multikilogram per hour continuous photochemical benzylic

S1

Supporting Information

Multikilogram per Hour Continuous

Photochemical Benzylic Brominations Applying a

Smart Dimensioning Scale-up Strategy

Alexander Steiner,†,‡ Philippe M. C. Roth,§ Franz J. Strauss,∥ Guillaume Gauron,§ Günter

Tekautz,∥ Marc Winter,§ Jason D. Williams,*,†,‡ C. Oliver Kappe*,†,‡

S2

Contents 1. General ................................................................................................................................... 3

2. Starting Material Quality ..................................................................................................... 4

2.1. Analysis ............................................................................................................................ 4

2.2. Use test ............................................................................................................................. 7

3. Risk Assessment ..................................................................................................................... 8

3.1. Calorimetric measurements .............................................................................................. 8

3.2. Reaction Heat Calculations ............................................................................................ 15

3.3. Detailed Process Risk Assessment ................................................................................. 17

4. Setup ..................................................................................................................................... 21

4.1. PID with part list ............................................................................................................ 21

4.2. Photos of the Setup ......................................................................................................... 23

4.3. Webcam Photos .............................................................................................................. 27

5. Experimental Results .......................................................................................................... 29

5.1. Additional Process Data ................................................................................................. 29

5.2. Reactor Fouling .............................................................................................................. 32

5.3. NMRs ............................................................................................................................. 33

6. References ............................................................................................................................. 47

S3

1. General

2,6-Dichlorotoluene was purchased from TCI (Catalog #D0422, batch #HNDSJOI, stated purity

>99.0%), sodium bromate (Catalog #8.45066.1000, batch #S7485966 933, stated purity ≥99.0%)

and HBr (Catalog #1.00304.2500, batch #B1692904 920, stated concentration 47%) from Merck,

sodium thiosulfate pentahydrate from Roth (Catalog #T109.3, batch #030290641, stated purity

≥99%). Sodium bromate and sodium thiosulfate solutions were prepared in 2 and 5 L batches, by

dissolving 332 g NaBrO3 or 655 g Na2S2O3·5H2O per liter of solution. To facilitate the dissolution

process, the flasks were put in a water bath (~40 °C). HBr and DCT were used without further

treatment.

1H NMR spectra were recorded using a low field benchtop NMR (Magritek, Spinsolve Ultra,

43 MHz).

HPLC analysis was carried out on a C18 reversed-phase analytical column (150 × 4.6 mm,

particle size 5 µm) at 37 °C using mobile phases: A (water/MeCN 90:10 (v/v) + 0.1% TFA) and

B (MeCN + 0.1% TFA) at a flow rate of 1.5 mL min–1. The following gradient was applied: linear

increase from 30% to 100% B over 13 minutes.

GC-FID analysis was performed on a Shimadzu GC FID 2030 with a flame ionization detector,

using a RTX -5MS column (30 m × 0.25 mm ID × 0.25 μm) and helium as carrier gas (40 cm sec-

1 linear velocity). The injector temperature was set at 280 °C. Within the GC oven, after 1 min at

50 °C, the temperature was increased by 25 °C min-1 to 300 °C and kept constant at 300 °C for

4 min. The detector gases used for flame ionization were hydrogen and synthetic air (5.0 quality).

ICP-MS analysis was performed on an Agilent 7700x instrument. 200 µL of the sample were

digested using 5 mL HNO3 and heating in a MLS UltraClave (ramp 30 min to 250 °C, hold 30 min

at 250 °C) and subsequently diluted for the measurement.

S4

2. Starting Material Quality

2.1. Analysis

The following two samples of the substrate 2,6-dichlorotoluene (CAS Number 118-69-4) are

compared:

Supplier Batch # Observed

conversiona

Sample 1 TCI HNDSJOI > 90%

Sample 2 AKScientific LC27600 10-20%

aLab reactor: tR = 15 sec, 1.1 equiv. Br2, 55 °C.

Visual comparison:

Figure S1. Visual comparison of the samples 1 (left) and 2 (right). The substrate on the left was colorless,

while the one on the right was a pale blue color.

ICP-MS: ICP-MS measurements showed no difference in metal content in either of the two

samples. In both cases, the metal content was lower than the detection limit for all screened metals.

S5

HPLC: No impurities could be detected on the HPLC, in sample 1 (Figure S2a). Two peaks

accounting for 1.1 area% (5.12 min) and 0.3 area% (6.46 min) at 254 nm were found in sample 2

(Figure S2b).

Figure S2. HPLC analysis, a) sample 1; b) sample 2.

S6

GC-FID: The impurity at 5.6 minutes was found in both samples, accounting for 0.05 area%.

However, in sample 2 further impurities were found, the most significant one being the shoulder

at 5.4 minutes (~0.15 area%).

Figure S3. GC-FID analysis, a) sample 1; b) sample 2.

S7

2.2. Use test

To rule out issues with the starting material quality, a use test was performed in the Corning®

Advanced-Flow™ Lab Photo Reactor. Using the previous reaction setup,S1 the results listed in

Table S1 were obtained. These are in agreement with the previously reported data.S1

Figure S4. Schematic representation of the set up of the lab scale reactor. Flowrates correspond to Table

S1 entry 1.

Table S1. Results of the use test of the material batches for large scale experiments

Entry Temperature [°C] Residence time [s] Equivalents Br2 Assay Yield

[%]a

1 60 18 1.1 93

2 60 18 1.2 97

3 60 20 1.1 94

4 60 20 1.1 97

5 60 15 1.2 64

aDetermined by 1H benchtop NMR as the ratio of starting material 1 vs product 2 benzylic signals.

S8

3. Risk Assessment

3.1. Calorimetric measurements

Calorimetric measurements were performed using a THT µRC microcalorimeter in isothermal

titration mode. Both the measurement and reference vials in the calorimeter were charged with

1 mL of solution A and kept at a constant temperature T. A disposable 1 mL syringe (used due to

compatibility issues with other syringe materials) was filled with solution B. After the temperature

stabilized a portion of 41.5 µL of solution B was injected and the change in heating/cooling power

was recorded as a function of time. A series of 5 separate injections was used for the reaction heat

determination. For the use of the disposable syringe, a calibration factor had to be determined, to

ensure accuracy.

S9

Calibration

41.5 µL portions of a 0.15 M HNO3 solution (6.3 µmol per injection) were injected into a 0.5 M

NaOH solution at 25 °C. Integration of the peaks gives an average compensation energy of 391

mJ, corresponding to an exotherm of −61.9 kJ mol-1. Using a literature value for the heat of

neutralization (−57.7 kJ mol-1), a calibration factor of 0.93 was determined.

Table S2. Calibration data for the disposable syringe setup in the calorimeter.

Injection No 1 2 3 4 5 Average

Energy [mJ] 423 405 386 376 366 391

Figure S5. Calibration of the calorimeter using the disposable syringe.

S10

Br2 formation (Manuscript Table 1 entry 1)

41.5 µL portions of a 0.1 M NaBrO3 solution (4.15 µmol per injection) were injected into a

0.5 M HBr solution at 25 °C. Integration of the peaks gave an average energy of 870 mJ,

corresponding to an exotherm of −69.9 kJ mol-1 of Br2. Correction with the calibration factor of

0.93 results in an exotherm of −65.1 kJ mol-1 of Br2.

Table S3. Calorimetry: Bromine formation.


Energy [mJ] 820 882 883 881 879 869

Figure S6. Calorimetry: Bromine formation.

S11

Bromine quench with sodium thiosulfate (Manuscript Table 1 entry 3)

41.5 µL portions of a 0.09 M Br2 solution (3.62 µmol per injection) were injected into a 0.5 M

Na2S2O3 solution at 25 °C. Integration of the peaks gives an average energy of 447 mJ,

corresponding to an exotherm of −123.4 kJ mol-1 of Br2. Correction with the calibration factor of

0.93 results in an exotherm of −115.0 kJ mol-1 of Br2.

Table S4. Calorimetry: Bromine quench.


Energy [mJ] 442 456 458 442 437 447

Figure S7. Calorimetry: Bromine quench.

S12

Sodium thiosulfate and HBr (Manuscript Table 1 entry 4)

41.5 µL portions of a 2.64 M Na2S2O3 solution (109 µmol per injection) were injected into a

47% HBr solution at 25 °C. The observed peaks decrease with each injection, so the measurement

was stopped after the fourth. This is proposed to be caused by the formation of large amounts of

sulfur in the test vial, due to the concentrated solutions used. A pressure sensor attached to the vial

showed no increase in pressure during the measurements (implying no gas formation). To estimate

the maximum possible exotherm from this reaction, only the first (most major) peak was

integrated. The compensation energy of 2344 mJ corresponds to an exotherm of −21.4 kJ mol-1 of

Na2S2O3. Correction with the calibration factor of 0.93 results in an exotherm of −20.0 kJ mol-1 of

Na2S2O3.

Table S5. Calorimetry: Thiosulfate and HBr.


Energy [mJ] 2344 n.d. n.d. n.d. n.d. n.d.

Figure S8. Calorimetry: Thiosulfate and HBr.

S13

Sodium bromate and sodium thiosulfate (Manuscript Table 1 entry 5)

41.5 µL portions of a 2.2 M NaBrO3 solution (91 µmol per injection) were injected into a 2.64 M

Na2S2O3 solution at 25 °C. Since the peaks decreased significantly over the course of five

injections, only the first peak was integrated for the estimation of the maximum exotherm. The

obtained energy of 32.1 mJ, corresponds to an exotherm of −0.4 kJ mol-1 of NaBrO3.

Table S6. Calorimetry: Sodium thiosulfate and sodium bromate.


Energy [mJ] 32.1 n.d. n.d. n.d. n.d. n.d.

Figure S9. Calorimetry: Thiosulfate and bromate.

S14

2,6-Dichlorotoluene and sodium bromate (Manuscript Table 1 entry 6)

41.5 µL portions of neat 2,6-dichlorotoluene 1 (323 µmol per injection) were injected into a

2.2 M NaBrO3 solution at 25 °C. No significant exotherm was observed.

Figure S10. Calorimetry: 2,6-Dichlorotoluene 1 and NaBrO3.

S15

3.2. Reaction Heat Calculations

The reaction enthalpies ∆𝐻𝑟0 were calculated as the difference of the standard formation

enthalpies ∆𝐻𝑓0 of the products and the reactants. Standard formation enthalpies were taken from

the Handbook of Chemistry and Physics.S2

Bromine formation (Manuscript Table 1 entry 1)

Reaction BrO3−

(aq) + 6 HBr(aq) 3 Br2(aq) + 3 H2O(l) + Br−(aq)

∆𝐻𝑓0 [kCal mol−1] −16.03 + 6×(−29.05) 3×(−0.62) + 3×(−68.315) −29.05

∆𝐻𝑟0 = −235.86 – (−190.33) = −45.5 kCal per reaction

Therefore, the reaction enthalpy per mole of Br2 is −15.2 kCal mol−1 (−63.5 kJ mol−1).

S16

Bromine quench (Table 1 entry 3)

Reaction 5 H2O(l) + 4 Br2(aq) + S2O32−

(aq) 8 Br−(aq) + 2 SO4

2−(aq) + 10 H+

(aq)

∆𝐻𝑓0 [kCal mol−1] 5×(−68.315) + 4×(−0.62) −155.9 8×(−29.05) + 2×(−217.32) + 0

∆𝐻𝑟0 = −667.0 – (−500.0) = −167.1 kCal per reaction

Therefore, the reaction enthalpy per mole of Br2 is −41.8 kCal mol−1 (−174.9 kJ mol−1).

Thiosulfate and HBr (Table 1 entry 4)

Reaction 2 HBr(aq) + S2O32−

(aq) 2 Br−(aq) + SO2 (aq) + S(s) + H2O(l)

∆𝐻𝑓0 [kCal mol−1] 2×(−29.05) −155.9 2×(−29.05) −80 + 0 −68.315

∆𝐻𝑟0 = −206.4 – (−214.0) = 7.6 kCal per reaction

Therefore, the reaction enthalpy is 31.8 kJ per mole of thiosulfate.

Radical substitution (Manuscript Table 1 entry 2)

The heat of the radical substitution was estimated using the energies of the bonds that are broken

and formed during this reaction.

Reaction

Bond Energy(S3, S4)

[kCal mol−1] 90 46 63 88

∆𝐻𝑟0 = (90 + 46) – (63 + 88) = –15 kCal per reaction

Therefore, the reaction enthalpy estimated to be 63 kJ mol-1.

S17

3.3. Detailed Process Risk Assessment

Estimated maximum volume of Br2 in the Photoreactor (first FM) at any point:

Under normal operation: reactor volume = 50 mL, ratio input volumes to Br2 volume: 321 mL per 2389 mL

321 𝑥 50

2389= 𝟔. 𝟕 𝐦𝐋

In the event of failure: should the substrate 1 pump (HNP, DCT) cease pumping, the Br2 volume in the first FM would increase to 10 mL

Possible risk/failure Possible Observation Consequence Action Preventative measure(s)

Pump 1 (Fuji, HBr)

failure No Br2 formation

Mass flow meter

shows low measured

value

Pressure decrease

No reaction occurs

Buildup of NaBrO3 in

output

NaBrO3 and Na2S2O3

mixed in collection flask

(minor exotherm expected)

Switch NaBrO3 and Na2S2O3 feeds

to water immediately. Dilute

collection/waste if necessary

Then apply shutdown procedure

Thorough testing and monitoring of

pumps

Add ice to the plastic bund around

the collection/waste flask to cool

mixture

Pump 2 (HNP, DCT)

failure Mass flow meter

shows low measured

value

Pressure decrease

No Br2 consumption

Output is not biphasic

Substantial exotherm in

FM 2 and collection vessel

All Na2S2O3 is consumed –

Br2 accumulates in

collection vessel

Switch HBr pump to water.



pumps

Waste vessel temperature will be

monitored



mixture.

Pump 3 (HNP,

NaBrO3) failure No Br2 formation

Mass flow meter

shows low measured

value

Pressure decrease

No reaction occurs.

Na2S2O3 will be acidified

(minor exotherm expected)

Switch HBr and Na2S2O3 feeds to

water immediately

Then apply shutdown procedure.


pumps



mixture

S18

Pump 4 (HNP,

Na2S2O3) failure Mass flow meter

shows low measured

value

Pressure decrease

Br2 is not quenched

Br2 remains in output

solution (accumulates in

organic phase) – can be a

significant hazard.

Switch NaBrO3 and HBr feed to

water immediately

Apply shutdown procedure


pumps



mixture

Add Na2S2O3 solution to waste vessel

and mix phases well between

experimental runs, using an overhead

stirrer

LED failure Light visibly not on

Reduced temperature

difference between

thermostat bath and

thermal fluid channel

Br2 is not quenched

Br2 remains in output

solution (accumulates in

organic phase) – can be a

significant hazard.


water immediately




mixture

Add Na2S2O3 solution to waste vessel

and mix phases well between

experimental runs, using an overhead

stirrer

Use of intense visible

light (405 nm)

Normal operation Potential eye damage In the event of exposure, apply

shutdown procedure

Keep tinted reactor case shut at all

times when operating LEDs

Everyone in the room during

operation must wear tinted goggles

Access to room is restricted to

authorized users and “do not enter”

sign is displayed on door

LED thermostat or

booster pump failure Increase in LED

temperature (heat

exchange channel)

LEDs will overheat and

break, leading to no Br2

consumption in the reactor.

Turn off LEDs as soon as possible

to prevent damage


water



LED thermostat

S19

Reaction thermostat

failure/incapable of

dealing with exotherm

Increase in reaction

channel temperature

Exotherm, potential

vaporization of Br2

Apply shutdown procedure Thorough testing and monitoring of

thermostat and booster pump

Corrosion/failure of

reaction channel

tube/connector

Leakage of

acidic/corrosive

fluid

Potential injury and

damage of equipment

Apply shutdown procedure Leak/pressure test reaction setup at

10 bar prior to use

Keep reactor case closed during

operation and fumehood sashes

closed wherever possible

Buildup of gas in

collection/waste

containers – reaction

of Na2S2O3 with acid

over time may form

SO2 gas

Waste vessels may

begin to bulge after

some time

Potential explosion of

container(s), spreading

corrosive mixture

Keep collection vessels cooled

with ice during operation

Clean spill as soon as possible

(spill kit in the lab)

Ensure that containers are not sealed

fully and are left to stand for at least

a week prior to closing for further

disposal.

Mix phases well between experiment

runs, using an overhead stirrer.

Blockage of process

stream tubing/FM Dramatic increase in

pressure

Potential for fittings to

burst, reactor to shatter

Turn off pumps, then LEDs.

Allow pressure to return to

ambient, then attempt to unblock

tubing

Pressure relief valves are present on

each pump, to prevent overpressure

Apply thermal lagging to output

tubing to stay above melting point of

product

FM breaks/shatters Noise/visible signs

Sudden drop of

pressure

Leakage of reaction

mixture.

Potential injury and

damage of equipment.

Apply shutdown procedure Leak/pressure test all parts at 10 bar

prior to use

Backflow into feed

vessels due to pump

failure

Mass flow meter

shows low or

negative

measurement

Pressure decrease

Potential to mix large

volumes of incompatible

materials (HBr and

NaBrO3 most dangerous

combination)

Switch all feeds to wash solvent

(backflow will then be redirected to

water/isopropanol feeds).


Thoroughly test pumps prior to use

Monitor pressure and flow rates

closely

S20

Power cut Loss of power

(including fumehood

extraction)

Pumps, thermostats and

LEDs turn off, resulting in

Br2 buildup in reactor

Potential exotherm and Br2

vaporization

Open windows

Unplug LEDs and pumps (to

prevent sudden restart when power

is restored)

Then evacuate lab until power is

restored

No additional measures possible

Internal breakage of

glass (reaction channel

into heat exchange

channel)

Noise/visible signs

Sudden drop of

pressure

Anticipated smell of

heated

substrate/product

mixture

All relevant streams (e.g.

Br2 and product) will leak

into the heat exchange

channel (heat exchange

medium is water)

Large exotherm, corrosion

of thermostat and loss of

containment

Switch pumps to water and switch

off thermostat

Open lab windows

Apply shutdown procedure (if

sufficient time)

Evacuate lab until the exotherm has

settled

Pressure testing of both process and

heat exchange channel

Careful monitoring of pressure

S21

4. Setup

4.1. PID with part list

Figure S11. Piping and instrumentation diagram (PID) showing the process streams in black, heat exchange

channels for the reaction and quench FMs in red, and the LED cooling cycle in blue. PI = pressure sensor;

FI = flow meter; TI = temperature sensor.

The reactions were conducted in a commercial continuous-flow reactor: Corning® Advanced-

Flow™ G3 Photo Reactor. The reactor used in this work consisted of two fluidic modules (310 ×

250 mm, 1.5 mm channel depth, 50 mL internal volume per FM), encased within a high capacity

heat exchange channel. An LED panel, equipped with an array of 405 nm LEDs (192 × 2.17 W

LEDs per panel, 384 LEDs in total), was mounted on both sides of the first fluidic module. A

Lauda Proline RP 890 thermostat (1.1 kW cooling power, ethanol as heat exchange fluid) set to 10

°C was used to cool the LEDs. A temperature sensor was place in the heat exchange channel at the

outlet of the LED panels. For controlling the temperature in the fluidic modules, a Lauda Proline

S22

RP 4090 CW thermostat (4.0 kW cooling power, water as heat exchange fluid) was used in

combination with a Gather gear pump (2M-J/24/) as booster pump to increase the flowrate to 6 L

min-1. A pressure sensor and three temperature sensors were added to the heat exchange channels

as indicated in Figure S11 and Figure S15.

Pumps: sodium thiosulfate: HNP mzr-7208-hs-f S +SW, 2,6-dichlorotoluene: HNP mzr-7255-

hs-f S +W sodium bromate: HNP mzr-7255-cs-f S, HBr: Fuji Super Metering Pump HYM P0-

B2-NS-PL-08

Inline filters: sodium bromate and 2,6-dichlorotoluene: HNP F-MI3-T, sodium thiosulfate:

Swagelok filter 40 micron.

Pressure relief valves HBr: Fuji Safety Valve AZ02505, others: Swagelok proportional relief

valves. All relief valves were set to 10 bar.

S23

4.2. Photos of the Setup

Figure S12. Left fumehood containing the closed reactor housing with the LEDs turned on. Outside the

fumehood are the two thermostats: the Lauda Proline RP 4090 (connected via the booster pump, located

under the reactor) and the Lauda Proline RP 890.

S24

Figure S13. Left fumehood, showing the opened reactor housing.

Figure S14. Inside of the reactor housing.

S25

Figure S15. Inside of the reactor a) left side of reactor FMs, b) right side of FMs. 1: pressure sensor in the

heat exchange channel before the fluidic modules. 2: Temperature sensor measuring the ambient T inside

the reactor box. 3: Temperature sensor measuring the cooling liquid for the LEDs, after passing through the

two LED arrays. 4: Temperature sensor measuring the heat exchange channel before passing through the

fluidic modules. 5: Temperature sensor measuring the heat exchange channel after passing through the

second (quench) FM. 6: Temperature sensor measuring the heat exchange channel after passing through

the first FM. 7: Webcam allowing visual monitoring of the reaction mixture inside the quench FM.

S26

Figure S16. Right fumehood containing pumps and their periphery, containers for the reaction and washing

liquids and for collection as well as the hardware necessary for controlling the pumps, as well as pressure

and temperature sensors. Photo was taken prior to installation of mass flow meters.

S27

4.3. Webcam Photos

Table S7. Details on the conditions of the snapshots shown in Figure S17.

Photograph in

Figure S17

Entry in

Manuscript Table 2

Conversion [%] Flow rate NaS2O3

[mL min−1]

a 1 10 85

b 2 31 85

c 5 81 85

d 3 76 70

e 11 77 70

f 4 77 62

g 13 84 50

h 9 88 58

S28

Figure S17: Images are snapshots from the video captured by the webcam, showing the quench FM. The

purple light on the right originates from the reactor LEDs. Details are given in Table S7.

S29

5. Experimental Results

5.1. Additional Process Data

Figure S18. Stability test run over 14 minutes. After about 8 minutes the flowrates were adjusted to match

the best conditions found previously (22 seconds and 1.1 equivalents Br2). The dotted lines mark the average

conversion over the two sets of conditions.

S30

Figure S19. Observed pressure drop values in the reactor. Observed pressures after the DCT pump (p1),

the bromate pump (p2) and the thiosulfate pump (p4), plotted against the residence time in the reaction FM.

S31

Figure S20. Trend of the thermal fluid temperatures after passing through the LED panels (blue dots,

equilibrating around 19 °C) and the air temperature inside the reactor housing (orange dots, equilibrating

around 30-33 °C), over the course of three optimization runs. Since these temperatures are also influenced

by the reaction temperature, the red line indicates the corresponding temperature set point in the reactor

thermostat. The timeframes of these runs are ~12 min (1a-1d), ~32 min (2a-2h) and ~19 min (3a-3e).

S32

5.2. Reactor Fouling

Figure S21. Quench FM, fouling by sulfur. The fouling was only observed during runs with low

conversion, since the sulfur is formed from thiosulfate under acidic conditions (excess HBr).

S33

5.3. NMRs

Figure S22. 1H NMR corresponding to Manuscript Table 2 entry 1.

S34

Figure S23. 1H NMR corresponding to Manuscript Table 2 entry 1 (duplicate).


S35

Figure S25. 1H NMR corresponding to Manuscript Table 2 entry 2 (duplicate).


S36



S37



S38



S39



S40



S41

Figure S37. 1H NMR corresponding to Figure S18 entry “2 minutes”.


S42



S43



S44



S45



S46


S47

6. References

S1 Steiner, A.; Williams, J. D.; De Frutos, O.; Rincón, J. A.; Mateos, C.; Kappe, C. O.

Continuous photochemical benzylic bromination using in situ generated Br2: process

intensification towards optimal PMI and throughput. Green Chem. 2020, 22, 448–454.

S2 Weast, R. C.; Astle, M. J.; Beyer W. H. Handbook of Chemistry and Physics; CRC Press:

Boca Raton 1984.

S3 Blanksby, S. J.; Ellison, G. B. Bond Dissociation Energies of Organic Molecules. Acc.

Chem. Res. 2003, 36, 255–263.

S4 Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies, CRC Press: Boca

Raton 2007.

multikilogram per hour continuous photochemical benzylic

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