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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]

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- 1 -

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)

[email protected]

b Department für Chemie und Pharmazie, Lehrstuhl für Physikalische Chemie I, Friedrich-Alexander-

Universität Erlangen-Nürnberg, Egerlandstr. 3, 91058 Erlangen (Germany)

[email protected]

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)

- 2 -

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

0,4

0,6

0,8

1

1,2

300 350 400 450 500

No

rma

lize

d I

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420 nm Blue LED

0

0,2

0,4

0,6

0,8

1

1,2

300 350 400 450 500

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rma

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455 nm Blue LED

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0,4

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0,8

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1,2

300 350 400 450 500

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d I

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UVA LED

- 5 -

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

- 6 -

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.

- 7 -

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).

- 8 -

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).

- 9 -

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

- 12 -

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)


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)


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


(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)


16 455 45 22

20 1:2 DMSO (0.1 M)


16 455 1 44

21 1:2 Fluorobenzene


(PF6) (2.5) 16 455 54 31

22 1:2 1,4-Dioxane


(PF6) (2.5) 16 455 54 32

23 1:2 CHCl3 (0.1 M)


16 455 43 6

24 1:1 DCE


(PF6) (2.5) 16 455 53 35

25 1:3 DCE


(PF6) (2.5) 16 455 69 1

26 1:2 DCE


(PF6) (2.5) 16 455 67 4

27 1:2 DCE


(PF6) (2.5) 16 455 61 23

28 1:2 DCE


(PF6) (1.0) 16 455 68 2

29 1:2 DCE


(PF6) (5.0) 16 455 61 3

30 1:2 DCE


(PF6) (0.5) 16 455 52 29

31 1:2 DCE


(PF6) (0.1) 16 455 19 72

32 1:0 DCE


(PF6) (1.0) 16 455 0 97

33 1:2 MeCN/H2O (1:1)


(PF6) (1.0) 16 455 53 19

34[b] 1:2 MeCN (0.1 M)


16 455 18 25

35 1:2 MeCN (0.1 M)


16 420 69 11

36 1:2 MeCN (0.1 M)


16 400 66 19

37 1:2 MeCN (0.1 M)


16 365 52 2

38 1:2 MeCN (0.1 M)


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%).


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.


- 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



(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%).


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.


- 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.


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.


(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.


(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


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:


(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).


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.


- 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.


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 -


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 -


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



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


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]



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



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



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


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.


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.



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


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.


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



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


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 -


based screening using ((allyloxy)carbonyl)-L-phenylalanine 1ai.

Entry Remaining

SM[a]

Product


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


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


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.


based screening using 1an.

Entry Remaining

SM[a]

Product


29

22%

72%

78%

/

/

30 19% 73% 81% Cell lysate:H2O

(1:10 v/v) n. d.


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


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.


based screening using 1au as alkene.

Entry Remaining

SM[a]

Product


31

9%

67%

93%

/

/

32 4% 72% 96% Cell lysate

(1:10 v/v) n. d.


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

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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.

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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.

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Commun. 2015, 51, 12036.

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12 C. T. Ronayne et al., Bioorganic & Medicinal Chemistry Letters 2017, 27, 776.

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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,

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22 R. Cano, D. J. Ramón, M. Yus, J. Org. Chem. 2011, 76, 654.

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28 H. J. Kuhn, S. E. Braslavsky, R. Schmidt, Pure Appl. Chem. 2004, 76, 2105.

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30 E. E. Wegner, A. W. Adamson, J. Am. Chem. Soc. 1966, 88, 394.

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- 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)

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