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Articleshttps://doi.org/10.1038/s41557-018-0102-z
The energy-transfer-enabled biocompatible disulfide–ene reactionMichael Teders1, Christian Henkel2, Lea Anhäuser3, Felix Strieth-Kalthoff1, Adrián Gómez-Suárez 1, Roman Kleinmans1, Axel Kahnt 2, Andrea Rentmeister 3,4, Dirk Guldi 2* and Frank Glorius 1*
1Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany. 2Department für Chemie und Pharmazie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 3Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany. 4Cells-in-Motion Cluster of Excellence (EXC1003-CiM), Westfälische Wilhelms-Universität, Münster, Germany. *e-mail: [email protected]; [email protected]
SUPPLEMENTARY INFORMATION
In the format provided by the authors and unedited.
NATuRe CHeMiSTRy | www.nature.com/naturechemistry
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Supplementary Information
The Energy Transfer Enabled Biocompatible Disulfide–Ene
Reaction
Michael Teders,a Christian Henkel,b Lea Anhäuser,c Felix Strieth-Kalthoff,a
Adrián Gómez-Suárez,a Roman Kleinmans,a Axel Kahnt,b Andrea
Rentmeister,c,d Dirk Guldi,b,* and Frank Gloriusa,*
a Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster,
Corrensstr. 40, 48149 Münster (Germany)
b Department für Chemie und Pharmazie, Lehrstuhl für Physikalische Chemie I, Friedrich-Alexander-
Universität Erlangen-Nürnberg, Egerlandstr. 3, 91058 Erlangen (Germany)
c Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2,
48149 Münster (Germany)
d Cells-in-Motion Cluster of Excellence (EXC1003-CiM), Westfälische Wilhelms-Universität Münster,
48149 Münster (Germany)
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Table of Contents
1. General Information ............................................................................................................. 4
2. Hypothesis-Driven Luminescence Screening ........................................................................... 9
2.1. General Procedure for Screening Studies ............................................................................... 9
2.2. Results ................................................................................................................................... 12
2.3. Luminescence Spectra ........................................................................................................... 13
3. Photosensitized Disulfide-Ene-Reaction – Hydroalkyl- and Hydroarylthiolation of Unactivated
Alkenes and Alkynes ................................................................................................................... 17
3.1. Optimization Studies for the Disulfide-Ene-Reaction Using Carvone and Dimethyl Disulfide ..
............................................................................................................................................... 17
3.2. Scope and Limitation Studies ................................................................................................ 19
3.2.1. Symmetric Disulfides ..................................................................................................... 19
3.2.2. Asymmetric Disulfides ................................................................................................... 34
4. Mechanistic Experiments .................................................................................................... 35
4.1. Transient Absorption Spectroscopy and Related Spectroscopic Studies .............................. 35
4.2. Kinetic Analysis ...................................................................................................................... 40
4.3. Electrochemistry .................................................................................................................... 43
4.4. Determination of the Reaction Quantum Yield..................................................................... 44
4.5. Stern-Volmer Luminescence Quenching Studies .................................................................. 47
4.6. UV/Vis Absorption Studies .................................................................................................... 48
4.7. Reaction Profile for the Disulfide-Ene-Reaction using Carvone, Dimethyl Disulfide and [Ir-F]
............................................................................................................................................... 49
4.8. TEMPO Radical Trapping Experiment .................................................................................... 50
4.9. Deuteration Experiment ........................................................................................................ 51
4.10. Thiylradical Scrambling Experiment ...................................................................................... 52
4.11. Luminescence-Screening Utilizing Sterically Demanding Disulfides ..................................... 53
4.12. Selectivity Competition Experiment – Disulfide–Ene vs. Thiol–Ene Reaction ....................... 56
4.13. Isolation of polysulfide side-products ................................................................................... 58
5. The Disulfide-Ene Click Reaction using an Alloxazine Photocatalyst ...................................... 60
5.1. Optimization Studies ............................................................................................................. 60
5.2. General Procedure (GP2) Using Alloxazine as Photocatalyst ................................................ 61
5.3. Reaction Profile for the Disulfide-Ene-Reaction Alloxazine (10) as Photocatalyst ............... 63
5.4. Stern-Volmer Luminescence Quenching Analysis ................................................................. 64
6. Additive-based Robustness Screen ...................................................................................... 65
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7. Oxidation of Methylthioethers to Sulfoxides and Sulfones ................................................... 67
8. Additive-based Biocompatibility Screening .......................................................................... 69
8.1. Investigating Aqueous Reaction Conditions .......................................................................... 69
8.2. Investigating the Biocompatibility of the Disulfide–Ene Reaction ........................................ 70
9. References .......................................................................................................................... 84
10. Spectra ............................................................................................................................... 86
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1. General Information
General information regarding reaction discovery, optimization and evaluation of the scope
Unless otherwise noted, all reactions were carried out under an atmosphere of argon in oven-dried
glassware. The solvents used were purified by distillation over standard drying agents or were bought
as commercials with less than 50 ppm water and were stored over molecular sieves and transferred under
argon. Blue LEDs (5 W, λmax = 455 nm or 3 W, λmax = 420 nm) or UV-A LEDs (3 W, λmax = 365 nm)
were used for irradiation (for emission spectra, see Figure 1). All LEDs were obtained from
www.avonec.de and were bought fitted on a circuit board, which has been attached to a cooling body
(see Figure 1).
Supplementary Figure 1. Emission spectra of the used light sources recorded using a Jasco FP-8300
fluorescence spectrometer and picture of LED with cooling body.
The light source was placed in ~ 5 cm distance from the reaction vessel. A custom made “light box”
was used with 6 LEDs arranged around the reaction vessels (see Figure 2). A fan attached to the
apparatus was used to maintain the temperature inside the “light box” at no more than 9 °C above room
temperature.
0
0,2
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300 350 400 450 500
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420 nm Blue LED
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Supplementary Figure 2. Photographs of the “light box” used for reactions conducted under LED
irradiation.
Photocatalysts [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) ([Ir-F], dF(CF3)ppy = 2-(2,4-difluorophenyl)-3-
trifluoromethylpyridine),1 [Ru(bpy)3]2(PF6)2 (13, bpy = 2,2′-bipyridine),2 [Ru(phen)3](PF6)2 (14, phen =
1,10-phenanthroline),3 [Ir(ppy)2(dtbbpy)](PF6) (15, ppy = 2-phenylpyridine, dtbbpy = 4,4ʹ-di-tert-butyl-
2,2ʹ-bipyridine),4 [Ru(bpz)3](PF6)2 (16, bpz = 2,2′-bipyrazine),5 fac-[Ir(ppy)3] (17),6 [Ir(ppy)2(NHC-F2)]
(18, NHC-F2 = 1-(2,4-difluorophenyl)-3-methyl-2,3-dihydro-1H-imidazolydene),7 fac-[Ir(dF-ppy)3]
(19, dF(ppy) = 2-(2,4-difluorophenyl)pyridine),8 FlIrPic (20, Fl = 2-(2,4-difluorophenyl)pyridine, pic =
picolinate)9 and 1-butyl-7,8-dimethoxy-3-methylalloxazine (21)10 were prepared according to literature
known procedures. Riboflavine was purchased from Aldrich and used as received.
Starting Materials 1ag-1ai were prepared following a procedure from Dexter et al.11 Starting Materials
1k, 1am-1ao and 1au-1av were prepared in analogy to a procedure published by Ronayne et al.12 The
azide 1af was synthesized following a procedure by Lobez and Swager.13 Acrylamide 1w was
synthesized according to a literature procedure by Fabry et al.14 Saccharin derivative 1x was prepared
following a procedure by D’Ascenzio et al.15 Carvone derivative 1n was prepared according to a
literature procedure by Srikishna, Ravi and Satyanarayana.16 Substrates 1a, 1c, 1d, 1f, 1m, 1o and 1v
were purchased enantiomerically pure, as well as the amino acids used for the synthesis of 1ag-1ai.
Flash chromatography was performed on Merck silica gel (40-63 µm mesh) using standard techniques.
NMR-spectra were recorded on a Bruker AV-300, AV-400 MHz or on a Varian Associated, Varian 600
unity plus spectrometer. Chemicals shifts (δ) are quoted in ppm downfield of tetramethylsilane. The
residual solvent signals were used as references for 1H and 13C NMR spectra (CDCl3: δH = 7.26 ppm,
δC = 77.16 ppm). 19F NMR spectra are not calibrated by an internal reference. Coupling constants (J)
are quoted in Hz.
GC-MS spectra were recorded on an Agilent Technologies 7890A GC-system with an Agilent
5975C VL MSD or an Agilent 5975 inert Mass Selective Detector (EI) and a HP-5MS column (0.25
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mm × 30 m, film: 0.25 µm). The major signals are quoted in m/z with the relative intensity in
parentheses. The method indicated as ‘50_40’ starts with an injection temperature T0 (50 °C). After
holding this temperature for 3 min, the column is heated by 40 °C/min to temperature T1 (290 °C or
320 °C) and this temperature is held for an additional time. ESI mass spectra were recorded on a Bruker
Daltonics MicroTof spectrometer or a Bruker Orbitrap. Infrared spectra were recorded on an ATR
Shimadzu FTIR 8400S spectrometer. The wave numbers () of recorded IR-signals are quoted in cm-1.
Luminescence quenching screening and full Stern-Volmer luminescence quenching analysis were
conducted using a Jasco FP-8300 fluorescence spectrometer. The following parameters were employed:
excitation bandwidth = 5 nm, data interval = 0.2 nm, scan speed = 500 nm/min, response time = 0.2 sec.
UV/Vis Absorption spectra were recorded on a Jasco V-650 spectrophotometer, equipped with a
temperature control unit at 25 °C. The samples were measured in Hellma fluorescence QS quartz
cuvettes (chamber volume = 1.4 mL, H × W × D = 46 mm × 12.5 mm × 12.5 mm) fitted with a PTFE
stopper.
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General information regarding transient absorption and related spectroscopic studies
Absorption spectra between 250 and 800 nm were measured with a PerkinElmer Lambda2 dual beam
absorption spectrometer with a scan rate of 480 nm/min and a resolution of 1 nm.
Steady state emission measurements were carried out using a Fluoromax-3-spectrometer from HORIBA
Jobin Yvon. Cryostat supported measurements were conducted by an Optistat DN2 of the Oxford
Instruments brand at 90 K. The measurement parameters include a slit width of 2 nm for both, excitation
slit and the emission slit, and an integration time of 0.1 s.
Femtosecond transient absorption experiments were carried out with Clark MXR CPA-2110 and
CPA 2101 amplified Ti:Sapphire fs laser systems (output ~775 nm, ~1 kHz repetition rate, and 150 fs
pulse width) using a transient absorption pump/probe detection system (Ultrafast Systems Helios and
EOS). The excitation wavelengths were generated either by a harmonic generator (387 and 258 nm,
Clark MXR Storc harmonic generator) or by a noncollinear optical parametric amplifier with subsequent
frequency doubling (640 → 320 nm, Clark MXR NOPA). For the excitation wavelength, the energy of
150-200 nJ/pulse was selected. The spectral data were evaluated using the TIMP based GloTarAn
program.17 For every dataset, a global analysis with one to three decay associated components was used.
Phosphorescence lifetime quenching experiments were conducted using a self-constructed ns-TAS
system. A Nd:YAG laser (Brilliant B, Quantel: output 1064 nm, 10 Hz, 4-8 ns pulse width) is used to
excite the sample. The laser is tuned by a third harmonic generator (Quantel) to reach a 355 nm output.
The emitted light passes a filter wheel (used long pass filter: 395 nm) to avoid the redirection of scattered
higher harmonic wavelengths. After passing a monochromator, selecting the desired emission
wavelength, the light is detected by a photomultiplier (230 – 880 nm, 10 ns time resolution). Eventually,
the data are digitalized by a LeCroy digital storage oscilloscope.
The samples are prepared in Hellma cuvettes with the characteristics: 10 x 10 mm QS cuvettes for
steady-state absorption and emission spectroscopy, 8 x 10 mm QS cuvettes for phosphorescence lifetime
quenching experiments, 2 x 10 mm OS cuvettes for TAS (> 350 nm excitation), 2 x 10 mm QS cuvettes
(< 350 nm excitation).
To record electrochemical data, a Metrohm FRA 2 µAutolab Type III potentiostat is used. A three
electrode cell configuration, composed of a glassy carbon working electrode (3 mm diameter), a Ag-
wire quasi-reference electrode and a platinum wire counter electrode is used to perform square wave
voltammetry, differential pulse voltammetry, and cyclic voltammetry. For cyclic voltammetry, scan
rates between 0.025 and 0.1 V/s with varying steps of 0.025 V/s are chosen. As conducting salt predried
tetrabutylammonium hexafluorophosphate is used in a concentration of 0.1 mol/L. Potentials are
referred to the ferrocene/ferrocenium (Fc/Fc●+) redox couple.
The samples are saturated with dry Ar gas before measurement of cryostat supported emission, as well
as electrochemical and TAS experiments, to ensure oxygen expulsion. Furthermore, the cuvettes are
sealed by precision seal rubbers.
The used solvents are of spectroscopical grade and are supplied by Sigma-Aldrich. For UV/Vis
absorption and emission measurements, as well as electrochemistry, and for TAS experiments, dry
acetonitrile was used. Cryostat supported low-temperature emission spectroscopy was performed by
using a mixture of dry propan-1-ol and propan-2-ol (1:1, v:v).
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General information regarding the biocompatibility screening
LC-MS measurements were performed on a Bruker maXis II ultra-high resolution QTOF coupled to a
Thermo Scientific UltiMate 3000® UHPLC using a Nucleodur® C18 Pyramid reversed-phase column
(5 µm, 125 x 10 mm, 2 mm ID) from Macherey-Nagel. Elution was performed at a flow rate of
0.6 mL/min applying a linear gradient for buffer A (20 mM ammonium formiate, pH = 3.5) and buffer
B (MeOH).
For protein analysis, an aliquot of the reaction mixture (100 µL) was taken after photoreaction. Analysis
was performed by gel electrophoresis using 15% Tris-glycine gel (30% acrylamide, 0.8%
bisacrylamide).
The sequence of single stranded DNA (ssDNA) was 5′-TAA ATG GAT CCT TAC TTG TAC AGC
TCG TCC ATG CC-3′ (Biolegio, purification: desalination) and the sequence of the short RNA was 5′-
GUG ACC GCG GAU CGA CUU CAC CGC GCA GUG-3′ (biomers.net, purification: HPLC).
For nucleic acid analysis, an aliquot of the reaction mixture (100 µL) containing ssDNA, short RNA or
total RNA was precipitated (3 vol. 100% EtOH, 0.3 M NaOAc) after photoreaction and redissolved in
water. Analysis was performed by gel electrophoresis using 15% denaturing polyacrylamide gel (25%
acrylamide/bisacrylamide 19:1 and 50% urea) for short DNA and short RNA and using 7.5% denaturing
PAA-gel for total RNA, respectively.
For isolation of total RNA, HeLa cells were cultured in DMEM Earle’s (Merck Millipore) media
supplemented with 2 mM L-glutamine, 1% non-essential amino acids, 1% penicillin and streptomycin
and 10% fetal calf serum (FCS) under standard conditions (5% CO2, 37 °C). 24 h before isolation of
total RNA, 1 x 105 cells were seeded in 1 mL media in a 12-well plate. Cells were incubated with lysis
buffer (1% Nonident® P40 (Applichem), 10 mM Tris-HCl, pH = 7.5) and then, the total RNA was
extracted using phenol-chloroform (4:1 and 2:1), precipitated (1.2 vol. 100% isopropanol, 0.3 M
NaOAc) and redissolved in water.
For preparation of human cell lysate, HeLa cells were cultured as described above. 24 h before cell lysis
3 x 106 cells were seeded in 10 mL media in a 90 mm plate. Cells were washed with 1x PBS (10 mL)
and incubated with CellLyticTM M reagent (1 mL, Sigma Aldrich) for 15 min on a shaker. Lysed cells
were collected using a sterile cell scraper and 100 µL aliquots were stored at -80 °C.
The protein concentration of human cell lysate was determined from a Bradford assay using BSA
calibration standards and a dilution series of cell lysate. Samples (15µL) were incubated (rt, 15 min,
exclusion of light) with 1x Roti®-Quant (Carl Roth) staining solution (100 µL) and then, the absorption
at 595 nm was determined. The protein concentration of cell lysate preparations for OD595
were ~ 5 - 8 mg/mL.
Absorption measurements and determination of nucleic acid concentration were recorded using a
TECAN Infinite M1000 PRO® (Tecan).
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2. Hypothesis-Driven Luminescence Screening
2.1. General Procedure for Screening Studies
All samples used in the luminescence screening studies were prepared under oxygen-free conditions.
The photocatalysts and potential quenchers were weighed into vials and placed inside a glovebox (a
common glovebag can alternatively be used) under a positive pressure of argon. Acetonitrile was
degassed by argon sparging for one hour and also placed inside along with micropipettes and tips,
cuvettes, empty vials, waste containers and parafilm. Each photocatalyst and substrate sample was then
dissolved in acetonitrile. For each measurement, the appropriate amount of the photocatalyst and
substrate were added to a cuvette and diluted to 1 mL with acetonitrile using micropipettes. A
photocatalyst concentration of 10 μM was used throughout the screening studies along with substrate
concentrations of 25 mM, which equates to 2500 equivalents of each potential quencher relative to the
photocatalyst. The cuvette was then capped with a PTFE stopper and sealed further with parafilm before
being removed from the glovebox and transferred to the fluorescence spectrometer. After the
measurements, the sealed cuvette was brought back into the glovebox, emptied, cleaned with acetonitrile
and dried under a stream of argon before preparing the next sample.
The luminescence emission spectrum of each photocatalyst excited at 420 nm was measured six times
(three different samples, measured twice each) and an average was taken as the standard reference
spectrum. The samples containing potential quenchers were each measured twice and an average was
taken. The emission intensity (I) at a pre-defined wavelength was noted and compared with that of the
photocatalyst in isolation (I0). The amount of decrease in the emission intensity was then quantified as
a “quenching percentage” (F) defined by the following formula:
F(%)=100 (1-I
I0
)% Equation 1
The structures of the photocatalysts employed in this study are shown in Figure 3A. UV/Vis absorption
spectra and extinction coefficients at 420 nm and 455 nm for the photocatalyst [Ir-F] can be found in
Figure 3B.
- 10 -
Supplementary Figure 3A. Structures of photocatalysts and the wavelengths used to calculate the
quenching percentage (F).
- 11 -
[Ir(dF(CF3)ppy)2(dtbbpy))(PF6) ([Ir-F])
Extinction coefficient:
Irradiation wavelength / nm Extinction coefficient ϵ / L mol-1 cm-1
420 2177
455 376
Supplementary Figure 3B. UV/Vis absorption spectra and extinction coefficients at 420 and 455 nm
for [Ir-F]. The concentration of the photocatalyst was 0.5 mM. Extinction coefficients were determined
using three data points.
0
0,5
1
1,5
2
2,5
3
3,5
4
350 400 450 500 550 600 650 700
Ab
sorb
ance
/ a
.u.
λem / nm
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2.2. Results
The quenching fractions F obtained at the maximum emission wavelengths of the specific photocatalyst
in the presence of dimethyl disulfide (2) are depicted in Table 1 below. The luminescence spectra for
each combination are shown below. Hypothesis-Driven Stern-Volmer luminescence quenching studies
were carried out using 2 x 10-6 M solutions of the photocatalyst in the presence of 2500 equiv of
dimethyldisulfide.
Supplementary Table 1. Quenching fractions F of different photocatalysts in the presence of dimethyl
disulfide (2). F values were obtained in one single luminescence quenching experiment.
Photocatalyst Quenching Fraction F
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) ([Ir-F])
[Ru(bpy)3]2(PF6)2 (13)
[Ru(phen)3](PF6)2 (14)
[Ir(ppy)2(dtbbpy)](PF6) (15)
[Ru(bpz)3](PF6)2 (16)
fac-[Ir(ppy)3] (17)
[Ir(ppy)2(NHC-F2)] (18)
fac-[Ir(dF(ppy)3)] (19)
- 13 -
2.3. Luminescence Spectra
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) ([Ir-F]) and dimethyl disulfide (2)
[Ru(bpy)3]2(PF6)2 (13) and dimethyl disulfide (2)
- 14 -
[Ru(phen)3](PF6)2 (14) and dimethyl disulfide (2)
[Ir(ppy)2(dtbbpy)](PF6) (15) and dimethyl disulfide (2)
- 15 -
[Ru(bpz)3](PF6)2 (16) and dimethyl disulfide (2)
fac-[Ir(ppy)3] (17) and dimethyl disulfide (2)
- 16 -
[Ir(ppy)2(NHC-F2)] (18) and dimethyl disulfide (2)
fac-[Ir(dF(ppy)3)] (19) and dimethyl disulfide (2)
- 17 -
3. Photosensitized Disulfide-Ene-Reaction – Hydroalkyl- and
Hydroarylthiolation of Unactivated Alkenes and Alkynes
3.1. Optimization Studies for the Disulfide-Ene-Reaction Using Carvone and
Dimethyl Disulfide
The photocatalyst was added to an oven-dried Schlenk tube containing a magnetic stirring bar. The
photocatalyst was dissolved in the solvent and (R)-(–)-Carvone (1a) (15.7 µL, 0.1 mmol, 1.0 equiv) and
dimethyl disulfide were added via syringe using schlenk techniques. The resulting solution was degassed
using three freeze-pump-thaw cycles and the tube was finally backfilled with argon. The samples were
irradiated with the respective light source for the mentioned time. After the indicated time, mesitylene
(14 µL, 0.1 mmol, 1.0 equiv) was added as internal standard. The yield of product 3a and the remaining
starting material was quantified using GC-FID.
Entry Ratio 1a:2
Solvent Photocatalyst
(mol%) Time / h
Light source / nm
Yield 3a[a]
Yield 1a[a]
1 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (2.5)
16 455 58 1
2 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (2.5)
16 / 0 103
3 1:2 MeCN (0.1 M)
/ 16 455 0 102
4 1:2 MeCN (0.1 M)
[Ir(ppy)2(dtbbpy)](PF6) (2.5)
16 455 0 102
5 1:2 MeCN (0.1 M)
[Ir(ppy)2(NHC-F2)] (2.5) 16 455 47 8
6 1:2 MeCN (0.1 M)
fac-[Ir(ppy3)] (2.5) 16 455 46 2
7 1:2 MeCN (0.1 M)
fac-[Ir(dF-ppy3)] (2.5) 16 455 53 4
8 1:2 MeCN (0.1 M)
[Ru(bpy)3]2(PF6)2 (2.5) 16 455 0 87
10 1:2 MeCN (0.1 M)
[Ru(phen)3]2(PF6)2 (2.5) 16 455 0 96
11 1:2 MeCN (0.1 M)
[Ru(bpz)3](PF6)2 (2.5) 16 455 0 93
12 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2bpy)](PF
6) (2.5) 16 455 47 2
13 1:2 MeCN (0.1 M)
FlIrPic (5.0) 16 455 56 3
14 1:2 MeCN (0.1 M)
Riboflavine (5.0) 16 400 0 97
15 1:2 MeCN (0.1 M)
Benzophenone (5.0) 16 365 25 35
16 1:2 EtOAc (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (2.5)
16 455 52 26
17 1:2 DMF
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 32 45
18 1:2 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 74 1
- 18 -
Entry Ratio 1a:2
Solvent Photocatalyst
(mol%) Time / h
Light source / nm
Yield 3a[a]
Yield 1a[a]
19 1:2 Acetone (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (2.5)
16 455 45 22
20 1:2 DMSO (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (2.5)
16 455 1 44
21 1:2 Fluorobenzene
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 54 31
22 1:2 1,4-Dioxane
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 54 32
23 1:2 CHCl3 (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (2.5)
16 455 43 6
24 1:1 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 53 35
25 1:3 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 69 1
26 1:2 DCE
(0.05 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 67 4
27 1:2 DCE
(0.2 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (2.5) 16 455 61 23
28 1:2 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (1.0) 16 455 68 2
29 1:2 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (5.0) 16 455 61 3
30 1:2 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (0.5) 16 455 52 29
31 1:2 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (0.1) 16 455 19 72
32 1:0 DCE
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (1.0) 16 455 0 97
33 1:2 MeCN/H2O (1:1)
(0.1 M) [Ir(dF(CF3)ppy)2(dtbbpy)]
(PF6) (1.0) 16 455 53 19
34[b] 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1.0)
16 455 18 25
35 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1.0)
16 420 69 11
36 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1.0)
16 400 66 19
37 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1.0)
16 365 52 2
38 1:2 MeCN (0.1 M)
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1.0)
16 / 0 98
39 1:2 MeCN (0.1 M)
/ 16 455 0 101
[a] Yields were determined by GC-FID using mesitylene as internal standard. [b] No degassing of the reaction solution prior
to irradiation. Optimization reactions 1-37 were performed once. The reactions 38 and 39 have been independently three times
repeated with similar results.
- 19 -
3.2. Scope and Limitation Studies
General Procedure (GP1) for the Disulfide-Ene-Reaction using [Ir-F]
The photocatalyst [Ir-F] (3.4 mg, 0.003 mmol, 1.0 mol%) was added to an oven-dried Schlenk tube
containing a magnetic stirring bar. Anhydrous DCE (3.0 mL, 0.1 M) was added under Argon. In the
absence of light, the alkene (0.30 mmol, 1.0 equiv) and the disulfide (0.60 mmol, 2.0 equiv) were added
under an argon stream. The resulting solution was degassed using three freeze-pump-thaw cycles and
the tube was finally backfilled with argon. The reaction mixture was allowed to stir at room temperature
for 16 h under irradiation with visible light from six blue LEDs (5 W, λmax = 455 nm). For workup the
solvent was evaporated. The crude reaction products were purified by column chromatography over
silica gel (dry load of crude material, n-pentane/ethyl acetate or dichloromethane/methanol mixtures as
eluent) to afford the pure products 3a-3ap.
Hydrothiolation reactions were performed one single time. The benchmark reaction yielding 3a was
repeated three times by different co-workers with similar results.
3.2.1. Symmetric Disulfides
(5S)-2-methyl-5-(1-(methylthio)propan-2-yl)cyclohex-2-en-1-one (3a)
Prepared from (R)-(–)-carvone (47.1 µL) and dimethyl disulfide (53.1 µL)
following the GP1 to give the product 3a as a colorless oil (44.0 mg, 0.22 mmol,
74%) as a 1:1 mixture of diastereomers.
1H NMR of diastereomers (400 MHz, chloroform-d): δ 6.74 (d, J = 6.7 Hz, 1H), 2.54 (dd, J = 8.8,
5.5 Hz, 1H), 2.47 (ddd, J = 12.5, 4.7, 2.5 Hz, 1H), 2.37 (ddd, J = 12.7, 7.9, 6.8 Hz, 2H), 2.29 – 2.10 (m,
4H), 2.07 (s, 3H), 1.76 (dt, J = 2.7, 1.4 Hz, 3H), 1.00 (dd, J = 6.9, 1.0 Hz, 3H); 13C{1H} NMR (101 MHz,
chloroform-d): δ 200.1, 145.0, 144.9, 135.5, 42.6, 40.6, 39.4, 39.2, 39.2, 39.1, 36.8, 36.6, 30.5, 28.3,
16.3, 16.2, 15.9, 15.9, 15.7, 15.7; Rf (n-pentane:ethyl acetate = 95:5): 0.18; GC-MS: tR (50_40): 8.3
min; EI-MS: m/z (%): 41 (11), 61 (14), 77 (6), 79 (12), 81 (9), 107 (11), 108 (37), 109 (100), 121 (18),
150 (29), 198 (25); HR-MS (ESI): m/z calculated for [(C11H18OS)Na]+: 221.0971, found: 221.0998; IR
(ATR): ν (cm-1): 2962, 2314, 1667, 1519, 1373, 1257, 1111, 1064, 964, 748.
3-(Methylthio)cyclohexan-1-one (3b)
Prepared from 2-cyclohexen-1-one (28.8 µL) and dimethyl disulfide (53.1 µL) following
the GP1 to give the product 3b as a colorless oil (24.2 mg, 0.17 mmol, 56%).
1H NMR (400 MHz, chloroform-d): δ 3.02 – 2.91 (m, 1H), 2.75 – 2.67 (m, 1H), 2.43 – 2.26 (m, 3H),
2.19 – 2.12 (m, 2H), 2.11 (s, 3H), 1.75 – 1.66 (m, 2H); 13C{1H} NMR (101 MHz, chloroform-d): δ 13C
- 20 -
NMR (101 MHz, CDCl3) δ 209.2, 47.9, 44.5, 41.0, 31.7, 24.6, 14.0; Rf (n-pentane:ethyl
acetate = 95:5): 0.21; GC-MS: tR (50_40): 6.9 min; EI-MS: m/z (%):39 (23), 41 (61), 55 (38), 67 (16),
68 (29), 69 (65), 74 (17), 96 (61), 97 (54), 144 (100).
(4S)-4-(1-(Methylthio)propan-2-yl)cyclohex-1-ene-1-carbaldehyde (3c)
Prepared from (S)-(–)-perillaldehyde (47.1 µL) and dimethyl disulfide (53.1 µL)
following the GP1 to give the product 3c as colorless oil (28.4 mg, 0.14 mmol,
48%) as a 1:1 mixture of the two diastereomers.
1H NMR of diastereomers (300 MHz, chloroform-d): δ 9.42 (s, 1H), 6.80 (d, J = 4.8 Hz, 1H), 2.68 –
2.34 (m, 4H), 2.09 (s, 3H), 1.88 – 1.63 (m, 4H), 1.27 (dt, J = 11.5, 5.5 Hz, 2H), 1.06 – 0.97 (m, 3H); 13C{1H} NMR of diastereomers (75 MHz, chloroform-d): δ 194.0, 194.0, 151.0, 141.6, 141.6, 39.7,
37.4, 37.2, 36.8, 30.8, 28.5, 25.7, 23.6, 21.9, 21.8, 16.3, 16.2, 15.9, 15.6; Rf (n-pentane:ethylacetate =
95:5): 0.28; GC-MS: tR (50_40): 8.5 min; EI-MS: m/z (%): 41 (13), 61 (19), 77 (14), 79 (41), 81 (15),
91 (12), 107 (26), 109 (23), 150 (100), 198 (19); HR-MS (ESI): m/z calculated for [(C11H18OS)Na]+:
221.0971, found 221.0977; IR (ATR): ν (cm-1): 2916, 1643, 1381, 1257, 956, 748, 694.
Methyl(2-((R)-4-methylcyclohex-3-en-1-yl)propyl)sulfane (3d)
Prepared from (R)-(+)-limonene (48.5 µL) and dimethyl disulfide (53.1 µL) following GP1
to give product the 3d as yellow oil (44.7 mg, 0.24 mmol, 81%) as a 1:1 mixture of the two
diastereomers. The product contains minor traces of the dithiolated compound 3o and the
trisulfide 9.
1H NMR of diastereomers (300 MHz, chloroform-d): δ 5.36 (s, 1H), 2.63 – 2.30 (m, 3H), 2.08 (s,
3H), 1.95 – 1.72 (m, 5H), 1.63 (m, 3H), 1.42 – 1.23 (m, 2H), 1.00 – 0.94 (m, 3H); 13C{1H} NMR of
diastereomers (75 MHz, chloroform-d): δ 134.1, 120.6, 52.9, 39.9, 37.7, 37.5, 37.3, 37.2, 37.1, 36.1,
35.6, 35.6, 30.8, 30.7, 29.9, 29.6, 28.2, 27.3, 27.2, 25.2, 23.5, 20.4, 16.2, 16.2, 16.1, 15.7; Rf (n-
pentane:ethyl acetate = 97:3): 0.60; GC-MS: tR (50_40): 7.6 min; EI-MS: m/z (%): 39 (10), 41 (19),
53 (10), 61 (19), 67 (20), 77 (17), 79 (66), 81 (25), 91 (18), 93 (42), 94 (100), 107 (35), 121 (21), 136
(84), 184 (23); IR (ATR): ν (cm-1): 2916, 1635, 1373, 1057, 956, 887, 748.
Cyclooctyl(methyl)sulfane (3e)
Prepared from cyclooctene (39.0 µL) and dimethyl disulfide (53.1 µL) following GP1 to
give product 3e as colorless oil (59.4 mg). The product contains trisulfide 9 as an impurity.
The overall yield of 3e (83%) was determined by NMR via subtraction of the impurities.
1H NMR (300 MHz, chloroform-d): δ 2.17 – 2.16 (m, 1H), 2.08 (s, 3H), 1.97 – 1.91 (m, 2H), 1.77 –
1.72 (m, 2H), 1.65 – 1.47 (m, 10H); 13C{1H} NMR (75 MHz, chloroform-d): δ 46.2, 32.1, 27.1, 25.9,
25.2, 14.3; Rf (n-pentane:ethyl acetate = 98:2): 0.27; GC-MS: tR (50_40): 7.1 min; EI-MS: m/z (%):
39 (20), 41 (49), 45 (10), 53 (11), 54 (23), 55 (54), 61 (18), 67 (65), 68 (23), 69 (100), 74 (11), 81 (44),
- 21 -
82 (78), 87 (21), 95 (22), 110 (37), 111 (21), 143 (22), 158 (60); IR (ATR): ν (cm-1): 2916, 2851, 1373,
1056, 887, 748.
The NMR data were consistent with the reported data.18
(4R)-1-Methyl-4-(1-(methylthio)propan-2-yl)-7-oxabicyclo[4.1.0]heptane (3f)
Prepared from (+)-limonene oxide (49.5 µL) and dimethyl disulfide (53.1 µL)
following GP1 to give product 3f as a white solid (48.0 mg, 0.24 mmol, 80%).
1H NMR (400 MHz, chloroform-d): δ 2.98 (d, J = 5.3 Hz, 1H), 2.56 – 2.45 (m, 1H), 2.38 – 2.27 (m,
1H), 2.07 (s, 3H), 2.03 – 1.87 (m, 2H), 1.71 – 1.49 (m, 3H), 1.43 – 1.33 (m, 1H), 1.30 (s, 3H), 1.27 –
1.10 (m, 2H), 0.91 (dd, J = 6.9, 2.3 Hz, 3H); 13C{1H} NMR (101 MHz, chloroform-d): δ 59.5, 57.8,
39.5, 36.6, 30.8, 28.7, 25.9, 23.1, 21.1, 16.2, 16.1; Rf (n-pentane:ethyl acetate = 98:2): 0.17; GC-MS:
tR (50_40): 8.2 min; EI-MS: m/z (%): 39 (13), 41 (44), 43 (32), 55 (39), 61 (46), 67 (19), 69 (28), 81
(22), 95 (22), 111 (100), 137 (62), 152 (97), 200 (21); IR (ATR): ν (cm-1): 2916, 1604, 1519, 1257,
1018, 887, 748.
N-(3-(Methylthio)propyl)benzamide (3g)
Prepared from N-allylbenzamide (47.3 µL) and dimethyl disulfide (53.1 µL)
following GP1 to give product 3g as colorless oil (52.9 mg, 0.25 mmol, 84%).
1H NMR (300 MHz, chloroform-d): δ 7.79 – 7.73 (m, 2H), 7.51 – 7.45 (m, 1H), 7.44 – 7.38 (m, 2H),
6.64 (s, 1H), 3.56 (q, J = 6.7 Hz, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.10 (s, 3H), 1.92 (pent, J = 6.9 Hz, 2H); 13C{1H} NMR (75 MHz, chloroform-d): δ 167.6, 134.6, 131.4, 128.6, 126.9, 39.3, 31.6, 28.5, 15.5;
Rf (n-pentane:ethyl acetate = 50:50): 0.47; GC-MS: tR (50_40): 9.1 min; EI-MS: m/z (%): 51 (10), 77
(43), 105 (100), 134 (49), 135 (14), 162 (52), 163 (7), 209 (6); HR-MS (ESI): m/z calculated for
[(C11H15NOS)Na]+: 232.0767, found 232.0776; IR (ATR): ν (cm-1): 3309, 2916, 2862, 1635, 1543,
1435, 1311, 1157, 1026, 864, 802, 694, 671.
The NMR data were consistent with the reported data.19
- 22 -
2-(3-(Methylthio)propyl)phenol (3h)
Prepared from meta-allylphenol (39.6 µL) and dimethyl disulfide (53.1 µL)
following GP1 to give product 3h as a colorless oil (50.6 mg, 0.28 mmol, 93%).
1H NMR (500 MHz, chloroform-d): δ 7.15 – 7.05 (m, 2H), 6.91 – 6.77 (m, 2H), 5.62 (s, 1H), 2.75 (t,
J = 7.2 Hz, 2H), 2.54 (t, J = 6.9 Hz, 2H), 2.12 (s, 3H), 2.02 – 1.86 (m, 2H); 13C{1H} NMR (126 MHz,
chloroform-d): δ 154.1, 130.5, 127.5, 127.4, 120.9, 115.8, 33.5, 28.9, 28.3, 15.4; Rf (n-pentane:ethyl
acetate = 95:5): 0.29; GC-MS: tR (50_40): 8.3 min; EI-MS: m/z (%): 61 (14), 74 (21), 77 (38), 78
(12), 78 (11), 91 (27), 107 (42), 115 (13), 117 (11), 118 (43), 133 (100), 182 (77); HR-MS (ESI): m/z
calculated for [(C10H14OS)Na]+: 205.0663, found 205.0655; IR (ATR): ν (cm-1): 2916, 1589, 1489,
1450, 1342, 1234, 1095, 1041, 848, 748.
3-(Methylthio)tetrahydro-2H-pyran (3i)
Prepared from 3,4-dihydro-2H-pyran (27.1 µL) and dimethyl disulfide (53.1 µL) following
GP1. The yield of 3i (42%) was determined by crude 1H NMR using CH2Br2 as internal
standard with respect to the thiomethyl functionality.
GC-MS: tR (50_40): 5.8 min; EI-MS: m/z (%): 39 (8), 41 (32), 43 (22), 55 (19), 57 (28), 67 (31), 74
(5), 85 (100), 132 (24).
(2-(Benzyloxy)ethyl)(methyl)sulfane (3j)
Prepared from benzyl vinyl ether (43.7 µL) and dimethyl disulfide (53.1 µL)
following the GP1 to give the product 3j as white solid (30.7 mg, 0.17 mmol,
56%).
1H NMR (300 MHz, chloroform-d): δ 7.36 – 7.30 (m, 5H), 4.56 (s, 2H), 3.66 (t, J = 6.7 Hz, 2H), 2.73
(t, J = 6.7 Hz, 2H), 2.14 (s, 3H); 13C{1H} NMR (75 MHz, chloroform-d): δ 128.4, 128.0, 127.8, 127.7,
73.1, 69.4, 33.7, 16.1; Rf (n-pentane:ethyl acetate 95:5): 0.37; GC-MS: tR (50_40): 7.6 min; EI-MS:
m/z (%): 51 (5), 61 (39), 65 (15), 75 (53), 77 (11), 91 (100), 92 (9), 105 (9), 107 (7), 182 (15); IR (ATR):
ν (cm-1): 2916, 1257, 1195, 1103, 1026, 964, 902, 748, 570.
- 23 -
3-(4-(Methylthio)butoxy)pyridine (3k)
Prepared from 3-(but-3-en-1-yloxy)pyridine (44.7 mg) and dimethyl disulfide
(53.1 µL) following GP1 to give product 3k as a yellowish oil (41 mg,
0.21 mmol, 69%).
1H NMR (400 MHz, chloroform-d): δ 8.28 (d, J = 2.7 Hz, 1H), 8.18 (dd, J = 4.3, 1.7 Hz, 1H), 7.21 –
7.13 (m, 2H), 4.00 (t, J = 6.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.09 (s, 3H), 1.94 – 1.85 (m, 2H), 1.82 –
1.73 (m, 2H); 13C{1H} (100 MHz, chloroform-d): δ 155.2, 142.1, 138.0, 123.9, 121.1, 67.8, 33.9, 28.3,
25.6, 15.6; Rf (n-pentane:ethyl acetate = 2:1): 0.23; GC-MS: tR (50_40): 8.3 min; EI-MS: m/z (%):
39 (18), 51 (10), 55 (26), 61 (100), 78 (17), 95 (18), 96 (21), 103 (66), 151 (12), 197 (20); HR-MS
(ESI): m/z calculated for [(C10H15NOS)Na]+: 220.0767, found 220.0771; IR (ATR): ν (cm-1): 3054,
2941, 2916, 2872, 1585, 1574, 1487, 1472, 1425, 1391, 1277, 1263, 1230, 1188, 1132, 1112, 1104,
1051, 1013, 935, 802, 708, 624, 601.
3-(Methylthio)propyl 2,2,2-trifluoroacetate (3l)
Prepared from allyltrifluoro acetate (39.0 µL) and dimethyl disulfide (53.1 µL)
following GP1. The yield of 3l was determined via 19F NMR using
(trifluoromethoxy) benzene as internal standard to be 75%.
Crude 13F{1H} NMR (282 MHz, chloroform-d): δ –75.3 Hz; GC-MS: tR (50_40): 5.3 min; EI-MS:
m/z (%): 41 (26), 43 (17), 45 (17), 47 (14), 61 (100), 69 (43), 73 (40), 88 (21), 97 (10), 202 (96); HR-
MS (ESI): m/z calculated for [(C6H9F3O2S)Na]+: 225.0168, found 225.0179.
(4R,4aS,6S)-4,4a-dimethyl-6-(1-(methylthio)propan-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-
2(3H)-one (3m)
Prepared from (+)-nootkatone (65.4 mg) and dimethyl disulfide (53.1 µL)
following the GP1 to give the product 3m as yellow oil (51.2 mg, 0.19 mmol,
64%) as a 1:1 mixture of the two diastereomers.
1H NMR of diastereomers (300 MHz, chloroform-d): δ 5.73 (s, 1H), 2.63 – 2.21 (m, 6H), 2.08 (s,
3H), 1.96 (dt, J = 19.6, 5.3 Hz, 2H), 1.89 – 1.52 (m, 5H), 1.07 (d, J = 3.8 Hz, 3H), 0.94 (s, 3H), 0.93 (s,
3H); 13C{1H} NMR of diastereomers (75 MHz, chloroform-d): δ 199.7, 171.0, 124.5, 43.1, 42.1, 40.6,
40.6, 40.0, 39.6, 39.4, 39.2, 37.3, 37.3, 36.3, 36.3, 33.1, 33.0, 30.6, 28.0, 17.0, 16.3, 16.2, 16.0, 15.7,
15.0, 15.0; Rf (n-pentane:ethyl acetate = 90:10): 0.20; GC-MS: tR (50_40): 10.0 min; EI-MS: m/z
(%): 41 (19), 55 (11), 61 (23), 77 (17), 79 (19), 91 (33), 105 (21), 107 (18), 121 (19), 161 (22), 176 (58),
177 (100), 203 (19), 219 (15), 266 (79),; HR-MS (ESI): m/z calculated for [(C16H26OS)Na]+: 289.1597,
found 289.1601; IR (ATR): ν (cm-1): 2916, 2878, 1712, 1620, 1435, 1288, 1203, 1041, 949, 733.
- 24 -
(5R)-2,3-dimethyl-5-(1-(methylthio)propan-2-yl)cyclohex-2-en-1-one (3n)
Prepared from 2,3-dimethyl-5-((R)-prop-1-en-2-yl)cyclohex-2-en-1-one (49.2 µL)
and dimethyl disulfide (53.1 µL) following GP1 to give the product 3n as colorless
oil (47.1 mg, 0.22 mmol, 74%) as a 1:1 mixture of the two diastereomers.
1H NMR of diastereomers (300 MHz, chloroform-d): δ 2.64 – 2.33 (m, 3H), 2.29 – 2.10 (m, 4H),
2.08 (s, 3H), 1.94 (s, 3H), 1.75 (s, 3H), 1.74 – 1.64 (m, 1H), 1.00 (dd, J = 6.8, 3.4 Hz, 3H); 13C{1H}
NMR of diastereomers (75 MHz, chloroform-d): δ 199.4, 154.6, 130.8, 41.8, 39.8, 39.4, 39.2, 37.9,
37.8, 37.3, 36.7, 36.6, 35.2, 21.7, 21.6, 16.3, 16.2, 15.9, 15.8, 10.8; Rf (n-pentane:ethyl acetate = 95:5):
0.16; GC-MS: tR (50_40): 8.7 min; EI-MS: m/z (%): 41 (8), 61 (8), 107 (8), 122 (14), 123 (100), 124
(11), 212 (8); HR-MS (ESI): m/z calculated for [(C12H20OS)Na]+: 235.1127, found 235.1135;
IR (ATR): ν (cm-1): 2955, 2916, 1381, 1257, 1072, 964, 895, 748, 702.
Methyl(2-((1R,3R)-4-methyl-3-(methylthio)cyclohexyl)propyl)sulfane (3o)
Prepared following a modified version of the GP1 from (R)-(+)-limonene (48.5 mg) and
dimethyl disulfide (106.2 µL, 4.0 equiv) to give product 3o as white solid (49.9 mg,
0.22 mmol, 71%) as a 1:1 mixture of the two diastereomers. The product contains trisulfide
9 as impurity. The given yield has been determined by NMR subtraction of the trisulfide
impurity.
1H NMR of diastereomers (600 MHz, chloroform-d): δ 2.61 – 2.56 (m, 1H), 2.40 – 2.28 (m, 2H),
2.09 (d, J = 4.1 Hz, 6H), 1.94 – 1.65 (m, 5H), 1.48 – 1.33 (m, 4H), 1.02 (d, J = 10.0 Hz, 3H), 0.96 (d, J
= 6.6 Hz, 3H); 13C{1H} NMR of diastereomers (151 MHz, chloroform-d): δ 52.6, 52.4, 39.1, 39.0,
38.2, 38.1, 30.8, 30.7, 29.9, 29.7, 28.2, 27.3, 25.2, 25.0, 23.5, 20.4, 20.2, 16.2, 16.0, 15.1; Rf (n-
pentane:ethylacetate = 97:3): 0.52; GC-MS: tR (50_40): 8.6 min; EI-MS: m/z (%): 41 (27), 55 (23),
61 (46), 67 (28), 79 (27), 81 (70), 89 (19), 93 (37), 94 (31), 95 (69), 107 (42), 121 (24), 123 (31), 136
(100), 137 (33), 142 (26), 169 (39), 184 (47), 185 (20), 232 (47); IR (ATR): ν (cm-1): 2916, 1634, 1373,
1057, 956, 887.
6-(Methylthio)hexan-1-ol (3p)
Prepared from 5-hexen-1-ol (36.0 µL) and dimethyl disulfide (53.1 µL)
following GP1 to give product 3p as a yellow oil (33.8 mg, 0.23 mmol, 76%).
1H NMR (600 MHz, chloroform-d): δ 3.63 (t, J = 6.6 Hz, 2H), 2.48 (t, J = 7.4 Hz, 2H), 2.08 (s, 3H),
1.63 – 1.53 (m, 5H), 1.40 (m, 4H); 13C{1H} NMR (151 MHz, chloroform-d): δ 63.0, 34.3, 32.7, 29.2,
28.7, 25.5, 15.7. Rf (n-pentane:ethyl acetate = 75:25): 0.16; GC-MS: tR (50_40): 7.3 min; EI-MS:
m/z (%): 41 (42), 54 (29), 55 (38), 57 (17), 61 (93), 67 (85), 82 (100), 83 (13), 114 (26), 130 (13), 148
(54); IR (ATR): ν (cm-1): 2931, 2854, 1604, 1431, 1242, 1180, 1049, 956, 887.
- 25 -
2,3-Bis(methylthio)bicyclo[2.2.1]heptane (3q)
Prepared from norbornene (28.2 mg) and dimethyl disulfide (106.2 µL, 4.0 equiv)
following a slightly modified version of GP1 to give product 3q as a red oil (37.9 mg,
0.20 mmol, 67%). The product was obtained as mixture of a 1:1 mixture of both
diastereomers.
1H NMR of diastereomers (500 MHz, chloroform-d): δ 2.91 (d, J = 1.9 Hz, 1H), 2.74 – 2.70 (m, 1H),
2.38 – 2.29 (m, 2H), 2.24 (dd, J = 5.0, 2.0 Hz, 1H), 2.16 (s, 3H), 2.14 (d, J = 0.5 Hz, 2H), 2.10 (d, J =
0.5 Hz, 2H), 1.91 – 1.73 (m, 2H), 1.68 – 1.59 (m, 2H), 1.46 – 1.30 (m, 2H), 1.26 – 1.15 (m, 3H); 13C{1H}
NMR of diastereomers (126 MHz, chloroform-d): δ 56.9, 56.4, 56.2, 43.5, 42.8, 40.6, 36.5, 34.1, 29.0,
28.8, 22.4, 17.7, 16.0, 15.6; Rf (n-pentane:ethyl acetate = 99:1): 0.22; GC-MS: tR (50_40): 7.8 min;
EI-MS: m/z (%): 39 (18), 45 (18), 61 (38), 66 (44), 67 (20), 77 (28), 87 (29), 91 (48), 93 (74), 112 (45),
125 (95), 140 (16), 141 (29), 188 (100) ; IR (ATR): ν (cm-1): 2916, 2885, 1375, 1257, 1049, 964, 903,
868, 748, 702.
The NMR data were in consistent with the reported data.20
6-(Methylthio)hexanenitrile (3r)
Prepared from 5-hexenenitrile (34.1 µL) and dimethyl disulfide (53.1 µL)
following GP1 to give product 3r as a yellow oil (28.1 mg, 0.20 mmol, 68%).
1H NMR (500 MHz, chloroform-d): δ 2.51 (t, J = 7.1 Hz, 2H), 2.35 (t, J = 7.1 Hz, 2H), 2.10 (s, 3H),
1.72 – 1.60 (m, 4H), 1.60 – 1.52 (m, 4H); 13C{1H} NMR (126 MHz, chloroform-d): δ 119.5, 33.7,
28.2, 27.7, 25.0, 17.0, 15.5; Rf (n-pentane:ethyl acetate = 95:5): 0.12; GC-MS: tR (50_40): 7.3 min;
EI-MS: m/z (%): 41 (21), 55 (30), 61 (100), 69 (22), 97 (14), 143 (59); IR (ATR): ν (cm-1): 2916, 1424,
1257, 1072, 964, 895, 748.
Methyloctylsulfane (3s)
Prepared from 1-octene (47.4 µL) and dimethyl disulfide (53.1 µL) following the
GP1 to give the product 3s as a colorless liquid (35.8 mg, 0.23 mmol, 74%).
1H NMR (400 MHz, chloroform-d): δ 2.48 (dd, J = 8.0, 6.8 Hz, 2H), 2.09 (s, 3H), 1.63 – 1.54 (m,
2H), 1.39 – 1.25 (m, 10H), 0.90 – 0.86 (m, 3H); 13C{1H} NMR (101 MHz, chloroform-d): δ 34.3, 31.8,
29.2, 29.2, 29.2, 28.9, 22.7, 15.6, 14.1; Rf (n-pentane:ethyl acetate = 98:2): 0.48; GC-MS: tR (50_40):
6.7 min; EI-MS: m/z (%): 39 (12), 41 (40), 43 (22), 48 (16), 55 (38), 56 (39), 61 (65), 69 (43), 70 (39),
83 (33), 84 (27), 103 (16), 112 (10), 145 (84), 160 (100); IR (ATR): ν (cm-1): 2924, 1257, 1087, 1026,
964, 856, 748.
The NMR data were in consistent with the reported data.21
- 26 -
Diethyl 2-(3-(methylthio)propyl)malonat (3t)
Prepared from diethylallylmalonate (59.1 mg) and dimethyl disulfide (53.1 µL)
following GP1 to give product 3t as a colorless oil (61.9 mg, 0.25 mmol, 83%).
1H NMR (600 MHz, chloroform-d): δ 4.18 – 4.02 (m, 4H), 3.33 (t, J = 7.5 Hz, 1H), 2.50 (t, J = 7.2 Hz,
2H), 2.07 (s, 3H), 1.98 (q, J = 7.6 Hz, 2H), 1.66 – 1.60 (m, 2H), 1.25 (t, J = 7.2 Hz, 6H); 13C{1H} NMR
(151 MHz, chloroform-d): δ 169.4, 61.5, 51.7, 33.8, 27.9, 26.8, 15.5, 14.2; Rf (n-pentane:ethyl
acetate = 95:5): 0.12; GC-MS: tR (50_40): 8.2 min; EI-MS: m/z (%): 55 (18), 61 (30), 74 (17), 86
(41), 99 (14), 109 (32), 127 (34), 128 (20), 156 (79), 159 (100), 173 (26), 174 (58), 201 (17), 248 (40);
HR-MS (ESI): m/z calculated for [(C11H20O4S)Na]+: 271.0980, found 271.0975; IR (ATR): ν (cm-1):
3340, 2931, 2854, 1735, 1265, 1033, 956.
Cyclopentyl(methyl)sulfane (3u)
Prepared from cyclopentene (26.5 µL) and dimethyl disulfide (53.1 µL) following GP1. The
yield of 3u (57%) was determined by crude 1H NMR analysis using CH2Br2 as internal
standard with respect to the thiomethyl functionality.
GC-MS: tR (50_40): 5.2 min; EI-MS: m/z (%): 39 (19), 41 (42), 45 (13), 67 (64), 68 (100), 69 (44), 87
(11), 101 (37), 116 (66).
(11R,Z)-7,7,11-trimethyl-4-((methylthio)methyl)-12-oxabicyclo[9.1.0]dodec-4-ene (3v)
Prepared from (–)-caryophyllene oxide (66.1 mg) and dimethyl disulfide (53.1 µL)
following general procedure GP1 to give the product 3v as a viscous colorless oil
(49.1 mg, 0.18 mmol, 61%).
1H NMR (600 MHz, chloroform-d): δ 5.40 (dd, J = 11.4, 2.5 Hz, 1H), 3.45 (d,
J = 12.6 Hz, 1H), 2.81 – 2.75 (m, 2H), 2.69 (ddq, J = 10.7, 5.4, 2.6 Hz, 1H), 2.20 – 2.11 (m, 2H), 2.04
(dd, J = 12.1, 9.3 Hz, 1H), 1.98 (s, 4H), 1.72 – 1.66 (m, 1H), 1.48 – 1.39 (m, 2H), 1.24 – 1.19 (m, 2H),
1.18 (s, 3H), 0.95 (s, 3H), 0.86 (s, 3H), 0.84 – 0.77 (m, 2H); 13C{1H} NMR (151 MHz, chloroform-d):
δ 132.9, 127.3, 62.7, 62.5, 40.6, 38.3, 37.3, 33.6, 33.1, 31.5, 29.4, 28.2, 24.5, 18.4, 17.9, 14.6. Rf (n-
pentane:ethyl acetate = 95:5): 0.26; GC-MS: tR (50_40): 9.0 min; EI-MS: m/z (%): 41 (37), 55 (47),
61 (43), 69 (49), 80 (40), 83 (38), 95 (54), 109 (66), 121 (37), 164 (100), 268 (14); HR-MS (ESI): m/z
calculated for [(C16H28OS)Na]+: 291.1759, found 291.1748; IR (ATR): ν (cm-1): 2931, 1435, 1234,
1057, 902, 748.
- 27 -
1,3-dimethyl-3-((methylthio)methyl)indolin-2-one (3w)
Prepared from N-methyl-N-phenylmethacrylamide (52.5 mg) and dimethyl disulfide
(53.1 µL) following GP1 to give product 3w as colorless oil (55.8 mg, 0.26 mmol,
85%).
1H NMR (300 MHz, chloroform-d): δ 7.30 – 7.22 (m, 2H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.83 (d,
J = 7.7 Hz, 1H), 3.20 (s, 3H), 3.01 – 2.87 (m, 2H), 1.89 (s, 3H), 1.39 (s, 3H); 13C{1H} NMR (75 MHz,
chloroform-d): δ 179.5, 143.6, 132.9, 128.3, 123.0, 122.5, 108.1, 49.4, 42.5, 26.3, 23.0, 17.5; Rf (n-
pentane:ethyl = acetate 80:20): 0.42; GC-MS: tR (50_40): 8.5 min; EI-MS: m/z (%): 61 (48), 77 (11),
117 (13), 130 (19), 132 (12), 159 (13), 160 (100), 161 (12), 174 (11), 221 (51); HR-MS (ESI): m/z
calculated for [(C12H15NOS)Na]+: 244.0767, found 244.0771; IR (ATR): ν (cm-1): 2962, 1705, 1612,
1473, 1419, 1257, 1026, 864, 748.
2-(4-(Methylthio)butyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3x)
Prepared from 2-(but-3-en-1-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide
(71.2 mg) and dimethyl disulfide (53.1 µL) following GP1 to give product 3x as
a yellowish oil (53.9 mg, 0.19 mmol, 63%).
1H NMR (400 MHz, chloroform-d): δ 8.07 – 8.02 (m, 1H), 7.94 – 7.89 (m, 1H), 7.84 (dtd, J = 16.1,
7.4, 1.4 Hz, 2H), 3.80 (t, J = 7.3 Hz, 2H), 2.55 (t, J = 7.3 Hz, 2H), 2.09 (s, 3H), 2.01 – 1.91 (m, 2H),
1.77 – 1.67 (m, 2H); 13C{1H} NMR (75 MHz, chloroform-d): δ 159.1, 137.8, 134.9, 134.4, 127.5,
125.3, 121.0, 39.0, 33.6, 27.6, 26.4, 15.6; Rf (n-pentane:ethyl = acetate 65:35): 0.61; GC-MS: tR
(50_40): 10.2 min; EI-MS: m/z (%): 61 (34), 76 (23), 77 (26), 104 (21), 105 (100), 132 (10), 146 (37),
196 (35), 206 (55), 238 (12), 185 (16); HR-MS (ESI): m/z calculated for [(C12H15NO3S2)Na]+:
309.0386, found 308.0399.
(5R)-5-(1-(Ethylthio)propan-2-yl)-2-methylcyclohex-2-en-1-one (3y)
Prepared from (R)-(–)-carvone (47.1 µL) and diethyl disulfide (73.5 µL)
following GP1 to give product 3y as a colorless oil (50.9 mg, 0.24 mmol, 80%)
as 1:1 mixture of the two diastereomers.
1H NMR of diastereomers (600 MHz, chloroform-d): δ 6.73 (d, J = 5.4 Hz, 1H), 2.59 (ddd, J = 15.2,
12.6, 5.5 Hz, 1H), 2.49 (dddd, J = 15.1, 13.4, 7.5, 2.2 Hz, 3H), 2.40 (td, J = 12.7, 7.8 Hz, 1H),
2.37 – 2.27 (m, 1H), 2.24 – 2.07 (m, 3H), 1.76 (s, 3H), 1.72 – 1.66 (m, 1H), 1.24 (t, J = 7.4 Hz, 3H),
1.00 (dd, J = 6.9, 1.3 Hz, 3H); 13C{1H} NMR of diastereomers (151 MHz, chloroform-d): δ 200.1,
200.0, 144.9, 144.9, 135.5, 135.4, 42.6, 40.6, 39.3, 39.1, 37.1, 37.0, 36.6, 36.5, 30.5, 28.4, 26.7, 26.6,
16.0, 15.9, 15.7, 15.6, 14.8, 14.8; Rf (n-pentane:ethyl acetate = 95:5): 0.19; GC-MS: tR (50_40): 8.6
min; EI-MS: m/z (%): 41 (13), 73 (20), 75 (13), 107 (11), 108 (47), 109 (100), 121 (27), 150 (33), 212
(16); HR-MS (ESI): m/z calculated for [(C12H20OS)Na]+: 235.1133, found 235.1128; IR (ATR): ν (cm-
1): 2916, 2885, 1519, 1373, 1257, 1111, 1049, 964, 903, 748, 702.
- 28 -
(5R)-5-(1-(Butylthio)propan-2-yl)-2-methylcyclohex-2-en-1-one (3z)
Prepared from (R)-(–)-carvone (47.1 µL) and dibutyl disulfide (114.0 µL)
following GP1 to give product 3z as a colorless oil (52.1 mg, 0.22 mmol,
72%) as 1:1 mixture of the two diastereomers.
1H NMR of diastereomers (500 MHz, chloroform-d): δ 6.73 (dq, J = 5.6, 1.7 Hz, 1H), 2.58 (dt,
J = 12.6, 6.3 Hz, 1H), 2.47 (tt, J = 8.8, 2.1 Hz, 3H), 2.42 – 2.36 (m, 1H), 2.34 – 2.26 (m, 1H), 2.22 – 2.09
(m, 3H), 1.76 (s, 3H), 1.57 – 1.51 (m, 2H), 1.39 (q, J = 7.4 Hz, 2H), 1.26 – 1.23 (m, 1H), 1.00 (dd,
J = 6.8, 0.9 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13C{1H} NMR of diastereomers (126 MHz, chloroform-
d): δ 200.2, 200.2, 145.1, 145.0, 135.6, 42.7, 40.8, 39.4, 39.3, 37.3, 37.2, 37.1, 32.8, 32.6, 31.9, 31.9,
30.6, 28.5, 22.1, 16.1, 16.1, 15.8, 15.8, 13.8; Rf (n-pentane:ethyl acetate = 95:5): 0.33; GC-MS: tR
(50_40): 8.6 min; EI-MS: m/z (%): 41 (23), 56 (12), 60 (12), 79 (13), 107 (13), 108 (64), 109 (100), 121
(42), 150 (48), 240 (11); HR-MS (ESI): m/z calculated for [(C14H24OS)Na]+: 263.1446, found 263.1442;
IR (ATR): ν (cm-1): 2924, 2870, 1519, 1419, 1365, 1111, 1057, 949, 902, 748, 709.
(5R)-5-(1-((2-Hydroxyethyl)thio)propan-2-yl)-2-methylcyclohex-2-en-1-one (3aa)
Prepared from (R)-(–)-carvone (47.1 µL) and 2-hydroxyethyl disulfide
(73.5 µL) following GP1 to give product 3aa as a colorless oil (42.9 mg,
0.19 mmol, 63%) as 1:1 mixture of the two diastereomers.
1H NMR of diastereomers (500 MHz, chloroform-d): δ 6.73 (d, J = 5.5 Hz, 1H), 3.72 (t, J = 6.0 Hz,
2H), 2.70 (td, J = 6.0, 1.6 Hz, 2H), 2.61 (td, J = 12.9, 5.4 Hz, 1H), 2.51 – 2.38 (m, 2H), 2.33 – 2.28 (m,
1H), 2.25 – 2.04 (m, 4H), 1.76 (dt, J = 2.6, 1.4 Hz, 3H), 1.69 (dq, J = 12.6, 5.8 Hz, 1H), 1.01 (dd, J =
6.8, 2.3 Hz, 3H); 13C{1H} NMR of diastereomers (126 MHz, chloroform-d): δ 200.3, 200.3, 145.2,
145.1, 135.9, 60.8, 42.9, 40.9, 39.6, 39.5, 37.7, 37.6, 37.1, 37.0, 36.4, 36.3, 30.9, 30.1, 28.8, 16.3, 16.3,
16.1, 16.0; Rf (n-pentane:ethyl acetate 95:5): 0.33; HR-MS (ESI): m/z calculated for
[(C12H20O2S)Na]+: 251.1082, found 251.1080; IR (ATR): ν (cm-1): 2924, 1419, 1365, 1049, 1010, 949,
902.
Octyl(phenyl)sulfane (3ac)
Prepared from 1-octene (37.5 µL) and diphenyl disulfide (130.8 mg) following
a modified version of GP1 using acetone (3.0 mL, 0.1 M) as solvent to give
product 3ac as a colorless liquid (58.6 mg, 0.26 mmol, 88%).
1H NMR (300 MHz, chloroform-d): δ 7.32 – 7.29 (m, 2H), 7.28 – 7.24 (m, 2H), 7.16 – 7.12 (m, 1H),
2.92 – 2.88 (m, 2H), 1.66 – 1.60 (m, 2H), 1.40 (ddt, J = 12.4, 9.0, 4.4 Hz, 2H), 1.31 – 1.20 (m, 8H), 0.86
(t, J = 7.0 Hz, 3H); 13C{1H} NMR (75 MHz, chloroform-d): δ 137.0, 128.8, 128.8, 125.6, 33.6, 31.8,
29.1, 29.1, 29.1, 28.8, 22.6, 14.1; Rf (n-pentane): 0.45; GC-MS: tR (50_40): 8.6 min; EI-MS: m/z (%):
41 (10), 109 (12), 110 (100), 123 (20), 222 (42); IR (ATR): ν (cm-1): 2924, 1581, 1435, 1273, 1219,
1079, 895, 740, 703.
The NMR data were consistent with the reported data.22
- 29 -
Octyl(p-chlorophenyl)sulfane (3ad)
Prepared from 1-octene (37.5 µL) and p-chlorophenyl disulfide
(172.3 mg) following a modified version of GP1 using acetone (3.0
mL, 0.1 M) as solvent to give product 3ad as a colorless liquid (64.7
mg, 0.25 mmol, 84%, with respect to the impurities). The product
contains p-chlorothiophenol and p-chlorophenyl disulfide as impurities.
1H NMR (300 MHz, chloroform-d): δ 7.27 – 7.18 (m, 4H), 2.94 – 2.87 (m, 2H), 1.64 (dt, J = 15.0,
7.4 Hz, 2H), 1.46 – 1.39 (m, 2H), 1.30 (tq, J = 10.1, 5.5 Hz, 8H), 0.93 – 0.87 (m, 3H); 13C{1H} NMR
(75 MHz, chloroform-d): δ 135.6, 131.7, 130.2, 128.9, 33.9, 31.8, 29.1, 29.1, 29.0, 28.8, 22.6, 14.0;
Rf (n-pentane): 0.40; GC-MS: tR (50_40): 8.6 min; EI-MS: m/z (%): 41 (25), 43 (19), 108 (19), 143
(17), 144 (100), 145 (10), 146 (35), 157 (19), 256 (62); IR (ATR): ν (cm-1): 3078, 2924, 2854, 1473,
1435, 1388, 1226, 1095, 1032, 810, 740, 702.
The NMR data were consistent with the reported data.23
Octyl(p-tolyl)sulfane (3ae)
Prepared from 1-octene (37.5 µL) and p-tolyl disulfide (147.8 mg)
following a modified version of GP1 using acetone (3.0 mL, 0.1 M) as
solvent to give product 3ae as a colorless liquid (62.8 mg, 0.26 mmol,
89%).
1H NMR (300 MHz, chloroform-d): 7.27 (dt, J = 8.5, 2.3 Hz, 2H), 7.14 – 7.10 (m, 2H), 2.93 – 2.84
(m, 2H), 2.34 (s, 3H), 1.64 (pent, J = 7.4 Hz, 2H), 1.48 – 1.37 (m, 2H), 1.35 – 1.22 (m, 8H), 0.94 – 0.86
(m, 3H); 13C{1H} NMR (75 MHz, chloroform-d): δ 135.8, 133.1, 129.7, 129.6, 34.4, 31.8, 29.2, 29.2,
29.1, 28.8, 22.6, 21.0, 14.1; Rf (n-pentane): 0.35; GC-MS: tR (50_40): 8.7 min; EI-MS: m/z (%): 41
(10), 91 (25), 123 (13), 124 (100), 125 (10), 137 (24), 236 (64); IR (ATR): ν (cm-1): 2924, 2854, 1720,
1472, 1056, 1018, 887, 803, 725.
The NMR data were consistent with the reported data.24
(6-Azidohexyl)(methyl)sulfane (3af)
Prepared from 6-azidohex-1-ene (46.0 mg) and dimethyl disulfide (53.1 µL)
following GP1. The yield of 3af (41%) was determined by crude 1H NMR
analysis using CH2Br2 as internal standard with respect to the thiomethyl functionality.
GC-MS: tR (50_40): 5.1 min; EI-MS: m/z (%): 39 (48), 40 (10), 41 (100), 42 (47), 43 (35), 54 (23), 55
(24), 67 (16), 68 (37), 69 (29), 70 (16), 96 (25), 173 (19); HR-MS (ESI): m/z calculated for
[(C7H15N3S)Ag]+: 280.00321, found 280.00327.
- 30 -
((3-(methylthio)propoxy)carbonyl)-L-methionine (3ag)
Prepared from ((allyloxy)carbonyl)-L-methionine (69.9 mg) and dimethyl
disulfide (53.1 µL) following GP1 to give product 3ag as a brown solid
(57.8 mg, 0.21 mmol, 69%).
1H NMR (600 MHz, chloroform-d): δ 7.42 (s, 1H), 4.51 – 4.43 (m, 1H), 4.27 – 4.14 (m, 2H),
2.56 – 2.51 (m, 4H), 2.22 – 2.16 (m, 1H), 2.10 (s, 3H), 2.09 (s, 3H), 2.02 – 1.88 (m, 3H) – carboxylic
acid proton missing; 13C{1H} NMR (126 MHz, chloroform-d): δ 176.4, 156.4, 64.1, 53.1, 36.2, 31.5,
30.5, 30.0, 28.5, 15.5; Rf (dichloromethane:methanol = 95:5): 0.52; HR-MS (ESI): m/z calculated for
[(C10H19NO4S2)Na]+: 304.0648, found 304.0639; IR (ATR): ν (cm-1): 3309, 2962, 2916, 1527, 1427,
1334, 1226, 1049, 956, 848, 748, 578.
(3S)-3-methyl-2-(((3-(methylthio)propoxy)carbonyl)amino)pentanoic acid (3ah)
Prepared from (3S)-2-(((allyloxy)carbonyl)amino)-3-methylpentanoic acid
(64.5 mg) and dimethyl disulfide (53.1 µL) following GP1 to give product
3ah as yellow oil (62.8 mg, 0.24 mmol, 80%).
1H NMR (300 MHz, chloroform-d): δ 4.34 (dd, J = 11.6, 4.2 Hz, 1H), 4.17 (t, J = 6.2 Hz, 2H),
2.80 – 2.72 (m, 1H), 2.55 (t, J = 7.2 Hz, 2H), 2.16 – 2.14 (m, 2H), 2.10 (s, 3H), 1.91 (d, J = 6.7 Hz, 2H),
0.96 – 0.92 (m, 6H) – amide and carboxylic acid proton are missing; 13C{1H} NMR (75 MHz,
chloroform-d): δ 176.3, 156.4, 63.9, 58.2, 37.7, 36.3, 30.5, 28.6, 24.9, 15.5, 11.6; Rf
(dichloromethane:methanol = 95:5): 0.19; HR-MS (ESI): m/z calculated for [(C11H20NO4S)]-:
262.1119, found 262.1126; IR (ATR): ν (cm-1): 2962, 2916, 1716, 1519, 1419, 1334, 1219, 1095, 1041,
956, 848, 663.
((3-(methylthio)propoxy)carbonyl)-L-phenylalanine (3ai)
Prepared from ((allyloxy)carbonyl)-L-phenylalanine (74.8 mg) and
dimethyl disulfide (53.1 µL) following GP1 to give the product 3ai as an
off-white solid (63.4 mg, 0.21 mmol, 71%).
1H NMR (600 MHz, chloroform-d): δ 7.31 – 7.24 (m, 3H), 7.18 (d, J = 7.0 Hz, 2H), 4.65 (tq, J = 8.9,
4.1 Hz, 1H), 4.16 – 4.10 (m, 2H), 3.22 – 3.07 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 2.08 (s, 3H), 1.91 – 1.82
(m, 2H) – amide and carboxylic acid proton are missing; 13C{1H} NMR (126 MHz, chloroform-d): δ
176.0, 156.1, 135.7, 129.3, 128.6, 127.2, 64.0, 54.7, 37.7, 30.4, 28.5, 15.5; Rf
(dichloromethane:methanol = 95:5): 0.34; HR-MS (ESI): m/z calculated for [(C14H19NO4S)Na]+:
320.0927, found 320.0926; IR (ATR): ν (cm-1): 3317, 2916, 1712, 1643, 1527, 1435, 1257, 1219, 1049,
702.
- 31 -
E/Z-oct-1-ene-1,2-diylbis(methylsulfane) (3aj)
Prepared from 1-octyne (44.3 µL) and dimethyl disulfide (106.2 µL, 4.0 equiv)
following a modified version of GP1 to give a mixture of the dithiolated E/Z
products 3aj as colorless liquid (55.1 mg, 0.25 mmol, 83%, E/Z = 40:60 by GC-
FID). The yield was determined by 1H NMR analysis using CH2Br2 as internal
standard with respect to the thiomethyl functionality.
Dithiolated Alkene 1:
GC-MS: tR (50_40): 7.8 min; EI-MS: m/z (%): 60 (22), 84 (16), 99 (75), 99 (13), 101 (14), 159 (18),
204 (100).
Dithiolated Alkene 2:
GC-MS: tR (50_40): 7.9 min; EI-MS: m/z (%): 41 (13), 61 (27), 67 (15), 78 (16), 85 (44), 87 (22), 88
(71), 95 (11), 99 (14), 109 (14), 117 (18), 141 (22), 204 (100).
Z/E-(1-phenylethene-1,2-diyl)bis(methylsulfane) (3ak)
Prepared from 1-phenyl-1-propyne (33.0 µL) and dimethyl disulfide (106.2 µL,
2.0 equiv) following a modified version of GP1 to give a mixture of the dithiolated E/Z
products 3aj as yellowish liquid (40.0 mg, 0.20 mmol, 68%, E/Z = 32:68 by 1H NMR).
1H NMR of Z/E-(1-phenylethene-1,2-diyl)bis(methylsulfane) (300 MHz, chloroform-d): δ 7.50 –
7.44 (m, 2H), 7.40 – 7.29 (m, 3H), 6.44 (s, 0.68H), 6.27 (s, 0.32), 2.43 (s, 1.97H), 2.29 (s, 0.93H), 2.13
(s, 0.93H), 2.08 (s, 2.04H); 13C{1H} NMR of Z/E-(1-phenylethene-1,2-diyl)bis(methylsulfane) (75
MHz, chloroform-d): δ 13C NMR (75 MHz, CDCl3) δ 138.6, 132.3, 131.9, 129.1, 128.6, 128.4, 128.2,
127.5, 127.4, 125.1, 18.2, 17.6, 16.8, 16.1; Rf (n-pentane): 0.33; GC-MS of Z/E-(1-phenylethene-1,2-
diyl)bis(methylsulfane): tR (50_40): 8.2-8.3 min; EI-MS of Z/E-(1-phenylethene-1,2-
diyl)bis(methylsulfane): m/z (%): 45 (10), 77 (11), 89 (14), 102 (17), 134 (100), 135 (15), 196 (60). IR
(ATR): ν (cm-1): 3059, 3023, 2921, 2852, 1964, 1894, 1813, 1747, 1597, 1571, 1542, 1487, 1146, 1365,
1318 1247, 1227, 1199, 1185, 1157, 1075, 1029, 966, 934, 912, 885, 843, 818, 774, 756, 736, 691, 633,
613.
2-Methyl-3-phenylbenzo[b]thiophene (3al)
Prepared from 1-phenyl-1-propyne (37.5 µL) and diphenyl disulfide (65.5 mg, 1.0 equiv)
following a modified version of GP1 using acetone (3.0 mL, 0.1 M) as solvent to give
product 3al as a colorless liquid (0.22 mmol, 73% yield with respect to the diphenyl
disulfide impurity).
1H NMR (300 MHz, chloroform-d): δ 7.88 – 7.83 (m, 1H), 7.55 – 7.53 (m, 3H), 7.48 – 7.44 (m, 3H),
7.29 – 7.27 (m, 2H), 2.56 (s, 3H); 13C{1H} NMR (75 MHz, chloroform-d): δ 140.5, 138.4, 136.2, 135.5,
134.0, 130.2, 128.7, 127.4, 124.3, 123.9, 122.6, 122.1, 14.7; Rf (n-pentane): 0.26; GC-MS: tR (50_40):
9.0 min; EI-MS: m/z (%): 147 (28), 221 (23), 223 (43), 224 (100); IR (ATR): ν (cm-1): 3055, 2916,
2731, 1435, 1373, 1273, 1089, 972, 918, 848, 749, 686.
The NMR data were consistent with the reported data.25
- 32 -
5-(Methylthio)pentyl 4-(N,N-dipropylsulfamoyl)benzoate (3am)
Prepared from pent-4-en-1-yl 4-(N,N-dipropylsulfamoyl)
benzoate (110.1 mg) and dimethyl disulfide (53.1 µL) following
GP1 to give product 3am as a colorless oil (87.1 mg, 0.22 mmol,
72%).
1H NMR (300 MHz, chloroform-d): δ 8.13 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 4.33 (t, J =
6.6 Hz, 2H), 3.11 – 3.03 (m, 4H), 2.50 (t, J = 7.2 Hz, 2H), 2.07 (s, 3H), 1.78 (dt, J = 14.5, 6.7 Hz, 2H),
1.66 (dt, J = 14.4, 7.0 Hz, 2H), 1.58 – 1.46 (m, 6H), 0.84 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (75 MHz,
chloroform-d): δ 165.3, 144.1, 133.7, 130.2, 127.0, 65.5, 49.9, 34.1, 28.7, 28.3, 25.2, 21.9, 15.5, 11.2;
Rf (n-pentane:ethyl acetate = 80:20): 0.53; HR-MS (ESI): m/z calculated for [(C19H31NO4S)Na]+:
424.1587, found 424.1606; IR (ATR): ν (cm-1): 2931, 1720, 1458, 1342, 1273, 1157, 995, 864, 694,
602.
5-(Methylthio)pentyl(4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-trioxohexadeca
hydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (3an)
Prepared from pent-4-en-1-yl (4R)-4-
((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12 -
trioxohexa decahydro-1H-cyclopenta[a]phenanthren-17-
yl)pentanoate (141.2 mg) and dimethyl disulfide (53.1 µL)
following GP1 to give product 3an as a yellowish solid
(130.9 mg, 0.25 mmol, 84%).
1H NMR (300 MHz, chloroform-d): δ 4.04 (t, J = 6.6 Hz, 2H), 2.95 – 2.77 (m, 3H), 2.50 – 2.12 (m,
11H), 2.06 (d, J = 3.5 Hz, 3H), 2.06 – 1.73 (m, 8H), 1.66 – 1.54 (m, 4H), 1.43 (td, J = 5.9, 5.2 Hz, 2H),
1.38 (s, 3H), 1.35 – 1.16 (m, 4H), 1.05 (s, 3H), 0.82 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (75 MHz,
chloroform-d): δ 212.0, 209.1, 208.8, 174.1, 64.2, 56.9, 51.7, 49.0, 46.8, 45.6, 45.5, 45.0, 42.8, 38.6,
36.5, 36.0, 35.5, 35.2, 34.1, 31.5, 30.4, 28.7, 28.3, 27.6, 25.1, 21.9, 18.6, 15.5, 11.9 – 1 signal missing
due to overlapping; Rf (dichloromethane:methanol = 98:2): 0.30; HR-MS (ESI): m/z calculated for
[(C30H46O5S)Na]+: 541.2958, found 541.2952; IR (ATR): ν (cm-1): 2955, 2916, 1705, 1427, 1296, 1273,
1172, 1103, 841, 733, 686.
- 33 -
(8R,9S,13S,14S)-13-Methyl-3-(4-(methylthio)butoxy)-6,7,8,9,11,12,13,14,15,16-decahydro-17H-
cyclopenta[a]phenanthren-17-one (3ao)
Prepared from (8R,9S,13S,14S)-3-(but-3-en-1-yloxy)-13-methyl
6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclope-nta[a]phenanthr
en-17-one (97.4 mg) and dimethyl disulfide (53.1 µL) following GP1
to give product 3ao (81.5 mg, 0.22 mmol, 73%) as a colorless oil.
1H NMR (300 MHz, chloroform-d): δ 7.19 (dd, J = 8.7, 1.1 Hz, 1H), 6.73 – 6.63 (m, 2H), 3.95 (t,
J = 6.1 Hz, 2H), 2.88 (dd, J = 7.6, 3.1 Hz, 2H), 2.60 – 2.45 (m, 4H), 2.24 (s, 2H), 2.11 (s, 3H), 1.98 – 1.71
(m, 8H), 1.60 – 1.42 (m, 5H), 0.90 (s, 3H); 13C{1H} NMR (75 MHz, chloroform-d): δ 221.0, 157.0,
137.7, 132.0, 126.3, 114.5, 112.1, 67.3, 50.4, 48.0, 44.0, 38.4, 35.9, 33.9, 31.6, 29.7, 28.4, 26.6, 25.9,
25.7, 21.6, 15.5, 13.9; Rf (n-pentane:ethyl acetate = 90:10): 0.19; HR-MS (ESI): m/z calculated for
[(C23H32NO2S)Na]+: 395.2015, found 395.2026; IR (ATR): ν (cm-1): 3047, 2916, 2862, 2341, 2337,
1736, 1604, 1532, 1234, 1157, 1057, 1010, 956, 817, 732.
14-(Methylthio)docosanoic acid (3ap)
Prepared from erucic acid (101.4 mg) and
dimethyl disulfide (53.1 µL) following the GP1
to give the product 3ap as white solid (71.4 mg,
0.18 mmol, 62%).
1H NMR (300 MHz, chloroform-d): δ 2.47 (pent, J = 6.4 Hz, 1H), 2.34 (t, J = 7.5 Hz, 2H), 2.01 (s,
3H), 1.65 – 1.59 (m, 2H), 1.48 (d, J = 6.6 Hz, 3H), 1.26 (m, 32H), 0.86 (d, J = 7.0 Hz, 3H) – proton
from the carboxylic acid functionality is missing; 13C{1H} NMR (75 MHz, chloroform-d): δ 180.2,
46.9, 34.1, 34.1, 31.9, 29.7, 29.7, 29.6, 29.4, 29.4, 29.3, 29.3, 29.1, 26.9, 24.7, 22.7; Rf (n-pentane:ethyl
acetate = 80:20): 0.35; HR-MS (ESI): m/z calculated for [(C23H45O2S)]-: 385.3146, found 385.3168;
IR (ATR): ν (cm-1): 2924, 2854, 2669, 1712, 1651, 1419, 1276, 1103, 933, 856, 748, 717.
- 34 -
3.2.2. Asymmetric Disulfides
Photosensitized Disulfide-Ene-Reaction using carvone and methyl propyl disulfide
Prepared from (R)-(-)-carvone (47.1 µL) and methyl propyl disulfide (20, 74.7 µL) following general
procedure GP1 to give products 3a (21.0 mg, 0.11 mmol, 35%) and 21 (17.6 mg, 0.08 mmol, 26%) as
colorless oil. The overall yield was determined to be 61% with a product ratio formation of 3a to 21 of
58:42, suggesting that the sterically less bulky thiyl radical will be transferred preferentially.
Hydrothiolation reactions utilizing asymmetric disulfides were performed one time.
(5R)-5-(1-(Methylthio)propan-2-yl)-2-methylcyclohex-2-en-1-one (3a)
The analytical data of 3a is in correlation with that reported before.
(5R)-5-(1-(Propylthio)propan-2-yl)-2-methylcyclohex-2-en-1-one (21)
1H NMR (400 MHz, chloroform-d): δ 6.74 (d, J = 6.1 Hz, 1H), 2.58 (ddd, J = 12.9, 7.6, 5.6 Hz, 1H),
2.52 – 2.43 (m, 3H), 2.42 – 2.36 (m, 1H), 2.24 – 2.04 (m, 4H), 1.77 (dt, J = 2.7, 1.4 Hz, 3H), 1.69 (m,
1H), 1.65 – 1.52 (dd, J = 7.9, 4.4 Hz, 2H), 1.03 – 0.96 (m, 6H); 13C{1H} NMR (101 MHz, chloroform-
d): δ 200.2, 145.0, 135.5, 42.6, 40.6, 39.1, 36.9, 34.9, 30.5, 28.4, 23.0, 15.7, 13.5; Rf (n-pentane:ethyl
acetate = 95:5): 0.20; GC-MS: tR (50_40): 8.8 min; EI-MS: m/z (%): 38 (10), 41 (23), 43 (13), 76 (10),
78 (13), 107 (12), 108 (56), 109 (100), 121 (37), 150 (42), 226 (19); HR-MS (ESI): m/z calculated for
[(C13H22OS)Na]+: 249.1284, found 249.1290; IR (ATR): ν (cm-1): 2924, 1519, 1435, 1365, 1242, 1111,
1057, 902, 748, 709.
- 35 -
4. Mechanistic Experiments
4.1. Transient Absorption Spectroscopy and Related Spectroscopic Studies
Supplementary Figure 4. Top: Differential absorption spectra (visible) registered upon femtosecond
transient absorption spectroscopy (258 nm, 200 nJ) of dimethyl disulfide (2) (9.3 x 10-3 M) in Ar-
saturated acetonitrile with time delays between 0 and 7.5 ns at room temperature. Bottom:
Corresponding global analysis results showing the normalized decay associated states (DAS) of 1*(dimethyl disulfide) and the products of decomposition. Spectroscopic experiment was performed one
single time.
Supplementary Figure 5. Differential absorption spectra (visible) registered upon nanosecond transient
absorption spectroscopy (387 nm, 200 nJ) of left: a mixture of [Ir-F] (2.0 x 10-4 M) and dimethyl
disulfide (7.0 x 10-2 M) and right: a mixture of [Ir-F] (2.0 x 10-4 M) and dimethyl disulfide (2) (7.0 x
10-2 M) and 1-octene (1.0 x 10-4 M) in Ar-saturated acetonitrile with time delays between 0 and 400 µs
at room temperature. Spectroscopic experiment was performed one single time.
- 36 -
Supplementary Figure 6. Global analysis results (kinetics) using GloTarAn. Top: Kinetics of the 3*[Ir-
F]-state decay and its TTET to the 3*(dimethyl disulfide) state. Bottom left: Kinetics of the 3*[Ir-F]-state
upon subsequent addition of dimethyl disulfide (2). Bottom right: Kinetics of the 3*(dimethyl disulfide)
state upon subsequent addition of 1-octene. Spectroscopic experiment was performed one single time.
0.01 0.1 1 10 1000.0
0.2
0.4
0.6
0.8
1.0
3*
MLCT/LC [Ir-F]
3*
2
no
rma
lize
d i
nte
ns
ity
/ a
.u.
t / µs
- 37 -
Supplementary Figure 7. Phosphorescence lifetimes of [Ir-F] (2 x 10-4 M) are quenched upon
subsequent addition of different amounts of dimethyl disulfide (2). Spectroscopic experiment was
performed one single time.
Supplementary Figure 8. Differential absorption spectra (visible) registered upon nanosecond transient
absorption spectroscopy (320 nm, 150 nJ) of Top left: Michler’s Ketone (5.0 x 10-5 M) and top right: a
mixture of Michler’s Ketone (5.0 x 10-5 M) and dimethyl disulfide (2) (7.0 x 10-2 M) in Ar-saturated
acetonitrile with time delays between 0 and 400 µs at room temperature. The corresponding global
analysis results showing the normalized decay associated states (DAS) of 3*(Michler’s Ketone) (bottom
left) and the possibility of energy transfer from the 3*(Michler’s Ketone) state to 3*2. Spectroscopic
experiment was performed one single time.
400 500 600 700 800 9000.0
0.2
0.4
0.6
0.8
1.0
no
rma
lize
d D
AS
/ a
.u.
l / nm
3*
Michler's Ketone
400 500 600 700 800 9000.0
0.2
0.4
0.6
0.8
1.0
no
rma
lize
d D
AS
/ a
.u.
l / nm
3*
Michler's Ketone
3*
2
- 38 -
Supplementary Figure 9. Differential absorption spectra (visible) registered upon nanosecond transient
absorption spectroscopy (320 nm, 150 nJ) of left: chrysene (1.0 x 10-3 M) and right: a mixture of
chrysene (1.0 x 10-3 M) and dimethyl disulfide (2) (7.0 x 10-2 M) in Ar-saturated acetonitrile with time
delays between 0 and 400 µs at room temperature. There is no evidence for energy transfer from 3*chrysene to dimethyl disulphide (2), which is also supported by the corresponding global analysis
results (bottom left and right). Spectroscopic experiment was performed one single time.
Supplementary Figure 10. Steady state emission spectra of [Ir-F] (ambient conditions) in acetonitrile
and dimethyl disulfide (2) (90 K) in Ar-saturated propan-1-ol/propan-2-ol mixture (1:1, v:v). The
400 500 600 700 800 9000.0
0.2
0.4
0.6
0.8
1.0
no
rma
lize
d D
AS
/ a
.u.
l / nm
1*
chrysene
3*
chrysene
400 500 600 700 800 9000.0
0.2
0.4
0.6
0.8
1.0
1*
chrysene
3*
chrysene
no
rma
lize
d D
AS
/ a
.u.
l / nm
- 39 -
absorption at the excitation wavelengths were adjusted to 0.2. The peaks marked with an asterisk are
Raman peaks of the solvent. Spectroscopic experiment was performed one single time.
- 40 -
4.2. Kinetic Analysis
Energy Transfer of [IrF] to dimethyl disulfide (2)
① [Ir-F]3* kGSR, [Ir-F]→ [Ir-F] Equation 2
② [Ir-F]3* + 2 kEnT→ [Ir-F]+ 23* Equation 3
d[ [Ir-F]3* ]
dt=kobs[ [Ir-F]
3* ]= -[ [Ir-F]3* ]∙kGSR, [Ir-F]-[ [Ir-F]3* ]∙[2]∙kEnT Equation 4
d[ [Ir-F]3* ]
[ [Ir-F]3* ]∙dt = -kGSR, [Ir-F]-[2]∙kEnT Equation 5
d[ [Ir-F]3* ]
[ [Ir-F]3* ]= -(kGSR, [Ir-F]+[2]∙kEnT)∙dt Equation 6
∫d[ [Ir-F]3* ]
[ [Ir-F]3* ]= ∫ -(kGSR, [Ir-F]+[2]∙kEnT)∙dt Equation 7
∫d[ [Ir-F]3* ]
[ [Ir-F]3* ]= -∫(kGSR, [Ir-F] + [2]∙kEnT)∙dt Equation 8
kGSR, [Ir-F]+[2]∙kTTET=kobs Equation 9
ln[ [Ir-F]3* ]
t=0
[ [Ir-F]3* ]t
= -[kobs∙t]t=0t Equation 10
ln[ [Ir-F]3* ]
t=0
[ [Ir-F]3* ]t
= -kobs∙t Equation 11
[ [Ir-F]3* ]t= [ [Ir-F]3* ]
t=0∙e-kobs∙t Equation 12
[ [Ir-F]3* ]t= [ [Ir-F]3* ]
t=0∙e-kGSR, [Ir-F] + [2]∙kEnT∙t Equation 13
[2]∙kTTET = kobs - kGSR, [Ir-F] = f ([2]) Equation 14
→ linear relationship of (kobs -kGSR, [Ir-F]) vs. [2]
Supplementary Figure 11. Plot of the observed rate constant of 3*MLCT/LC ([Ir-F]) deactivation
corrected by the intrinsic GSR rate of [Ir-F] vs. the concentration of dimethyl disulfide (2) according to
Equation 14. Data were recorded by the use of ns-TAS. Regression was performed using n = 5
independent experiments.
- 41 -
Supplementary Figure 12. Plot of the observed rate constant of 3*MLCT/LC ([Ir-F]) deactivation
corrected by the intrinsic GSR rate of [Ir-F] vs. the concentration of dimethyl disulfide (2) according to
Equation 14. Data were recorded by the use of phosphorescence lifetime measurements. Regression was
performed using n = 7 independent experiments.
Reaction of 2 with 1-octene (Oct)
① 23* kGSR, 2→ 2 Equation 15
② 23*
+Oct kreact→ methyl(octyl)sulfane Equation 16
d[ 23* ]
dt=kobs[ 2
3* ]= -[ 23* ]∙kGSR, 2 - [ 23* ]∙[2]∙kreact Equation 17
d[ 23* ]
[ 23* ]∙dt=-kGSR, 2 - [2]∙kreact Equation 18
d[ 23* ]
[ 23* ]= -(kGSR, 2+[2]∙kreact)∙dt Equation 19
∫d[ 23* ]
[ 23* ]= ∫ -(kGSR, 2 + [2]∙kreact)∙dt Equation 20
∫d[ 23* ]
[ 23* ]= -∫(kGSR, 2 + [2]∙kreact)∙dt Equation 21
kGSR, 2 + [2]∙kreact=kobs Equation 22
ln[ 23* ]
t=0
[ 23* ]t
= -[kobs∙t]t=0t Equation 23
ln[ 23* ]
t=0
[ 23* ]t
= -kobs∙t Equation 24
[ 23* ]t= [ 23* ]
t=0∙e-kobs∙t Equation 25
[ 23* ]t= [ 23* ]
t=0∙e-kGSR, 2 + [2]∙kreact∙t Equation 26
[2]∙kreact = kobs - kGSR, 2 = f ([Oct]) Equation 27
→ linear relationship of (kobs-kGSR, 2) vs. [Oct]
- 42 -
Supplementary Figure 13. Plot of the observed rate constant of 3*(dimethyl disulphide) deactivation
corrected by the intrinsic GSR rate of dimethyl disulfide (2) vs. the concentration of 1-octene according
to Equation 27. Data were recorded by the use of ns-TAS. Regression was performed using n = 4
independent experiments.
Supplementary Figure 14. Plot of the observed rate constant of 3*MLCT/LC ([Ir-F]) deactivation
corrected by the intrinsic GSR rate of [Ir-F] divided by [2] vs. the ratio of [Ir-F] and [2] according to
Equation 6. Data were recorded by the use of ns-TAS. Regression was performed using n = 9
independent experiments.
0 2 4 6 8 100
1x108
2x108
3x108
4x108
5x108
6x108
forward reaction rate =
(5.26 ± 0.23) x 107 L mol
-1 s
-1
backward reaction rate =
(8.65 ± 0.88) x 106 L mol
-1 s
-1
R2 = 0.985
(ko
bs -
kG
SC)
/ [2
] /
L m
ol-1
s-1
[[Ir-F]] / [2]
- 43 -
4.3. Electrochemistry
Supplementary Figure 15. Overview regarding the oxidation and reduction recorded by cyclic
voltammetry (top) and differential pulse voltammetry (bottom) of 10 measured in dry Ar-saturated
acetonitrile with 0.1 M TBAPF6 as supporting electrolyte. Experiment was performed one single time.
Supplementary Figure 16. Cyclic voltammograms (top), differential pulse voltammograms (bottom
left) and square wave voltammograms (bottom right) of 10 measured in dry Ar-saturated acetonitrile
with 0.1 M TBAPF6 as supporting electrolyte. Experiment was performed one single time.
-2 -1 0 1 2-2x10
-5
-1x10-5
0
1x10-5
2x10-5
3x10-5
-2 -1 0 1 20.0
3.0x10-6
6.0x10-6
9.0x10-6
i / A
-1.763 V
-1.362 V
-1.196 V
+1.613 V
i / A
E / V vs. Fc/Fc+
- 44 -
4.4. Determination of the Reaction Quantum Yield
Supplementary Figure 17. Emission spectrum of blue LED used for quantum yield experiments
(λmax = 420 nm).
Determination of the light intensity at 415 nm:
According to the procedure of Yoon,26 the photon flux of the LED (λmax = 415 nm) was determined by
standard ferrioxalate actinometry.27, 28, 29 A 0.15 M solution of ferrioxalate was prepared by dissolving
potassium ferrioxalate hydrate (0.737 g) in H2SO4 (10 mL of a 0.05 M solution). A buffered solution of
1,10-phenanthroline was prepared by dissolving 1,10-phenanthroline (25 mg) and sodium acetate
(5.63 g) in H2SO4 (25 mL of a 0.5 M solution). Both solutions were stored in the dark. To determine the
photon flux of the LED, the ferrioxalate solution (1.0 mL) was placed in a cuvette and irradiated for 90
seconds at λmax = 415 nm. After irradiation, the phenanthroline solution (0.175 mL) was added to the
cuvette and the mixture was allowed to stir in the dark for 1.5 h to allow the ferrous ions to completely
coordinate to the phenanthroline. The absorbance of the solutions was measured at 510 nm. The
procedure was repeated three times. Three non-irradiated sample were also prepared and the absorbance
at 510 nm was measured. The average values of the irradiated and non-irradiated samples were taken
for the following calculations. Conversion was calculated using equation 28.
mol Fe2+ = V • ΔA(510 nm)
l • ε Equation 28
where V is the total volume (0.001175 L) of the solution after addition of phenanthroline, ΔA is the
difference in absorbance at 510 nm between the irradiated and non-irradiated solutions, l is the path
length (1.00 cm), and ε is the molar absorptivity of the ferrioxalate actinometer at 515 nm (11.100 L mol-
1 cm-1).26 The photon flux can be calculated using equation 29.
Photon flux = mol Fe
2+
Φ • t • f Equation 29
where Φ is the quantum yield for the ferrioxalate actinometer (1.12 at λex = 420 nm),30 t is the irradiation
time (90 s), and f is the fraction of light absorbed at λex = 420 nm by the ferrioxalate actinometer. This
value is calculated using equation 30 where A(415 nm) is the absorbance of the ferrioxalate solution at
0
0,2
0,4
0,6
0,8
1
1,2
380 400 420 440 460
No
rmal
ized
Inte
nsi
ty
lem (nm)
- 45 -
415 nm. An absorption spectrum gave an A(415 nm) value of > 3, indicating that the fraction of absorbed
light (f) is > 0.999.
f =1-10-A(420 nm) Equation 30
The photon flux was thus calculated (average of three experiments) to be 5.49 × 10-10 einsteins s-1.
Determination of the reaction quantum yield:
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv),
dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv) and anhydrous DCE (1.0 mL, 0.1 M) were added
via syringe under an argon stream. The resulting solution was degassed using three freeze-pump-thaw
cycles and the tube was finally backfilled with argon. The reaction mixture was transferred into a quartz
cuvette using schlenk techniques. The cuvette was capped with a PTFE stopper and sealed with
Parafilm. The sample was stirred and irradiated at λmax = 415 nm (see Figure 17 for an emission
spectrum) for 30 min. After irradiation, the yield of product 3a was determined by GC-FID analysis
using mesitylene as internal standard. The yield of 3a was determined to be 0.7% (7 × 10-7 mol). The
reaction quantum yield (Φ) was determined using equation 31 where the photon flux is 5.49 × 10-10
einsteins s-1 (determined by actinometry as described above), t is the reaction time (3600 s) and f is the
fraction of incident light absorbed by the reaction mixture, determined using equation 30. An absorption
spectrum of the reaction mixture gave an absorbance value of > 3 at 415 nm, indicating that essentially
all the incident light (f > 0.999) is absorbed by photocatalyst [Ir-F].
Φ = mol of product formed
photon flux • t •f Equation 31
The reaction quantum yield (Φ) was thus determined to be 0.71.
Determination of the quenching fraction:
Simple quenching experiments, following a modification of the procedure described by Yoon,19 were
conducted to determine the quenching fraction of the reaction. The reaction with (R)-(–)-carvone was
prepared as described above and the reaction mixture was transferred to a cuvette under an argon
atmosphere, which was then capped with a PTFE stopper and sealed with Parafilm. The luminescence
intensity under the reaction conditions (I) was recorded (λem = 484 nm) while being irradiated at
λex = 420 nm in a Jasco FP-8300 spectrofluorometer. The same reaction was set up in the absence of the
quencher 2 and the luminescence intensity (I0) was measured in the same fashion. The quenching
fraction (Q) was determined using equation 32.
Q = I0-I
I0 Equation 32
- 46 -
A quenching fraction (Q) of 0.991 was determined for the reaction.
Chain length calculation:
The chain length value was calculated using the method described by Yoon,19 and is a lower limit
approximation of the actual chain length. Using Q, as determined from the simple quenching
experiments described above, the chain length of the hydrothiolation reaction was determined using
equation 33.
chain length = Φ
Q Equation 33
The chain length of the reaction was thus determined to be 0.72. Therefore, no radical chain is operating
in this transformation.
- 47 -
4.5. Stern-Volmer Luminescence Quenching Studies
Stern-Volmer luminescence quenching studies were carried out using a 2 × 10-6 M solution of [Ir-F]
and variable concentrations of (R)-(–)-carvone and dimethyl disulfide in dry 1,2-dichloroethane at room
temperature under an argon atmosphere. The samples were prepared in 1.4 mL quartz cuvettes, equipped
with PTFE stoppers, and sealed with Parafilm inside an argon filled glove-box (see section 2.1 for the
general procedure). The solutions were irradiated at 420 nm and the luminescence was measured at 471
nm (I0 = emission intensity of the photocatalyst in isolation at the specified wavelength; I = observed
intensity as a function of the quencher concentration). To verify that the disulfide is the only productive
quenching species leading to product formation, an additional Stern-Volmer luminescence quenching
study using 1-octene was performed.
Supplementary Figure 18. Stern-Volmer luminescence quenching analysis for the Disulfide-Ene-
Reaction using [Ir-F] (2 × 10-6 M). Regression was performed using n = 6 (dimethyl disulfide or (R)-
carvone) or n = 5 (1-octene) independent experiments.
y = 344,19x + 1,0208R² = 0,9921
y = 31,347x + 1,0082R² = 0,9907
y = 0,9183x + 1,0096R² = 0,3773
0,8
1
1,2
1,4
1,6
1,8
2
2,2
0 0,002 0,004 0,006 0,008 0,01 0,012 0,014 0,016 0,018 0,02
I 0/I
Quencher Concentration (mol dm-3)
Dimethyl disulfide
R-(-)-Carvone
1-Octene
- 48 -
4.6. UV/Vis Absorption Studies
UV/Vis absorption spectroscopy has been performed using a Jasco V-650 spectrophotometer, equipped
with a temperature control unit at 25 °C. The samples were measured in Hellma fluorescence QS quartz
cuvettes (chamber volume = 1.4 mL, H × W × D = 46 mm × 12.5 mm × 12.5 mm) fitted with a PTFE
stopper. Stock solutions of the educts (R)-(–)-carvone (1a) and dimethyl disulfide (2) and of the
photocatalyst [Ir-F] were prepared and the measurements were performed using the reaction conditions.
The starting materials (R)-(–)-carvone and dimethyl disulfide did not show any absorption (see Figure
19). To proof that the photocatalyst is the only absorbing species within the reaction mixture, UV/vis
absorption spectra of the reaction mixture with and without the photocatalyst were measured. The
concentration of all reaction compounds is identical to those used under the scope reaction conditions.
In the absence of the photocatalyst, no absorption of the reaction mixture was observed. Under the
reaction conditions, the photocatalyst is the only absorbing species at a wavelength around 455 nm.
Supplementary Figure 19. UV/Vis absorption spectra of the starting materials in isolation and
combined recorded in DCE as solvent. UV/Vis absorption spectra recording was performed once.
0
0,5
1
1,5
2
2,5
3
3,5
4
350 400 450 500 550 600
Abso
rban
ce /
a.
u.
Wavelength / nm
R-(-)-Carvone
Dimethyl disulfide
R-(-)-Carvone + Dimethyl disulfide
R-(-)-Carvone + Dimethyl disulfide + [IrF]
- 49 -
4.7. Reaction Profile for the Disulfide-Ene-Reaction using Carvone, Dimethyl
Disulfide and [Ir-F]
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv),
dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv) and anhydrous DCE (1.0 mL, 0.1 M) were added
via syringe under an argon stream. The resulting solution was degassed using three freeze-pump-thaw
cycles and the tube was finally backfilled with argon. The samples were irradiated with visible light
from blue LEDs (λmax = 455 nm) for the respective time. After the indicated time, mesitylene (14 µL,
0.10 mmol, 1.0 equiv) was added as internal standard and the yield of the product 3a was quantified
using GC-FID. The reaction profile of the Disulfide-Ene-Reaction is depicted in Figure 20.
Supplementary Figure 20. Reaction profile for the Disulfide-Ene-Reaction to give 3a. Reaction profile
was independently determined twice with similar results.
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
yie
ld /
%
time / min
Product
Starting Material
- 50 -
4.8. TEMPO Radical Trapping Experiment
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) and 2,2,6,6-tetramethylpiperidinyloxyl
(31.2 mg, 0.20 mmol, 2.0 equiv) were added to a dried Schlenk tube containing a magnetic stirring bar.
In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv), dimethyl disulfide (17.7 µL,
0.20 mmol, 2.0 equiv) and anhydrous DCE (1.0 mL, 0.1 M) were added via syringe under an argon
stream. The resulting solution was degassed using three freeze-pump-thaw cycles and the tube was
finally backfilled with argon. The sample was irradiated with visible light from blue LEDs
(λmax = 455 nm) for 16 h. The mixture was analyzed using HR-ESI-MS (see Figure 21) and GC-MS.
The formation of the hydrothiolated product 3a was not observed via GC- and ESI-MS analysis.
Furthermore, no trapped intermediates (for example TEMPO+Thiylradical adduct) could be identified.
TEMPO radical trappings experiments were performed one single time.
Supplementary Figure 21. ESI- and GC-MS trace of the radical trapping experiment using TEMPO.
mesitylene TEMPO
(R)-(–)-carvone
- 51 -
4.9. Deuteration Experiment
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv),
dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv) and anhydrous deuterated solvent (1.0 mL, 0.1 M)
were added via syringe under an argon stream. The resulting solution was degassed using three freeze-
pump-thaw cycles and the tube was finally backfilled with argon. The sample was irradiated with visible
light from blue LEDs (5 W, λmax = 455 nm). After 16 h, the deuterium incorporation was determined
using ESI-MS analysis. The results suggest that no hydrogen atom abstraction from the solvent occurs
(Table 2) when polar aprotic or nonpolar solvents are used. This mechanistic experiment backups the
role of dimethyl disulfide 2 as hydrogen atom source. In contrast, if polar protic solvents are used for
the reaction, almost complete deuterium incorporation within the product was observed. In those cases,
the solvent is the source of the hydrogen atom. All deuteration experiments are in full agreement with
our mechanistic hypothesis. Deuteration experiments were all repeated twice with similar results.
Supplementary Table 2. Deuteration experiment to verify the hydrogen atom abstraction event.
Solvent Solvent classification Deuterium incorporation[a] Product yield[b]
MeCN-d3
polar aprotic
0% 69%
CD2Cl2 0% 72%
Acetone-d6 2% 52%
CDCl3 nonpolar 0% 46%
Methanol-d4 polar protic
81% 59%
D2O 86% 33%
[a] Deuterium incorporation determined by electrospray ionization mass spectrometry [b] Yield determined by GC-FID using
mesitylene as internal standard.
- 52 -
4.10. Thiylradical Scrambling Experiment
To further proof the formation of the alkyl thiyl radical under the reaction conditions, a scrambling
experiment was performed. The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a
dried Schlenk tube containing a magnetic stirring bar. In the absence of light, dibutyl disulfide (19.0 µL,
0.10 mmol, 1.0 equiv), dimethyl disulfide (8.9 µL, 0.10 mmol, 1.0 equiv) and anhydrous DCE (1.0 mL,
0.1 M) were added via syringe under an argon stream. The resulting solution was degassed using three
freeze-pump-thaw cycles and the tube was finally backfilled with argon. The samples were irradiated
with visible light from blue LEDs (5 W, λmax = 455 nm) for 16 h. The crude reaction mixture was
analyzed using GC-MS.
The expected formation of the mixed disulfide 23 was observed via GC-MS, suggesting the formation
of thiyl radicals under the reaction conditions.
Supplementary Figure 22. GC-MS of the thiyl radical scrambling experiment. Experiment was
performed one single time.
- 53 -
4.11. Luminescence-Screening Utilizing Sterically Demanding Disulfides
When we investigated the scope and limitation of the disulfide-ene reaction we observed that sterically
demanding disulfides were not successfully transferred to the respective products. We therefore decided
to apply luminescence quenching-based screening studies to identify whether an interaction between the
photocatalyst [Ir-F] and sterically more demanding alkyl disulfides is taking place.
All samples used in the luminescence screening studies were prepared under oxygen-free conditions.
The photocatalyst and potential quenchers were weighed into vials and placed inside a glovebox (a
common glovebag can alternatively be used) under a positive pressure of argon. Acetonitrile was
degassed by argon sparging for one hour and also placed inside along with micropipettes and tips,
cuvettes, empty vials, waste containers and parafilm. Each photocatalyst and substrate sample was then
dissolved in acetonitrile. For each measurement, the appropriate amount of the photocatalyst and
substrate were added to a cuvette and diluted to 1 mL with acetonitrile using micropipettes. A
photocatalyst concentration of 10 μM was used throughout the screening studies along with substrate
concentrations of 25 mM, which equates to 2500 equivalents of each potential quencher relative to the
photocatalyst. The cuvette was then capped with a PTFE stopper and sealed further with parafilm before
being removed from the glovebox and transferred to the fluorescence spectrometer. After the
measurements, the sealed cuvette was brought back into the glovebox, emptied, cleaned with acetonitrile
and dried under a stream of argon before preparing the next sample.
The luminescence emission spectrum of [Ir-F] excited at 420 nm was measured six times (three different
samples, measured twice each) and an average was taken as the standard reference spectrum. The
samples containing potential quenchers were each measured twice and an average was taken. The
emission intensity (I) at a pre-defined wavelength was noted and compared with that of the photocatalyst
in isolation (I0). The amount of decrease in the emission intensity was then quantified as a “quenching
percentage” (F) defined by the following formula:
F(%)=100 (1-I
I0
)% Equation 34
The luminescence quenching spectra of [Ir-F] with dicyclohexyl disulfide, di-tert-butyl disulfide and
dibenzyl disulfide can be seen below. In all three cases, sufficient quenching between [Ir-F] and the
sterically demanding disulfides was observed, indicating that the energy transfer can take place. The
consecutive reaction steps therefore have to be the problematic ones. Each luminescence quenching
experiment was performed for one single time.
- 54 -
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) ([Ir-F]) and dicylohexyl disulfide
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) ([Ir-F]) and di-tert-butyl disulfide
- 55 -
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) ([Ir-F]) and dibenzyl disulfide
- 56 -
4.12. Selectivity Competition Experiment – Disulfide–Ene vs. Thiol–Ene Reaction
The selectivity of the disulfide–ene reaction over the thiol–ene reaction under the optimized reaction
conditions was investigated by two competition experiments.
Hydroalkylthiolation of carvone in the presence of dimethyl disulfide and ethanethiol
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv),
dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv), ethanethiol (14.7 µL, 0.2 mmol, 2.0 equiv) and
anhydrous DCE or deionized water (1.0 mL, 0.1 M) were added via syringe under an argon stream. The
resulting solution was degassed using three freeze-pump-thaw cycles and the tube was finally backfilled
with argon. The sample was irradiated with visible light from blue LEDs (5 W, λmax = 455 nm) for 16 h.
Mesitylene (14 µL, 0.1 mmol, 10. equiv) was added as internal standard and the yield of the products
3a and 3y as well as the amount of remaining starting material was quantified using GC-FID.
Entry Solvent Yield
1a[a]
Yield
3a[a]
Yield
3y[a]
1 DCE
(0.1 M) 3 65 <1
2 H2O
(0.1 M) 10 47 <1
[a] Quantified by GC-FID using mesitylene as internal standard. Experiments were performed once.
- 57 -
Hydroalkylthiolation of carvone in the presence of dibutyl disulfide and ethanethiol
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(-)-carvone (15.7 µL, 0.1 mmol, 1.0 equiv), dibutyl
disulfide (38.0 µL, 0.2 mmol, 2.0 equiv), ethanthiol (14.7 µL, 0.2 mmol, 2.0 equiv) and anhydrous DCE
or deionized water (1.0 mL, 0.1 M) were added via syringe under an argon stream. The resulting solution
was degassed using three freeze-pump-thaw cycles and the tube was finally backfilled with argon. The
samples were irradiated with visible light from blue LEDs (455 nm) for 16 h. After the indicated time,
mesitylene (14 µL, 0.1 mmol) was added as internal standard and the yield of the products 3z and 3y as
well as the amount of remaining starting material was quantified using GC-FID.
Entry Solvent Yield
1a[a]
Yield
3z[a]
Yield
3y[a]
3 DCE
(0.1 M) 2 66 6
4 H2O
(0.1 M) 4 68 <1
[a] Quantified by GC-FID using mesitylene as internal standard. Experiments were performed once.
Interpretation:
In accordance with the biocompatibility-screening, the results suggest that the disulfide-ene reaction
proceeds chemoselective in the presence of thiols. The hydroethylthiolation of carvone observed in entry
3 occurs due to the in situ generation of the disulfide species 26.
Previous experiments revealed that sterically less demanding thiyl radicals are more reactive. By
changing from dimethyl disulfide to dibutyl disulfide, resulting in the formation of the
hydrobutylthiolated product 3z as major or exclusive product, entry’s 1 and 2 are verified in terms of
steric influences. We therefore conclude that the disulfide-ene reaction proceeds chemoselective even
in the presence of thiols potentially capable of engaging in competitive thiol-ene reactions.
- 58 -
4.13. Isolation of polysulfide side-products
During the optimization process, the trisulfide 1-methyl-2-((methylthio)methyl)disulfane (9) was
observed as a byproduct and has consecutively been isolated and characterized. Hydrogen atom
abstraction in α-position to the sulfur atom of 2 by the carbon centered radical 7 leads to the formation
of the carbon centered disulfide radical 8. This radical consecutively reacts with a methyl thiyl radical
or another dimethyl disulfide molecule to yield trisulfide 9. The proposed mechanism is in accordance
with the deuterium label experiments. Notably, also side products bearing 4 or more sulfur atoms have
been observed, which further supports our mechanistic hydrogen abstraction hypothesis.
The photocatalyst [Ir-F] (3.3 mg, 0.003 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(-)-carvone (47.1 µL, 0.3 mmol, 1.0 equiv), dimethyl
disulfide (53.1 µL, 0.6 mmol, 2.0 equiv) and anhydrous DCE were added via syringe under an argon
stream. The resulting solution was degassed using three freeze-pump-thaw cycles and the tube was
finally backfilled with argon. The samples were irradiated with visible light from blue LEDs (455 nm)
for 16 h. The side-product 9 was isolated by column chromatography over silica gel (n-
pentane/ethyl acetate = 90/10, dry load of crude material) and was obtained as colorless oil (24.7 mg of
trisulfide and polysulfide mixture; see spectra below).
- 59 -
GC-MS of trisulfide/polysulfide mixture
1H NMR of trisulfide/polysulfide mixture (CDCl3, 300 MHz)
- 60 -
5. The Disulfide-Ene Click Reaction using an Alloxazine Photocatalyst
5.1. Optimization Studies
The alloxazine photocatalyst 10 was added to an oven-dried Schlenk tube containing a magnetic stirring
bar. The photocatalyst was dissolved in the solvent and (R)-(-)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv)
and dimethyl disulfide were added via syringe under an argon stream. The resulting solution was
degassed using three freeze-pump-thaw cycles and the tube was finally backfilled with argon. The
samples were irradiated with the respective light source for the mentioned time. After the indicated time,
mesitylene (14 µL, 0.10 mmol, 1.0 equiv) was added as internal standard and the yield product 3a and
the remaining starting material was quantified using GC-FID.
Entry Ratio 1a:2
Solvent Catalyst loading /
mol% Time / h
Light source / nm
Yield 3a[a]
Yield 1a[a]
1 1:2 DCE
(0.1 M) 10.0 16 400 82 1
2 1:2 DCE
(0.1 M) 5.0 16 400 79 2
3 1:2 DCE
(0.1 M) 1.0 16 400 62 1
4 1:2 DCE
(0.1 M) 0.5 16 400 36 52
5 1:2 MeCN (0.1 M)
5.0 16 400 71 0
6 1:2 Acetone (0.1 M)
5.0 16 400 2 89
7 1:5 DCE
(0.1 M) 5.0 16 400 78 3
8 1:1 DCE
(0.1 M) 5.0 16 400 41 39
9 1:2 DCE
(0.1 M) 5.0 16 420 60 15
10 1:2 DCE
(0.1 M) 5.0 16 365 68 1
11 1:2 DCE
(0.1 M) / 16 365 0 96
12 1:2 DCE
(0.1 M) 5.0 16 / 0 98
[a] Yields were determined by GC-FID using mesitylene (14 µL, 0.1 mmol, 1.0 equiv) as an internal standard. Optimization
reactions were performed once.
- 61 -
5.2. General Procedure (GP2) Using Alloxazine as Photocatalyst
The alloxazine photocatalyst 10 (5.2 mg, 0.015 mmol, 5.0 mol%) was added to an oven-dried Schlenk
tube containing a magnetic stirring bar. Anhydrous DCE (3.0 mL, 0.1 M) was added under argon. In the
absence of light, the alkene (0.30 mmol, 1.0 equiv) and the disulfide (0.60 mmol, 2.0 equiv) were added
under an argon stream. The resulting solution was degassed using three freeze-pump-thaw cycles and
the tube was finally backfilled with argon. The reaction mixture was allowed to stir at room temperature
for 16 h under irradiation with visible light from six blue LEDs (3 W, λmax = 400 nm). The solvent was
evaporated and the crude reaction products were purified by column chromatography over silica gel (dry
load of crude material, n-pentane:ethyl acetate or dichloromethane/methanol mixtures as eluent) to
afford the pure products 3aq-3av.
Hydrothiolation reactions using alloxazine as photocatalyst were performed once.
Diethyl (3-(methylthio)propyl)phosphonate (3aq)
Prepared from diethyl allylphosphonate (52.3 µL) and dimethyl disulfide (53.1 µL)
following GP2 to give product 3aq as a yellowish liquid (33.0 mg, 0.15 mmol, 49%).
1H NMR (400 MHz, chloroform-d): δ 4.15 – 4.00 (m, 4H), 2.58 – 2.16 (m, 2H),
2.07 (s, 3H), 1.94 – 1.79 (m, 4H), 1.30 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, chloroform-d):
δ 61.7 (d, J = 7 Hz), 34.8, 34.6, 25.3, 23.9, 22.1 (d, J = 4 Hz), 16.6 (d, J = 6 Hz), 15.3; 31P NMR
(162 MHz, chloroform-d): δ 31.6; Rf (n-pentane:ethyl acetate = 1:2): 0.18; GC-MS: tR (50_40): 7.8
min; EI-MS: m/z (%): 41 (16), 45 (11), 61 (16), 73 (13), 80 (15), 81 (20), 87 (16), 96 (11), 97 (49), 108
(28), 109 (15), 121 (32), 123 (17), 125 (100), 152 (82), 153 (18), 165 (21), 211 (28), 226 (40); HR-MS
(ESI): m/z calculated for [(C8H19O3PS)Na]+: 249.0685, found 249.0696; IR (ATR): ν (cm-1): 2980,
2914, 144, 1392, 1257, 1234, 1164, 1097, 1054, 1025, 955, 834, 810, 780, 688, 659, 626.
Trimethyl-(2-methyl-3-(methylthio)propyl)silane (3ar)
Prepared from 2-methylpropenyl trimethylsilane (52.7 µL) and dimethyl
disulfide (53.1 µL) following GP2. The yield of 3ar was determined via 1H
NMR (CH2Br2 as internal standard) to be 84%.
GC-MS: tR (50_40): 6.2 min; EI-MS: m/z (%): 45 (8), 59 (10), 73 (100), 105 (33), 115 (13), 161 (31).
Trimethyl((2-(methylthio)cyclohexyl)oxy)silane (3as)
Prepared from 1-(trimethylsiloxy)cyclohexene (58.3 µL) and dimethyl disulfide
(53.1 µL) following GP1. The yield of 3as (62%) was determined by 1H NMR analysis
using CH2Br2 as internal standard with respect to the thiomethyl functionality.
- 62 -
GC-MS: tR (50_40): 7.2 min; EI-MS: m/z (%) 43 (38), 45 (29), 61 (22), 75 (85), 79 (24), 80 (65), 81
(77), 87 (19), 105 (33), 129 (70), 142 (20), 155 (83), 170 (30), 203 (100), 218 (25).
5-(methylthio)pentyl (E)-6-(6-methoxy-7-methyl-4-((5-(methylthio)pentyl)oxy)-3-oxo-1,3-dihydro
isobenzofuran-5-yl)-4-methylhex-4-enoate (3at)
Prepared from pent-4-en-1-yl (E)-6-(6-methoxy-7-methyl-
3-oxo-4-(pent-4-en-1-yloxy)-1,3-dihydroisobenzofuran-5-
yl)-4-methylhex-4-enoate (136.8 mg) and dimethyl
disulfide (106.2 µL, 4.0 equiv) following a slightly
modified version of GP2 to give product 3at as a colorless
oil (106.9 mg, 0.19 mmol, 65%).
1H NMR (300 MHz, chloroform-d): δ 5.20 – 5.14 (m, 1H), 5.11 (d, J = 2.6 Hz, 1H), 4.24 – 3.99 (m,
4H), 3.76 (d, J = 8.7 Hz, 3H), 3.41 (t, J = 7.3 Hz, 2H), 2.55 – 2.40 (m, 5H), 2.40 – 2.35 (m, 1H), 2.31 –
2.27 (m, 1H), 2.18 – 2.14 (m, 3H), 2.11 – 2.05 (m, 6H), 1.89 – 1.81 (m, 2H), 1.79 (d, J = 1.3 Hz, 2H),
1.71 – 1.38 (m, 13H); 13C{1H} NMR (75 MHz, chloroform-d): δ 173.2, 168.9, 162.8, 155.8, 146.7,
133.7, 129.0, 123.7, 119.7, 112.6, 75.4, 68.2, 64.3, 64.2, 61.0, 60.9, 34.5, 34.1, 33.0, 29.9, 29.0, 28.7,
28.2, 25.1, 23.5, 23.3, 16.3, 15.5, 11.5; Rf (n-pentane:ethyl acetate = 70:30): 0.41; HR-MS (ESI): m/z
calculated for [(C29H44O6S2)Na]+: 575.2472, found 575.2493; IR (ATR): ν (cm-1): 2916, 2854, 1741,
1735, 1597, 1458, 1276, 1165, 1033, 964, 925, 732, 702.
chloroform-d5-(Methylthio)pentyl5-((3aS,4S,6aR)-2-oxohexahydro-1H-thienoimidazol-4yl)
pentanoat (3au)
Prepared from pent-4-en-1-yl 5-((3aS,4S,6aR)-2-oxohexahydro-
1H-thieno[3,4-d]imidazol-4-yl)pentanoate (93.6 mg) and
dimethyl disulfide (53.1 µL) following GP2 to give product 3au
as a brown solid (98.0 mg, 0.27 mmol, 91%).
1H NMR (600 MHz, chloroform-d): δ 6.07 (s, 1H), 5.76 (s, 1H), 4.47 (dd, J = 7.8, 5.0 Hz, 1H), 4.27
(ddd, J = 7.9, 4.5, 1.4 Hz, 1H), 4.03 (t, J = 6.7 Hz, 2H), 3.14 – 3.10 (m, 1H), 2.90 – 2.85 (m, 1H), 2.71
(d, J = 12.8 Hz, 1H), 2.47 (t, J = 7.3 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 2.06 (s, 3H), 1.69 – 1.57 (m, 8H),
1.44 – 1.38 (m, 4H); 13C{1H} NMR (126 MHz, chloroform-d): δ 173.7, 163.9, 64.2, 62.0, 60.0, 55.5,
40.5, 34.0, 33.9, 28.7, 28.4, 28.2, 28.2, 25.1, 24.8, 15.5; Rf (dichloromethane:methanol = 90:10): 0.62;
HR-MS (ESI): m/z calculated for [(C16H28N2O3S2)Na]+: 383.1434, found 383.1457;
IR (ATR): ν (cm-1): 3240, 2916, 2862, 1419, 1257, 1172, 1118, 1072, 1026, 841, 686.
- 63 -
5.3. Reaction Profile for the Disulfide-Ene-Reaction Alloxazine (10) as
Photocatalyst
The alloxazine photocatalyst 10 (1.7 mg, 0.005 mmol, 5.0 mol%) was added to a dried Schlenk tube
containing a magnetic stirring bar. In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol,
1.0 equiv), dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv) and anhydrous DCE (1.0 mL, 0.1 M)
were added via syringe under an argon stream. The resulting solution was degassed using three freeze-
pump-thaw cycles and the tube was finally backfilled with argon. The samples were irradiated with
visible light from blue LEDs (3 W, λmax = 400 nm) for the respective time. Mesitylene (14 µL, 0.1 mmol,
1.0 equiv) was added as internal standard and the yield of the product 3a and the remaining starting
material was quantified using GC-FID. The reaction profile of the disulfide-ene reaction is depicted in
Figure 23.
Supplementary Figure 23. Reaction profile using alloxazine photocatalyst 10 to give 3a. The reaction
profile determination was performed once.
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
yie
ld /
%
time / min
Product
Starting material
- 64 -
5.4. Stern-Volmer Luminescence Quenching Analysis
Stern-Volmer luminescence quenching studies were carried out using a 2 x 10-6 M solution of alloxazine
photocatalyst 10 and variable concentrations of dimethyl disulfide and 1-octene in dry acetonitrile at
room temperature under an argon atmosphere. The samples were prepared in 1.4 mL quartz cuvettes,
equipped with PTFE stoppers, and sealed with Parafilm inside an argon filled glove-box (see section
2.1 for the general procedure). The solutions were irradiated at 400 nm and the luminescence was
measured at 420 nm (I0 = emission intensity of the photocatalyst in isolation at the specified wavelength;
I = observed intensity as a function of the quencher concentration).
Supplementary Figure 24. Stern-Volmer luminescence quenching using Alloxaine 10 as photocatalyst
(2 x 10-6 M). Regression was performed using n = 6 independent experiments.
y = 35,464x + 0,9764
R² = 0,9798
y = 1,0634x + 1
R² = 0,5181
0,9
0,95
1
1,05
1,1
1,15
1,2
1,25
1,3
1,35
1,4
0 0,002 0,004 0,006 0,008 0,01 0,012 0,014 0,016 0,018 0,02
I 0/I
Quencher Concentration (mol dm-3)
Dimethyl disulfide
1-Octene
- 65 -
6. Additive-based Robustness Screen
In order to evaluate the robustness and the functional group preservation of the disulfide-ene reaction,
we decided to apply an intermolecular additive-based screen to this transformation.31 This screening
technique, previously reported by our group, evaluates the tolerance of a given reaction to a series of
additives (robustness), as well as the stability of these additives to the reaction conditions (functional
group preservation).32
The protocol requires to carry out the desired transformation under the standard reaction conditions in
the presence of equimolar amounts of a single functionalized additive. After a pre-determined reaction
time, the yield of the product and the remaining additive and starting materials are determined by GC-
FID analysis.7 Calibration of the additives and products of the reaction was done using a single point
batch calibration.
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv),
dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv), the respective additive (0.10 mmol, 1.0 equiv) and
anhydrous DCE (1.0 mL, 0.1 M) were added under an argon stream. The resulting solution was degassed
using three freeze-pump-thaw cycles and the tube was finally backfilled with argon. The samples were
irradiated with visible light from blue LEDs (5 W, 455 nm) for 16 h. Mesitylene (14 µL, 0.1 mmol,
1.0 equiv) was added as internal standard and the yield of the starting material, product and additive
were quantified using GC-FID.
Note:
Change in volume of the stock solution due to addition of liquid starting materials was not
accounted for, hence a control reaction (no additive) was carried out to determine the maximum
yield of the reaction in the screen.
N-Benzylpyrrole and acetanilide should be filtered through Celite® when preparing samples for
GC analysis. All other additives should be filtered through silica.
Due to screening nature of the robustness screen, all experiments were performed once.
- 66 -
Supplementary Table 3. Results of the additive-based screening for the Disulfide-Ene-Reaction.
Additive-based screening experiments were all performed one.
The color-coding for facilitated assessment of the results is scaled relative to the yield of the standard
reaction in the absence of any additive, representing > 50% in green, 25-50% in yellow and < 25% in
red for the product yields and > 66% in green, 34-66% in yellow and < 34% in red for the additive
recovery. * for details, see [32].
- 67 -
7. Oxidation of Methylthioethers to Sulfoxides and Sulfones
5-(methylsulfinyl)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-trioxo-
hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (11)
In an oven-dried Schlenk flask, scandium(III) triflate (9.8 mg, 0.02 mmol, 0.2 equiv) was dissolved in
a CH2Cl2/EtOH mixture (0.4 mL, 9:1). Hydrogen peroxide (15.3 µL, 0.50 mmol, 5.0 equiv, 30%) was
added followed by the addition of 5-(methylthio)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-
dimethyl-3,7,12-trioxohexadecahydro-1H-cyclopenta[a]-phenanthren-17-yl)pentanoate (3an, 51.9 mg,
0.10 mmol, 1.0 equiv), previously dissolved in 0.4 mL of CH2Cl2/EtOH (9:1). Additional 0.3 mL
solvent mixture was used to rinse the flask. The reaction was stirred at rt and monitored by ESI-MS.
After 6 h, the reaction was completed and H2O (10 mL) and CH2Cl2 (10 mL) were added. The aqueous
layer was extracted with CH2Cl2 (3 x 10 mL) and washed with H2O (10 mL). The organic phase was
dried over MgSO4 and all volatiles were removed under reduced pressure to afforded 5-
(methylsulfinyl)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-trioxohexadecahydro-
1H-cyclopenta[a]phen anthren-17-yl)pentanoate (11) as a light yellowish oil (51 mg, 0.095 mmol,
95%), which was pure without any further purification.
1H NMR (300 MHz, chloroform-d): δ 4.13 – 4.01 (m, 2H), 3.07 – 2.43 (m, 8H), 2.41 – 2.07
(m, 9H), 2.07 – 1.89 (m, 5H), 1.87 – 1.73 (m, 3H), 1.73 – 1.42 (m, 5H), 1.38 (s, 3H), 1.33 –
1.17 (m, 5H), 1.02 (s, 3H), 0.82 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (75 MHz, chloroform-d):
δ 212.1, 209.2, 208.9, 174.2, 63.9, 57.0, 54.5, 51.8, 49.1, 46.9, 45.7, 45.6, 45.1, 42.9, 38.7, 38.6,
36.6, 36.1, 35.6, 35.3, 31.5, 30.5, 28.4, 27.7, 25.4, 25.2, 22.4, 22.0, 18.7, 11.9; HR-MS (ESI):
m/z calculated for [(C30H46O6S)Na]+: 557.2907, found 557.2903; IR (ATR): ν (cm-1): 2963,
2880, 2360, 2342, 2254, 1711, 1465, 1387, 1269, 1175, 1104, 1031, 907, 857, 727, 648, 631.
- 68 -
5-(methylsulfonyl)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-
trioxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (12)
Under Schlenk conditions, 5-(methylsulfinyl)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-
3,7,12-trioxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (51 mg, 0.095 mmol,
1.0 equiv) was dissolved in dry CH2Cl2 (0.75 mL). At 0 °C, a solution of 3-chloroperbenzoic acid
(23.4 mg, 0.105 mmol, 1.1 equiv.) in CH2Cl2 (1.2 mL) was added dropwise. The reaction was monitored
by ESI-MS. After 2 h the spectra indicated absence of the starting material and the reaction mixture was
treated with 5% aq. NaOH (20 mL) and was diluted with CH2Cl2 (50 mL). After separation of the phases,
the organic phase was washed with 5% aq. NaOH (50 mL), dried over MgSO4 and concentrated under
reduced pressure to afforded 5-(methylsulfonyl)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-
dimethyl-3,7,12-trioxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (12) as a light
yellowish solid (46 mg, 0.084 mmol, 88%), which was pure without any further purification.
1H NMR (300 MHz, chloroform-d): δ 4.11 – 3.99 (m, 2H), 3.07 – 2.78 (m, 8H), 2.37 – 1.80 (m, 18H),
1.72 – 1.48 (m, 5H), 1.38 (s, 3H), 1.35 – 1.22 (m, 4H), 1.05 (s, 3H), 0.83 (d, J = 6.5 Hz, 3H); 13C{1H}
NMR (75 MHz, chloroform-d): δ 212.1, 209.2, 208.9, 174.2, 63.7, 57.0, 54.7, 51.8, 49.1, 46.9, 45.7,
45.6, 45.1, 42.9, 40.7, 38.7, 36.6, 36.1, 35.6, 35.4, 31.5, 30.5, 28.3, 27.7, 25.2, 25.1, 22.2, 22.0, 18.8,
12.0; HR-MS (ESI): m/z calculated for [(C30H46O7S)Na]+: 573.2856, found 573.2862.
- 69 -
8. Additive-based Biocompatibility Screening
8.1. Investigating Aqueous Reaction Conditions In order to evaluate the biocompatibility of the disulfide-ene-reaction, we firstly investigated suitable
physiological reaction conditions under which our hydrothiolation protocol can be carried out.
The photocatalyst was added to a dried Schlenk tube containing a magnetic stirring bar. In the absence
of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv), dimethyl disulfide (17.7 µL, 0.2 mmol,
2.0 equiv) and the solvent (1.0 mL) were added under an argon stream. The resulting solution was
degassed using three freeze-pump-thaw cycles and the tube was finally backfilled with argon. The
samples were irradiated with visible light from blue LEDs (λmax = 455 nm or 400 nm). After the indicated
time, acetone (1.0 mL) and mesitylene (14 µL, 0.1 mmol) were added and the yield of the product and
the amount of remaining starting material were quantified using GC-FID. All reactions were performed
one single time.
Entry Photocatalyst
(mol%) Solvent
Wavelength / nm
Time / h Yield 3a[a]
Yield 1a[a]
Conversion / %
1 [Ir-F]
(1.0) PBS
(1x, pH = 7.4) 455 20 68 0 100
2 FlIrPic (1.0)
PBS (1x, pH = 7.4)
455 20 30 17 83
3 Alloxazine 10
(5.0) PBS
(1x, pH = 7.4) 400 11 7 89 11
4 Alloxazine 10
(5.0) PBS
(5x, pH = 7.4) 400 11 9 78 22
5 Alloxazine 10
(5.0) Tris-HCl
(0.2 M, pH = 7.4) 400 11 10 89 11
6 [Ir-F]
(1.0) PBS
(5x, pH = 7.4) 455 11 40 41 59
7 [Ir-F]
(1.0) Tris-HCl
(0.2 M, pH = 7.4) 455 11 58 25 75
8 [Ir-F]
(1.0) Tris-HCl
(0.2 M, pH = 7.4) 455 24 67 1 99
- 70 -
8.2. Investigating the Biocompatibility of the Disulfide–Ene Reaction In order to evaluate the biocompatibility of the disulfide-ene-reaction, we subjected this transformation
to an intermolecular additive-based biocompatibility screen. This screening technique, previously
reported by Chen and coworkers,33 evaluates the tolerance of a given reaction to a series of bio-additives
(biological robustness), as well as the stability of these additives to the reaction conditions (biomolecule
preservation).
The protocol requires to carry out the desired transformation under the previously optimized
physiological reaction conditions in the presence of a single biomolecule additive (amino acid,
saccharide, protein, nucleoside, DNA, RNA). After a pre-determined reaction time, the yield of the
product and starting material are determined either by GC-FID or 1H NMR analysis. Calibration of the
starting materials and products of the reaction was done using a single point batch calibration. The
qualitative assessment of the stability of the additive was investigated using either UPLC-MS or gel
electrophoresis. For qualitative classification of this stability under the reaction conditions, four diverse
categories have been defined:
A = biomolecule identified; no degradation products detected.
B = biomolecule identified; small amounts of degradation products detected.
C = decreased amount of biomolecule identified; significant amount of degradation products detected.
D = no remaining biomolecule identified; many degradation products detected.
n. d. = not determined; a statement on the biomolecule additive preservation cannot be made.
A) Biocompatibility screening using carvone as alkene substrate
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, (R)-(–)-carvone (15.7 µL, 0.10 mmol, 1.0 equiv),
dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv), the respective additive (0.10 mmol, 1.0 equiv or
amount as stated in the table) and Tris-HCl (1.0 mL, 0.2 M) were added under an argon stream. The
resulting solution was degassed using three freeze-pump-thaw cycles and the tube was finally backfilled
with argon. The samples were irradiated with visible light from blue LEDs (λmax = 455 nm) for 24 h.
After the indicated time, an aliquot of the reaction mixture (100 µL) was taken for UPLC-MS or gel
electrophoresis to analyze the biomolecule preservation. The remaining solution was diluted with
acetone (1.0 mL) and mesitylene (12.6 µL, 0.9 mmol, 1.0 equiv after aliquot) was added as internal
standard and the yield of the remaining starting material and product was quantified using GC-FID.
- 71 -
Supplementary Table 4: Investigating the biocompatibility of the disulfide–ene reaction by additive-
based screening using carvone 1a.
Entry Remaining
SM[a]
Product
Yield[a] Conversion Additive Recovery
1
1%
68%
99%
-
-
2 1% 72% 99% L-Methionine
(0.1 mmol) A[b]
3 2% 58% 98% L-Arginine
(0.1 mmol) B[b]
4 2% 64% 98% L-Leucine
(0.1 mmol) A[b]
5 1% 53% 99% L-Alanine
(0.1 mmol) n. d.
6 2% 67% 98% L-Ascorbic acid
(0.1 mmol) A[b]
7 1% 66% 99% Citric acid
(0.1 mmol) A[b]
8 2% 66% 98% Linoleic Acid
(0.1 mmol) B[b]
9 2% 61% 98% D-(+)-Glucose
(0.1 mmol) A-B[b]
10 3% 73% 97% D-(+)-Sucrose
(0.1 mmol) A-B[b]
11 1% 64% 99% Adenosine
(0.1 mmol) A[b]
12 2% 68% 98% ATP
(0.1 mmol) A[b]
13 2% 65% 98% L-Glutathione
(0.1 mmol) B[b]
14 2% 66% 98% L-Cystine
(0.1 mmol) C[b]
15 3% 65% 97% D-Biotin
(0.1 mmol) B[b]
16 2% 54% 98% BSA
(100 µM) A[c]
17 2% 65% 98% BSA
(10 µM) A[c]
18 2% 63% 98% RNase A
(100 µM) A[c]
19 2% 63% 98% RNase A
(10 µM) A[c]
- 72 -
20 2% 66% 98% ssDNA
(5 µM) A[c]
21 1% 68% 99% ssDNA
(0.5 µM) A[c]
22 2% 68% 98% RNA
(2.5 µM) C[c]
23 2% 64% 98% RNA
(0.5 µM) D[c]
24 2% 64% 98% Total RNA
(5.5 µg/mL) C[c]
25 2% 64% 98% Cell lysate
(vol. 1 mL) n. d.
26 2% 62% 98% Cell lysate/H2O
(1:10 v/v) n. d.
n. d. = not determined; [a]quantified by GC-FID using mesitylene as internal standard; [b]qualitative
analysis by LC-MS; [c]qualitative analysis by gel electrophoresis. All reactions were performed one time.
B) Biocompatibility screening using ((allyloxy)carbonyl)-L-phenylalanine as alkene substrate
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, ((allyloxy)carbonyl)-L-phenylalanine (24.9 mg,
0.10 mmol, 1.0 equiv), dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv), cell lysate (100 µL) and
Tris-HCl (0.9 mL) were added under an argon stream. The resulting solution was degassed using three
freeze-pump-thaw cycles and the tube was finally backfilled with argon. The samples were irradiated
with visible light from blue LEDs (λmax = 455 nm) for 24 h. The solution was diluted with acetone
(1.0 mL). The yield of the remaining starting material and product was quantified using 1H NMR in
combination with CH2Br2 as internal standard.
- 73 -
Supplementary Table 5: Investigating the biocompatibility of the disulfide–ene reaction by additive-
based screening using ((allyloxy)carbonyl)-L-phenylalanine 1ai.
Entry Remaining
SM[a]
Product
Yield[a] Conversion Additive Recovery
27
5%
62%
95%
-
-
28 3% 64% 97% Cell lysate:H2O
(1:10 v/v) n. d.
n. d. = not determined; [a]quantified by 1H NMR using CH2Br2 as internal standard. All reactions were
performed one time.
C) Biocompatibility screening using 5-(methylthio)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-
dimethyl-3,7,12-trioxohexadecahydro-1H-cyclopenta[a]-phenanthren-17-yl)pentanoate as
alkene substrate
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, 5-(methylthio)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-
10,13-dimethyl-3,7,12-trioxohexadecahydro-1H-cyclopenta[a]-phenanthren-17-yl)pentanoate
(47.0 mg, 0.10 mmol, 1.0 equiv), dimethyl disulfide (17.7 µL, 0.20 mmol, 2.0 equiv), cell lysate
(100 µL) and Tris-HCl (0.9 mL) were added under an argon stream. The resulting solution was degassed
using three freeze-pump-thaw cycles and the tube was finally backfilled with argon. The samples were
irradiated with visible light from blue LEDs (λmax = 455 nm) for 24 h. The solution was diluted with
acetone (1.0 mL). The yield of the remaining starting material and product was quantified using 1H
NMR in combination with CH2Br2 as internal standard.
Supplementary Table 6: Investigating the biocompatibility of the disulfide–ene reaction by additive-
based screening using 1an.
Entry Remaining
SM[a]
Product
Yield[a] Conversion Additive Recovery
29
22%
72%
78%
/
/
30 19% 73% 81% Cell lysate:H2O
(1:10 v/v) n. d.
n. d. = not determined; [a]quantified by 1H NMR using CH2Br2 as internal standard. All reactions were
performed one time.
- 74 -
D) Biocompatibility screening using pent-4-en-1-yl 5-((3aS,4S,6aR)-2-oxohexahydro-1H-
thieno[3,4-d]imidazol-4-yl)pentanoate as alkene substrate
The photocatalyst [Ir-F] (1.1 mg, 0.001 mmol, 1.0 mol%) was added to a dried Schlenk tube containing
a magnetic stirring bar. In the absence of light, pent-4-en-1-yl 5-((3aS,4S,6aR)-2-oxohexahydro-1H-
thieno[3,4-d]imidazol-4-yl)pentanoate (31.2 mg, 0.10 mmol, 1.0 equiv), dimethyl disulfide (17.7 µL,
0.20 mmol, 2.0 equiv), cell lysate (100 µL) and Tris-HCl (0.9 mL) were added under an argon stream.
The resulting solution was degassed using three freeze-pump-thaw cycles and the tube was finally
backfilled with argon. The samples were irradiated with visible light from blue LEDs (λmax = 455 nm)
for 24 h. The solution was diluted with acetone (1.0 mL). The yield of the remaining starting material
and product was quantified using 1H NMR in combination with CH2Br2 as internal standard.
Supplementary Table 6: Investigating the biocompatibility of the disulfide–ene reaction by additive-
based screening using 1au as alkene.
Entry Remaining
SM[a]
Product
Yield[a] Conversion Additive Recovery
31
9%
67%
93%
/
/
32 4% 72% 96% Cell lysate
(1:10 v/v) n. d.
n. d. = not determined; [a]quantified by 1H NMR using CH2Br2 as internal standard. All reactions were
performed one time.
- 75 -
E) LC-MS and gel electrophoresis analysis of biomolecules after disulfide-ene reaction
Supplementary Figure 25. LC-MS analysis of amino acid recovery after disulfide-ene reaction.
(A) L-Methionine (entry 2): calculated mass of [C5H12NO2S]+ = 150.0583 [M+H]+, found 150.0580.
(B) L-Arginine (entry 3): calculated mass of [C6H15N4O2]+ = 175.1190 [M+H]+, found 175.1194.
(C) L-Leucine (entry 4): calculated mass of [C6H14NO2]+ = 132.1019 [M+H]+, found 132.1022.
- 76 -
Supplementary Figure 26. LC-MS analysis of carboxcylic and fatty acid recovery after disulfide-ene
reaction.
(A) L-Ascorbic acid (entry 6): calculated mass of [C6H9O6]+ = 177.0394 [M+H]+, found 177.0401.
(B) Citric acid (entry 7): calculated mass of [C6H9O7]+ = 193.0343 [M+H]+, found 193.0346.
(C) Linoleic acid (entry 8): calculated mass of [C18H33O2]+ = 281.2475 [M+H]+, found 281.2474.
- 77 -
Supplementary Figure 27. LC-MS analysis of saccharide recovery after disulfide-ene reaction.
(A) D-(+)-Glucose (entry 9): calculated mass of [C6H16NO6]+ = 198.0972 [M+NH4]+, found 198.0981.
(B) D-(+)-Sucrose (entry 10): calculated mass of [C12H26NO11]+ = 360.1500 [M+NH4]+, found 360.1508.
- 78 -
Supplementary Figure 28. LC-MS analysis of nucleoside recovery after disulfide-ene reaction.
(A) Adenosine (entry 11): calculated mass of [C10H14N5O4]+ = 268.1040 [M+H]+, found 268.1044.
(B) ATP (entry 12): calculated mass of [C10H17N5O13P3]+ = 508.0030 [M+H]+, found 508.0042.
- 79 -
Supplementary Figure 29. LC-MS analysis of other biomolecules recovery after disulfide-ene reaction.
(A) L-Glutathione (entry 13): calculated mass of [C10H18N3O6S]+ = 308.0911 [M+H]+, found 308.0911.
(B) L-Cystine (entry 14): calculated mass of [C6H13N2O4S2]+ = 241.0311 [M+H]+, found 241.0333.
(C) D-Biotin (entry 15): calculated mass of [C10H17N2O3S]+ = 245.0954 [M+H]+, found 245.0955.
- 80 -
Supplementary Figure 30. SDS-PAGE of proteins BSA and RNase A before (-) and after (+) disulfide-
ene reaction. Reactions were performed at 2 different concentrations ((a) 100 µM (entry 16/18) and (b)
10 µM (entry 17/19) and proteins were analyzed by Tris-glycine gel electrophoresis (15% Tris glycine
gel, 200 V, 50 min, rt) and staining using Coomassie. Lanes contain equal amounts of protein (1 µg)
and thus adjusted volumes of irradiated reaction mixture were loaded compared to the initial
concentration. M: PageRuler™ Prestained Protein Ladder (Thermo Fisher Scientific). SDS-PAGE was
repeated twice with similar results.
- 81 -
Supplementary Figure 31. PAA analysis of ssDNA (35 nt) before and after disulfide-ene reaction.
Reactions were performed at 2 different concentrations ((a) 5 µM (entry 20) and (b) 0.5 µM (entry 21)
and DNA samples were analyzed by PAA gel electrophoresis (15% PAA gel, 12 W, 3.5 h, rt) and
staining using SYBRTM Gold (Invitrogen). Lanes contain equal amounts of DNA (200 ng) and thus
adjusted volumes of irradiated reaction mixture were loaded compared to the initial concentration. M:
Low Molecular Weight Marker (Affimetrix/USB). PAA analysis was repeated three times with similar
results.
- 82 -
Supplementary Figure 32. PAA analysis of short RNA (30 nt) before and after disulfide-ene reaction.
Reactions were performed at 2 different concentrations ((a) 2.5 µM (entry 22) and (b) 0.5 µM (entry 23)
and RNA samples were analyzed by PAA gel electrophoresis (15% PAA gel, 12 W, 3.5 h, rt) and
staining using SYBRTM Gold (Invitrogen). Lanes contain equal amounts of RNA (500 ng) and thus
adjusted volumes of irradiated reaction mixture were loaded compared to the initial concentration. As
control RNA was digested (1 M NaOH, 10 min, 80 °C). M: Low Molecular Weight Marker
(Affimetrix/USB). PAA analysis was repeated twice with similar results.
- 83 -
Supplementary Figure 33. PAA analysis of total RNA before and after disulfide-ene reaction. Total
RNA (entry 24) was analyzed by PAA gel electrophoresis (7.5% PAA gel, 12 W, 4 h, 4 °C) and staining
using SYBRTM Gold (Invitrogen). Lanes contain equal amounts of RNA (500 ng) and thus adjusted
volumes of irradiated reaction mixture were loaded compared to the initial concentration. As control
total RNA was digested (1 M NaOH, 10 min, 80 °C). M: Low Molecular Weight Marker
(Affimetrix/USB). PAA analysis was performed one single time.
- 84 -
9. References
1 D. Hanss, J. C. Freys, G. Bernardinelli, O. S. Wenger, Eur. J. Inorg. Chem. 2009, 4850.
2 M. A. Ischay, Z. Lu, T. P. Yoon, J. Am. Chem. Soc. 2010, 132, 8572.
3 J. Bouzaid, M. Schultz, Z. Lao, J. Bartley, T. Bostrom, J. McMurtrie, Cryst. Growth Des. 2012, 12,
3906.
4 a) S. Sprouse, K. A. King, P. J. Spellane, R. J. Watts, J. Am. Chem. Soc. 1984, 106, 6647; b) J. D.
Slinker, A. A. Gorodetsky, M. S. Lowry, J. Wang, S. Parker, R. Rohl, S. Bernhard, G. G. Malliaras, J.
Am. Chem. Soc. 2004, 126, 2763.
5 D. N. Schultz, J. W. Sawicki, T. P. Yoon, Beilstein J. Org. Chem. 2015, 11, 61.
6 A. B. Tamayo, B. D. Alleyne, P. I. Djurovich, S. Lamansky, I. Tsyba, N. N. Ho, R. Bau, M. E.
Thompson, J. Am. Chem. Soc. 2003, 125, 7377.
7 B. D. Stringer, L. M. Quan, P. J. Barnard, D. J. D. Wilson, C. F. Hogan, Organometallics 2014, 33,
4860.
8 A. B. Tamayo, B. D. Alleyne, P. I. Djurovich, S. Lamansky, I. Tsyba, N. N. Ho, R. Bau, M. E.
Thompson, J. Am. Chem. Soc. 2003, 125, 7377.
9 Y. Zhou, W. Li, Y. Lin, L. Zeng, W. Su, M. Zhou, Dalton Trans. 2012, 41, 9373.
10 V. Mojr, E. Svobodová, K. Straková, T. Neveselý, J. Chudoba H. Dvoráková, R. Cibulka, Chem.
Commun. 2015, 51, 12036.
11 H. L. Dexter, H. E. L. Williams, W. Lewis, C. J. Moody, Angew. Chem. Int. Ed. 2017, 56, 3069.
12 C. T. Ronayne et al., Bioorganic & Medicinal Chemistry Letters 2017, 27, 776.
13 J. M. Lobez, T. M. Swager, Angew. Chem. Int. Ed. 2010, 49, 95.
14 D. C. Fabry, M. Stodulski, S. Hoerner, T. Gulder, Chem. Eur. J. 2012, 18, 10834.
15 M. D’Ascensio, S. Carradori, C. De Monte, D. Secci, M. Ceruso, C. T. Supuran, Bioorg. Med.
Chem. 2014, 22, 1821.
16 A. Srikrishna, G. Ravi, G. Satyanarayana, Tetrahedron Letters 2007, 48, 73.
17 J. J. Snellenburg, S. P. Laptenok, R. Seger, K. M. Mullen, I. H. M. van Stokkum, J. Stat. Softw.
2012, 49, 1-22.
18 S. R. Wilson, P. Caldera, M. A. Jester, J. Org. Chem. 1982, 47, 3319.
19 J. Barluenga, F. Foubelo, F. J. Fananás, M. Yus, Tetrahedron 1989, 45, 2183.
20 S. Poulain, S. Julien, E. Dunach, Tetrahedron Lett. 2005, 46, 7077.
21 T. Mitsudome, Y. Takahashi, T. Mizugaki, K. Jitsukawa, K. Kaneda, Angew. Chem. Int. Ed. 2014,
53, 8348.
- 85 -
22 R. Cano, D. J. Ramón, M. Yus, J. Org. Chem. 2011, 76, 654.
23 M. A. Fernández-Rodríguez, J. F. Hartwig, J. Org. Chem. 2009, 74, 1663.
24 M. A. Fernández-Rodríguez, Q. Shen, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 2180.
25 D.-T. D. Tang, K. D. Collins, F. Glorius, J. Am. Chem. Soc. 2013, 135, 7450.
26 M. A. Cismesia, T. P. Yoon, Chem. Sci. 2015, 6, 5426.
27 C. G. Hatchard, C. A. Parker, Proc. Roy. Soc. (London) 1956, A23, 518.
28 H. J. Kuhn, S. E. Braslavsky, R. Schmidt, Pure Appl. Chem. 2004, 76, 2105.
29 M. Monalti, et. al. Chemical Actinometry. Handbook of Photochemistry, 3rd Ed; Taylor & Francis
Group, LLC. Boca Raton, FL, 2006, 601.
30 E. E. Wegner, A. W. Adamson, J. Am. Chem. Soc. 1966, 88, 394.
31 K. D. Collins, A. Rühling, F. Glorius, Nat. Protoc. 2014, 9, 1348-1353.
32 T. Gensch, M. Teders, F. Glorius, J. Org. Chem. 2017, 82, 9154.
33 H. Huang, G. Zhang, L. Gong, S. Zhang, Y. Chen, J. Am. Chem. Soc. 2014, 136, 2280 .
- 86 -
10. Spectra (5S)-2-methyl-5-(1-(methylthio)propan-2-yl)cyclohex-2-en-1-one (3a)
- 87 -
3-(Methylthio)cyclohexan-1-one (3b)
- 88 -
(4S)-4-(1-(Methylthio)propan-2-yl)cyclohex-1-ene-1-carbaldehyde (3c)
- 89 -
Methyl(2-((R)-4-methylcyclohex-3-en-1-yl)propyl)sulfane (3d)
- 90 -
Cyclooctyl(methyl)sulfane (3e)
- 91 -
(4R)-1-Methyl-4-(1-(methylthio)propan-2-yl)-7-oxabicyclo[4.1.0]heptane (3f)
- 92 -
N-(3-(Methylthio)propyl)benzamide (3g)
- 93 -
2-(3-(Methylthio)propyl)phenol (3h)
- 94 -
(2-(Benzyloxy)ethyl)(methyl)sulfane (3j)
- 95 -
3-(4-(Methylthio)butoxy)pyridine (3k)
- 96 -
(4R,4aS,6S)-4,4a-dimethyl-6-(1-(methylthio)propan-2-yl)-4,4a,5,6,7,8-hexahydronaphthalen-
2(3H)-one (3m)
- 97 -
(5R)-2,3-dimethyl-5-(1-(methylthio)propan-2-yl)cyclohex-2-en-1-one (3n)
- 98 -
Methyl(2-((1R,3R)-4-methyl-3-(methylthio)cyclohexyl)propyl)sulfane (3o)
- 99 -
6-(Methylthio)hexan-1-ol (3p)
- 100 -
2,3-Bis(methylthio)bicyclo[2.2.1]heptane (3q)
- 101 -
6-(Methylthio)hexanenitrile (3r)
- 102 -
Methyloctylsulfane (3s)
- 103 -
Diethyl 2-(3-(methylthio)propyl)malonat (3t)
- 104 -
(11R,Z)-7,7,11-trimethyl-4-((methylthio)methyl)-12-oxabicyclo[9.1.0]dodec-4-ene (3v)
- 105 -
1,3-dimethyl-3-((methylthio)methyl)indolin-2-one (3w)
- 106 -
2-(4-(Methylthio)butyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3x)
- 107 -
(5R)-5-(1-(Ethylthio)propan-2-yl)-2-methylcyclohex-2-en-1-one (3y)
- 108 -
(5R)-5-(1-(Butylthio)propan-2-yl)-2-methylcyclohex-2-en-1-one(3z)
- 109 -
(5R)-5-(1-((2-Hydroxyethyl)thio)propan-2-yl)-2-methylcyclohex-2-en-1-one (3aa)
- 110 -
Octyl(phenyl)sulfane (3ac)
- 111 -
Octyl(p-chlorophenyl)sulfane (3ad)
- 112 -
Octyl(p-tolyl)sulfane (3ae)
- 113 -
((3-(methylthio)propoxy)carbonyl)-L-methionine (3ag)
- 114 -
(3S)-3-methyl-2-(((3-(methylthio)propoxy)carbonyl)amino)pentanoic acid (3ah)
- 115 -
((3-(methylthio)propoxy)carbonyl)-L-phenylalanine (3ai)
- 116 -
Z/E-(1-phenylethene-1,2-diyl)bis(methylsulfane) (3ak)
- 117 -
2-Methyl-3-phenylbenzo[b]thiophene (3al)
- 118 -
5-(Methylthio)pentyl 4-(N,N-dipropylsulfamoyl)benzoate (3am)
- 119 -
5-(Methylthio)pentyl(4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-trioxohexadeca
hydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (3an)
- 120 -
(8R,9S,13S,14S)-13-Methyl-3-(4-(methylthio)butoxy)-6,7,8,9,11,12,13,14,15,16-decahydro-17H-
cyclopenta[a]phenanthren-17-one (3ao)
- 121 -
14-(Methylthio)docosanoic acid (3ap)
- 122 -
(5R)-5-(1-(Propylthio)propan-2-yl)-2-methylcyclohex-2-en-1-on (21)
- 123 -
Diethyl (3-(methylthio)propyl)phosphonate (3aq)
- 124 -
- 125 -
5-(methylthio)pentyl (E)-6-(6-methoxy-7-methyl-4-((5-(methylthio)pentyl)oxy)-3-oxo-1,3-dihydro
isobenzofuran-5-yl)-4-methylhex-4-enoate (3at)
- 126 -
5-(Methylthio)pentyl 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thienoimidazol-4yl)pentanoat (3au)
- 127 -
5-(methylsulfinyl)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-trioxo-
hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (11)
- 128 -
5-(methylsulfonyl)pentyl (4R)-4-((8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-
trioxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate (12)