group was cleaved by
acidic ethanolysis to furnish 8-mercaptooctyltrimethylammo-
nium chloride (16) in quantitative yield. After oxidation with I2,
10 was obtained in 71% yield over four steps (Scheme 5).
The more electron-deficient aromatic disulfide 11 was
synthesized in four steps starting from 4-mercaptobenzoic acid
(18). Thiol protection with trityl chloride (17) was followed by
amide coupling to N,N-dimethylethylenediamine with 1-ethyl-
3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC·
HCl) as the coupling reagent. Quaternization of the NMe2
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Scheme 5. Synthesis of Disulfide 10 Starting from 8-
4‑Bromo-1-octene (12) over Four Steps
Scheme 6. Synthesis of Disulfide 11 Starting from
4-Mercaptobenzoic Acid (18)
group with methyl iodide and detritylation using TFA furnished
compound 21, which was again oxidized with I2 in a follow-up
step. The aromatic disulfide 11 was obtained with an overall
yield of 34% (Scheme 6).
After successful synthesis of the disulfide probes, they both
were applied in the reaction instead of the previously used sulfur
catalysts. Possible cationic intermediates to expect during the
reaction are depicted in Schemes 7 and 8 as well as the
intermediates observed during the ESI-liquid chromatography-
mass spectrometry (ESI-LCMS) studies.
As disulfide 11 is more similar to diphenyl disulfide
concerning its aromatic character and the resulting electron
density at sulfur, it was applied to the reaction conditions to
initially gain an overview about its performance during the
course of the reaction. The increased leaving group ability of
aromatic thiolates through decreased basicity and nucleophil-
icity is the probable cause for the increased catalytic efficiency of
diaryl disulfides over dialkyl disulfides. Kinetic measurements
were performed using 11 as a catalyst. To this end, the extracted
ion current of the individual ions has been recorded as a function
of the reaction time over a period of 180 min to gather
mechanistic information through the relative concentrations of
the intermediates.
As shown in Figure 3, the signal corresponding to disulfide 11
drops by more than two orders of magnitude during the first 50
min of reaction time. At the same time, the amount of
thiocyanate 22 increases and the respective ion counts are very
high, indicating a highly abundant species. This is in line with
our proposal that thiocyanate 22 must be formed from disulfide
11 through heterolytic cleavage of the disulfide bond. After 90
min, the intensity of the disulfide signal is increasing again,
which supports the assumption of a catalytic cycle. The ion
current corresponding to DAMN (1) increases during the same
time as the disulfide 11 decreases, which indicates that 11 as well
as 22 are key components involved in HCN tetramerization
under the reaction conditions. However, DAMN is devoid of the
cationic head group and its trace can therefore not be compared
with the other traces in terms of relative intensity. Regarding the
formation of the lower HCN oligomers, the HCN trimer
corresponding to intermediate 24 is built up rapidly during the
first 10 min of reaction time and reaches a plateau level after a
small initial peak; additionally, its ion intensity is quite low,
which also applies to the signal corresponding to the HCN-
dimer (23) and tetramer (25) intermediates. Both intermediates
do not show a significant dynamics over the course of the
reaction, which suggests the attack of cyanide onto the
thiocyanate to be the rate-limiting step, while all subsequent
transformations are rapid and do not seem to differ greatly in
their rates.7c The liberation of the free thiol in the release of
DAMN from tetramer 25, which must also be a rapid process as
judged by the lack of any buildup of the latter species over time,
ultimately permits the re-formation of the parent disulfide 11.
Furthermore, possible side reactions between thiocyanate 22
and the free thiol 21 to furnish (symmetrical) oligomers were
followed by ESI-LCMS and the results are reported in Scheme
S5 and Figure S6. Additionally, an experiment was set up using
the aromatic disulfide 11 and tracking the emerging
intermediates with hydrophilic interaction liquid chromatog-
raphy-high-resolution mass spectrometry (HILIC-HRMS) to
additionally confirm the postulated catalytic cycle. These results
can also be found in the Supporting Information (Table S8).
With this experiment, the aromatic disulfide 11 (m/z =
238.1136), the resulting thiocyanate 22 (m/z = 264.1169),
the free thiol 21 (m/z = 239.1210), and the HCN-dimer
intermediate 23 (m/z = 291.1298) could be detected. This
further supports our assumption of a thiocyanate-mediated
HCN oligomerization cycle starting from an organic disulfide as
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Scheme 7. Proposed Catalytic Cycle for Aromatic Disulfide 11 as well as Molecular Masses for the Corresponding Intermediates
Found in LC-MS Studies
Scheme 8. Proposed Catalytic Cycle for Aliphatic Disulfide 10 as well as Molecular Masses for the Corresponding Intermediates
Found in LC-MS Studies
the catalyst. Additionally, by creating a process using acetone
cyanohydrin as a cyanide source and integrating the disulfide
regulator reported by the Nippon Soda Company, we are now
able to produce DAMN in respectable yields for a reasonable
price from a liquid-phase reagent, which is more widely
applicable to basic processing equipment.
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Figure 3. Extracted ion intensity of various ionic intermediates of the main reaction mechanism.
array detector coupled to an LC/MSD Ion Trap mass spectrometer.
Ionization was achieved by an electron spray ionization source (ESI).
The kinetic experiment was performed in SCAN and SIM modes of
the mass spectrometry HPLC separation of the analytes applying the
following parameters:
Gradient: eluent A (H2O + 0.1% formic acid), eluent B
(acetonitrile); t = 0 min 90% A/10% B; t = 0.20 min 90% A/10% B;
t = 7.50 min 10% A/90% B; t = 10.00 min 10% A/90% B.
About 10 μL of the reaction mixture was dissolved in 1 mL of MeCN,
and the mixture was filtered through a 0.45 μm PTFE syringe filter. The
injection volume was set to 1.5 μL. As the column, an ASCENTIS
EXPRESS C18 (particle size: 2.7 μm; length: 3 cm; diameter: 2.1 mm)
was used with a flow rate of 0.7 mL/min and at a temperature of 40 °C.
Samples were withdrawn for analysis at the following time points: 20,
40, 60, 90, 120, and 180 min.
To increase the sensitivity, monitoring of the intermediates of
sequential HCN addition to the MS probes was performed by HPLC-
MS using single ion monitoring (SIM) with the time points depicted in
Figure 3. The HILIC-HRMS experiment for the reaction mixture was
performed at t = 60 min to confirm the results found in both ESI-LCMS
experiments (for more details, please see the Supporting Information).
High-resolution masses were recorded using a Q-ToF instrument
with a LockSpray interface and a suitable external calibrant. Melting
points were measured in open capillary tubes and are uncorrected.
Infrared spectra were recorded as Fourier transform infrared (FT-IR)
spectra using a diamond attenuated total reflection (ATR) unit and are
reported in terms of frequency of absorption (given in cm−1).
Diaminomaleonitrile (1) Synthesis. To a three-neck round-
bottom flask equipped with a magnetic stir bar and JKEM
thermocouple, diphenyl disulfide (0.6 g, 5.9 mmol, 0.2 equiv) was
added, followed by acetonitrile (19 mL) and triethylamine (1.6 mL, 0.8
equiv). Acetone cyanohydrin (5.4 mL, 58.7 mmol, 4.0 equiv) was added
to the reaction mixture while stirring over 1 min. The reaction
temperature was ramped to 70 °C over 30 min. The reaction was
considered complete when the HPLC assay revealed a 50% conversion.
The solvent was removed in vacuo, and dichloromethane (20 mL) was
added. The reaction mixture was cooled over an ice bath (0−5 °C) for
30 min. The residue was filtered by vacuum filtration, and the filter cake
was washed with dichloromethane (5 mL). The solid was collected and
dried in vacuo to afford the title compound (643 mg, 5.95 mmol, 41%*)
as a brown solid. Rf = 0.29 (1:1 cyclohexane/ethyl acetate). Mp: 178.2−
180.7 °C (dichloromethane), lit.18d mp: 184 °C. IR/cm−1 (ATR):
3440, 3369, 3348, 3208, 2213, 1647, 1620, 1362, 1320, 1247, 739, 623.
1H NMR (400 MHz, DMSO-d6) δ 5.31 (s, 4H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 117.0, 106.1. MS (ESI): m/z = 109.1 [M + H]+.
CONCLUSIONS
■
A low-cost, efficient, and reliable catalytic method for the
synthesis of diaminomaleonitrile (DAMN, 1) from acetone
cyanohydrin was identified and investigated. DAMN is an
important intermediate in the context of medicinal chemistry
and heterocyclic chemistry and plays a key role in several current
hypotheses on the origin of life within the field of prebiotic
chemistry. To elucidate the key components and the mechanism
of its formation, we developed a sensitive tool for detecting the
population of thiocyanate containing oligomers using two new
cationic “marker” molecules 10 and 11 in electrospray ionization
mass spectrometry. With this tool in hand, we were able to gain
insight into the reaction mechanism and detect the inter-
mediates 1, 11, 21, and 22, as well as 23. Based on these findings,
we managed to confirm our postulated mechanism about an
organosulfur-catalyzed, thiocyanate-mediated HCN oligomeri-
zation reaction.
EXPERIMENTAL SECTION
■
All air- and moisture-sensitive reactions were carried out under an inert
gas atmosphere. Unless stated otherwise, all commercially available
reagents and solvents were used as provided without further
purification. Reactions that require heating were performed in an oil
bath (the temperature indicated for individual reactions denotes the
bath temperature).
Analytical thin-layer chromatography (TLC) was performed on
silica gel 60 F245 and visualized by irradiation with UV light or TLC
staining reagents.
1H NMR and 13C NMR spectra were recorded on a 300, 400, or 600
MHz spectrometer using standard pulse sequences. Chemical shifts
were referred to the corresponding deuterated solvent (CDCl3: δ = 7.26
ppm, DMSO-d6: δ = 2.50 ppm, and methanol-d4: δ = 3.31 ppm for 1H
NMR; CDCl3: δ = 77.16 ppm, DMSO-d6: δ = 39.52 ppm, and
methanol-d4: δ = 49.00 ppm for 13C{1H} NMR) and reported in parts
per million (ppm, δ) relative to tetramethylsilane (TMS: δ = 0.00
ppm).25 Coupling constants (J) were reported in hertz and the
following splitting abbreviations were used: s (singlet), bs (broad
singlet), d (doublet), t (triplet), q (quartet), m (multiple), and
combinations of these. Structural assignments were made with
additional information from gCOSY, gHSQC, gNOESY, and
gHMBC experiments. Electron spray ionization (ESI) masses were
recorded by LC-MS with a binary pump system and an integrated diode
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*Yield is based on a smaller scaleexpect yield increases at higher
concentrations.
N,N,N-Trimethyl-oct-7-en-1-ammonium Bromide (14). The title
compound was prepared according to a modified procedure of Rotello
et al.26 In a 10 mL reaction vial were stirred 8-bromo-1-octene (12, 0.4
d6) δ 3.32−3.20 (m, 4H), 3.04 (s, 18H), 2.70 (t, J = 7.2 Hz, 4H), 1.74−
1.54 (m, 8H, 2-H), 1.41−1.21 (m, 16H). 13C{1H} NMR (75 MHz,
DMSO-d6) δ 64.7, 51.6, 37.2, 28.4, 27.6, 25.6, 22.0. MS (ESI): m/z =
203.2 [M]. HRMS (ESI) m/z: [M] Calcd for C22H50N2S22+ 203.1702;
found 203.1708.
mL, 2.5 mmol, 1.0 equiv) and trimethylamine in ethanol (13, 33%w/w
,
4-((Triphenylmethyl)thio)benzoic Acid (19). According to a
modified procedure of Kikuchi et al.,29 trityl chloride (17, 903.2 mg,
3.2 mmol, 1.0 equiv) and 4-mercaptobenzoic acid (18, 499.5 mg, 3.2
mmol, 1.0 equiv) were dissolved in anhydrous DMF (10 mL) and
stirred at room temperature under an inert gas atmosphere for 21 h. The
solvent was removed in vacuo, and the residue was dissolved in
chloroform (20 mL) and washed with water (4 × 15 mL). The
combined organic layers were dried over Na2SO4 and filtered, and the
solvent was removed in vacuo. The crude product was crystallized from
a mixture of n-hexane and ethyl acetate (10:1, 30 mL) to afford the title
compound (209.7 mg, 0.5 mmol, 77%) as a colorless solid. Rf = 0.72
(8:1 dichloromethane/methanol). Mp: 228.3−230.9 °C (n-hexane/
ethyl acetate). No mp given in the literature. IR/cm−1 (ATR): 2835,
0.6 mL, 7.5 mmol, 2.9 equiv) at room temperature for 42.5 h. The
solvent was removed in vacuo, and the crude product was layered with n-
hexane (3 × 10 mL) and washed under sonication for a few minutes.
The supernatant was removed, and the residue was dried in vacuo to
obtain the title compound (0.52 g, 2.10 mmol, 84%) as a colorless
powder. Rf = 0.06 (1:1 dichloromethane/methanol): 0.06. Mp: 140.1−
143.5 °C (n-hexane) lit.27 mp: 141 °C. IR/cm−1 (ATR): 3406, 2927,
1
2857, 1639, 1480, 1261, 1022, 909, 728, 579. H NMR (300 MHz,
CDCl3) δ 5.73 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.07−4.77 (m, 2H),
3.72−3.52 (m, 2H), 3.43 (s, 9H), 2.14−1.90 (m, 2H), 1.84−1.63 (m,
2H), 1.40−1.09 (m, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.5,
114.6, 66.8, 53.3, 33.4, 28.5, 26.0, 23.1. MS (ESI): m/z = 170.2 [M].
The obtained data match those reported in the literature.26
1
1680, 1561, 1489, 1443, 1421, 1314, 1291, 1180, 764, 743, 675. H
NMR (300 MHz, DMSO-d6) δ 12.93 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H),
7.34−7.30 (m, 12H), 7.30−7.21 (m, 3H), 6.98 (d, J = 8.4 Hz, 2H).
13C{1H} NMR (75 MHz, DMSO-d6) δ 166.6, 143.4, 140.7, 131.1,
129.3, 128.8, 128.7, 128.0, 127.1, 70.5. MS (ESI): m/z = 155.1
[M(C7H5O2S) + 2H]+, 243.1 [M(triphenylmethyl)]. The obtained
data match those reported in the literature.29,30
8-(Acetylsulfanyl)-N,N,N-trimethyloctan-1-ammonium Bromide
(15). According to a modified procedure of Prins et al.27 N,N,N-
Trimethyl-oct-7-en-1-ammonium bromide (14, 250.0 mg, 1.0 mmol,
1.0 equiv) was dissolved in a mixture of toluene and ethanol (10 mL,
1:1) and AIBN (82.1 mg, 0.5 mmol, 0.5 equiv) was added. Thioacetic
acid (380.0 mg, 5.0 mmol, 5.0 equiv) was added dropwise, and the
reaction mixture was heated under reflux for 4.5 h. The solvent was
removed in vacuo, and the residue was layered with a mixture of n-
hexane and ethyl acetate (9:1, 3 × 25 mL) and washed under sonication
for a few minutes. The supernatant was removed, and the residue was
dried in vacuo to obtain the title compound (0.3 g, 0.9 mmol, 94%) as a
colorless powder. Rf = 0.08 (1:1 dichloromethane/methanol). Mp:
95.4−100.6 °C (n-hexane/ethyl acetate), no mp given in the literature.
IR/cm−1 (ATR): 3420, 2927, 2855, 1684, 1481, 1354, 1134, 963, 910,
727, 627. 1H NMR (300 MHz, CDCl3) δ 3.60−3.50 (m, 2H), 3.39 (s,
9H), 2.76 (t, J = 7.3 Hz, 2H), 2.24 (s, 3H), 1.75−1.60 (m, 2H), 1.51−
1.40 (m, 2H), 1.37−1.17 (m, 8H). 13C{1H} NMR (75 MHz, CDCl3) δ
196.1, 66.7, 53.3, 30.7, 29.3, 28.9, 28.6, 28.4, 26.0, 23.0. MS (ESI): m/z
= 246.2 [M]. The obtained data match those reported in the
literature.27
N,N,N-Trimethyl-8-sulfanyloctan-1-ammonium Chloride (16).
According to a modified procedure of Prins et al.,27 8-(acetylsulfan-
yl)-N,N,N-trimethyloctan-1-ammonium bromide (15) (200.0 mg, 0.6
mmol, 1.0 equiv) was dissolved in ethanol (2 mL) and hydrochloric
acid (6 M, 2 mL) was added. The reaction mixture was heated to 78 °C
for 3 h. The solvent was removed in vacuo, and the resulting residue was
layered with a mixture of n-hexane and ethyl acetate (9:1, 3 × 10 mL)
and washed under sonication for a few minutes. The supernatant was
removed, and the residue was dried in vacuo to obtain the title
compound (155.5 mg 0.7 mmol, 100%) as a colorless powder. Rf = 0.48
(6:1 dichloromethane/methanol). Mp: 103.6−107.3 °C (n-hexane/
ethyl acetate), no mp given in the literature. IR/cm−1 (ATR): 3420,
3010, 2924, 2854, 2430, 1482, 1245, 1098 964, 912, 726. 1H NMR (300
MHz, CDCl3) δ 3.34 (s, 2H), 3.05 (s, 9H), 2.45 (dd, J = 8.96, 7.27 Hz,
1H), 2.25 (dd, J = 8.96, 7.27 Hz, 1H), 1.72−1.61 (m, 2H), 1.59−1.47
(m, 2H), 1.40- 1.20 (m, 8H). 13C{1H} NMR (75 MHz, CDCl3) δ 65.1,
52.0, 33.2, 28.3, 28.1, 27.5, 25.6, 23.7, 21.9. MS (ESI): m/z = 204.2
[M]. The obtained data match those reported in the literature.27
8,8′-Disulfanediylbis(N,N,N-trimethyloctan-1-ammonium) Diio-
dide (10). According to a modified procedure of Kuchin et al.,28 N,N,N-
trimethyl-8-sulfanyloctan-1-ammonium chloride (16) (74.7 mg, 0.3
mmol, 1.0 equiv) was dissolved in ethanol (1 mL). Iodine (48.2 mg, 0.2
mmol, 0.6 equiv) was dissolved in ethanol (1.6 mL) and added to the
reaction mixture together with NaHCO3 (31.3 mg, 0.4 mmol, 1.2
equiv). The reaction mixture was stirred at room temperature for 2 h.
The solvent was removed in vacuo, and the residue was washed with n-
hexane (3 × 3 mL) under sonication. The supernatant was removed,
and the resulting residue was dried in vacuo. The title compound (1.3 g,
3.2 mmol, 90%) was obtained as a reddish-brown viscous oil. Rf = 0.05
(6:1 dichloromethane/methanol). IR/cm−1 (ATR): 3422, 2925, 2854,
1644, 1537, 1477, 1245, 963, 907, 702. 1H NMR (300 MHz, DMSO-
N-[2-(Dimethylamino)ethyl]-4-(triphenylmethylthio)benzamide
(20). According to a modified procedure of Kikuchi et al.,29 4-
((triphenylmethyl)thio)benzoic acid (19, 230.0 mg, 0.6 mmol, 1.0
equiv) was dissolved in anhydrous DMF (15 mL) together with DMAP
(3.5 mg, 0.03 mmol, 0.05 equiv), HOBt (156.7 mg, 1.2 mmol, 2.0
equiv), and EDC·HCl (222.4 mg, 1.2 mmol, 2.0 equiv), degassed, and
stirred under an inert gas atmosphere at 0 °C. After 1 h, N,N-
dimethylethylenediamine (0.13 mL, 1.16 mmol, 2.0 equiv) was added
and the reaction mixture was stirred at room temperature for 5 h. After
completion of the reaction, the reaction mixture was diluted with ethyl
acetate (20 mL) and washed with saturated NaHCO3 solution (3 × 10
mL) and water (3 × 10 mL). The combined organic layers were dried
over Na2SO4 and filtered, and the solvent was removed in vacuo. After
crystallization from a mixture of n-hexane and ethyl acetate (10:1, 12
mL) the title compound (209.7 mg, 0.5 mmol, 78%) was obtained as a
colorless solid. Rf = 0.26 (10:1 dichloromethane/methanol). Mp:
141.5−145.2 °C (n-hexane/ethyl acetate). No mp given in the
literature. IR/cm−1 (ATR): 3320, 3058, 2944, 2772, 1638, 1594,
1
1541, 1486, 1460, 1303, 740, 700. H NMR (300 MHz, CDCl3) δ
7.45−7.37 (m, 8H), 7.29−7.16 (m, 9H), 6.99 (d, 2H), 6.73 (t, J = 4.9
Hz, 1H), 3.45 (q, 2H), 2.48 (t, J = 5.9 Hz, 2H), 2.24 (s, 6H). 13C{1H}
NMR (75 MHz, CDCl3) δ 166.8, 144.0, 139.8, 132.6, 132.2, 129.9,
127.8, 127.0, 126.6, 70.8, 57.6, 45.1, 37.1. MS (ESI): m/z = 467.3 [M +
H]+. The obtained data match those reported in the literature.29
N,N,N-trimethyl-2-[(4-sulfanylbenzoyl)amino]ethanammonium
Iodide (21). According to a modified procedure of Kikuchi et al.,29 N-
[2-(Dimethylamino)ethyl]-4-(triphenylmethylthio)benzamide (20)
(119.9 mg, 0.3 mmol, 1.0 equiv) was dissolved in dichloromethane
(10 mL). Methyl iodide (0.2 mL, 2.57 mmol, 10.0 equiv) was added,
and the reaction mixture was stirred at room temperature for 3 h. After
completion of the reaction, the solution was treated with a mixture of
TFA/DCM/triisopropylsilane (15:13.5:1.5 mL) and stirred under an
inert gas atmosphere at room temperature for another 3 h. The solvent
was removed in vacuo, and the residue was dissolved in water (30 mL)
and extracted with ethyl acetate (2 × 15 mL). The aqueous phase was
freeze-dried, and the title compound (76.0 mg, 0.3 mmol, 100%) was
obtained as a gray solid. Rf = 0.06 (10:1 dichloromethane/methanol).
Mp: 80.0−80.7 °C (water). No mp given in the literature. IR/cm−1
(ATR): 2988, 1684, 1653, 1595, 1541, 1396, 1339, 1315, 1201, 1066.
1H NMR (300 MHz, methanol-d4) δ 7.87−7.79 (m, 1H), 7.76−7.68
(m, 1H), 7.67−7.57 (m, 1H), 7.41−7.30 (m, 1H), 3.90−3.78 (m, 2H),
3.63−3.54 (m, 2H), 3.24 (s, 9H). 13C{1H} NMR (75 MHz, methanol-
d4) δ 167.3, 140.1, 128.9, 127.0, 125.5, 63.7, 52.4−51.4. MS (ESI): m/z
= 239.1 [M]. The obtained data match those reported in the
literature.29
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Article
2,2′-[Disulfanediylbis(benzene-4,1-diylcarbonylimino)]bis-
(N,N,N-trimethylethan ammonium) Diiodide (11). According to a
modified procedure of Kuchin et al.,28 N,N,N-trimethyl-2-[(4-
sulfanylbenzoyl)amino]ethanammonium iodide (21) (792.0 mg, 3.0
mmol, 1.0 equiv) was dissolved in ethanol (10 mL). Iodine (463.8 mg,
1.8 mmol, 0.6 equiv) was dissolved in ethanol (16 mL) and added to the
reaction mixture together with NaHCO3 (302.4 mg, 3.6 mmol, 1.2
equiv). The reaction mixture was stirred at room temperature for 2 h.
The solvent was removed in vacuo, and the residue was washed with n-
hexane (2 × 20 mL) under sonication. The supernatant was removed,
and the resulting residue was dried in vacuo. The title compound (900.0
mg, 1.9 mmol, 57%) was obtained as a yellow solid. Rf = 0.05 (5:1
dichloromethane/methanol). Mp: 273.1 °C (n-hexane, decomposi-
tion). No mp given in the literature. IR/cm−1 (ATR): 2988, 1675, 1558,
1434, 1205, 1127, 1077, 837, 803, 723. 1H NMR (600 MHz, methanol-
d4) δ 7.84 (d, J = 8.5 Hz, 4H), 7.63 (d, J = 8.5 Hz, 4H), 3.87 (tt, J = 6.7,
1.4 Hz, 4H), 3.60 (t, J = 6.7 Hz, 4H), 3.25 (s, 18H). 13C{1H} NMR
(151 MHz, methanol-d4) δ 167.5, 140.2, 131.3, 127.3, 125.5, 63.6, 52.2,
33.1. MS (ESI): m/z = 238.1 [M]. HRMS (ESI) m/z: [M] Calcd for
C24H36N4O2S22+ 238.1140; found 238.1144.
ACKNOWLEDGMENTS
■
The authors sincerely thank Professor Ramanarayanan
Krishnamurthy (Scripps Research Institute La Jolla, CA) for
helpful discussions, Dorota Ferenc and Jule Dietz for initial
experiments as well as substrate supply, Leander Geske for
HPLC support, Dr. Johannes Liermann for NMR spectroscopy
(all Johannes Gutenberg University Mainz), and Hari
Mangunuru (VCU Richmond) for starting material supply
and experimental support.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01023.
■
sı
(3) Begland, R. W. Aminomethyleneaminomaleonitriles. U.S. Patent
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General information for DAMN (1) synthesis; HPLC
method; initial disulfide studies; thiocyanate studies;
kinetic screening; reaction of DAMN with diphenyl
disulfide and thiophenol; mass spectrometry experiments;
general information for mass spectrometry; additional
information on ESI-LCMS experiments with respect to
possible side reactions; MS−MS fragmentation experi-
ments; results of HILIC-HRMS; 1H- and 13C{1H}-NMR
spectra of compounds; and ESI-LCMS chromatograms of
the aromatic disulfide 11 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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SSNMR: Solid state reaction of crystalline tetramer (diaminomaleoni-
trile). J. Chem. Phys. 2009, 130, No. 134504. (b) Minard, R.; Yang, W.;
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Bermejo, M.; José, L. Solid-state polymerization of diaminomaleoni-
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Polymer 2021, 223, No. 123696. (e) Mas, I.; Hortelano, C.; Ruiz-
Bermejo, M.; José, L. Highly efficient melt polymerization of
diaminomaleonitrile. Eur. Polym. J. 2021, 143, No. 110185. (f) Ruiz-
Bermejo, M.; de la Fuente, J. L.; Carretero-González, J.; García-
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Synthesized by Polymerization of NH4CN or Diaminomaleonitrile in
Aqueous Media: New Perspectives for Prebiotic Chemistry and
Materials Science. Chem. - Eur. J. 2019, 25, 11437−11455.
D. Tyler McQuade − Department of Chemical and Life Science
Engineering, Virginia Commonwealth University, Richmond,
Virginia 23220, United States; Email: tylermcquade@
gmail.com
Till Opatz − Department of Chemistry, Johannes Gutenberg
University, 55128 Mainz, Germany; orcid.org/0000-
0002-3266-4050; Email: opatz@uni-mainz.de
Authors
§Caroline Grundke − Department of Chemistry, Johannes
Gutenberg University, 55128 Mainz, Germany
§Caleb Kong − Department of Chemical and Life Science
Engineering, Virginia Commonwealth University, Richmond,
Virginia 23220, United States
Christopher J. Kampf − Department of Chemistry, Johannes
Gutenberg University, 55128 Mainz, Germany
B. Frank Gupton − Department of Chemical and Life Science
Engineering, Virginia Commonwealth University, Richmond,
Virginia 23220, United States; orcid.org/0000-0002-
8165-1088
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01023
Notes
The authors declare no competing financial interest.
§Shared First Authorship.
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