Supporting Information to Accompany:

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1 SI-1 Supporting Information to Accompany: Mixer based on Magnetically Driven Agitation in a Tube (MDAT) Affords ast og-resistant Mixing to acilitate low Chemistry. Sarah J. Dolman, Jason L. Nyrop and Jeffrey T. Kuethe Department of Process Research, Merck Research Laboratories and Chemical Process Development & Commercialization, Merck Manufacturing Division; Merck & Co., Inc., PO Box 2000, Rahway, NJ (USA) Table of Contents General...SI-1 ourth Bourne Competition Experiments SI-2 Continuous / low Preparation of Benzaldehyde SI-5 Batch Preparation of poly-halobenzaldehydes....s1-6 Continuous / low Preparation of poly-halobenzaldehydes si-8 1 H and 13 C Spectra SI-10 General Reactions were carried out under an atmosphere of dry nitrogen. Reagents and solvents were used as received from commercial sources. 1 H NMR spectra were recorded on a 400 MHz spectrometer. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CD 3 : δ 7.27). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz) and integration. 13 C NMR spectra were recorded on a 100 MHz spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent as the internal reference (CD 3 : δ 77.0). 19 NMR spectra were recorded on 376 MHz spectrometer with complete proton

2 SI-2 decoupling. Chemical shifts are reported in ppm with α,α,α-trifluorotoluene added as an internal reference (δ ). Experimental Section. Commercial n-butyllithium (2.5M in hexane) was used as received; solutions of ipr 2 NH, 1 and DM were prepared in volumetric flasks from inhibitor-free anhydrous TH (< 200ppm water by Karl-ischer titration). ourth Bourne Competition Experiment Setup: A syringe containing the hydrochloric acid mixture was connected to on of the following mixing with 1/16" OD, 0.02" ID PA tubing: (1) a stainless steel T-mixer with a 0.02" through hole distributed by UpChurch Scientific, (2) a multilaminar mixer possessing 50 µm channels, fabricated by the Institut für Mikrotechnik Mainz, GmbH, or (3) the MDAT mixer, created by joining a stainless steel T-mixer with a 0.02" through hole to a 30 mm 1/4" OD, 3.2 mm ID HPLC column, distributed by Restek (Cat# 25124) filled with two stir-bars. The mixed stream was transferred to collection with 1/8" OD, 0.60" ID PA tubing with a tubing internal volume of 2 ml. ourth Bourne Experiments: To a 100 ml volumetric flask, 0.45 eq of Na, 1.05 eq of 1N NaOH and 1.0 eq of 2,2-Dimethoxypropane was added to varying 2,2- Dimethoxypropane molarities. The flask was filled to the 100 ml mark with 25/75 w/w 99.9% EtOH and water. To a separate 100 ml volumetric flask, 0.45 eq of Na and 1.0 eq of 1N H was added and diluted to the 100 ml mark with 25/75 w/w 99.9% EtOH and water. Analysis of DMP decomposition was performed via GC.

3 SI-3 GC Method (Restek Rtx -1701, 30m, 0.32mmID, 1 um). Hold at 40 C for 1.5 minutes, ramp to 150 C at 50 C/min, hold at 150 C for 1 minute. Retention times as noted below: Compound R t (min) Methanol 0.89 Ethanol ,2-Dimethoxypropane 2.00 DM P Conversion [%] MDAT DMP = M, τ rxn = 333 ms DMP = M, τ rxn = 303 ms DMP = M, τ rxn = 278 ms DMP = M, τ rxn = 238 ms DMP = M, τ rxn = 167 ms Multilaminar Mixer T-mixer low Rate [ml/min] low Rate [ml/min] low Rate [ml/min]

4 SI-4 The analysis using the 4 th Bourne reaction relies on the technique of determining the characteristic mixing time of the equipment by using the known reaction rate and time of a reaction, in this case the hydrolysis of DMP at acidic conditions. Since the experiment is carried out with an excess of base, no DMP hydrolysis should be observed provided that the H is rapidly mixed and neutralized by NaOH. At the other extreme, a small drop of the DMP solution engulfed by a much larger volume of the H solution will quickly be exposed to acidic conditions as the NaOH reacts. Soon after, the DMP should be completely hydrolyzed at these acidic conditions. So, the effectiveness and time required to mix solutions can be probed by examining the extent of DMP hydrolysis. More dilute reactions will have a longer half-life, and so require less rapid mixing in order to neutralize H prior significant conversion of DMP by hydrolysis. More concentrated reactions naturally require more rapid mixing owing to a shorter reaction half-life.

5 SI-5 Thus, we see that for a flow of 7 ml/min in the Tee mixer, there is an increasing level of hydrolysis observed at each concentration change as the DMP half-life decreases from 333 ms to 167 ms. Generally, this observation holds for the full range of flow rate in all 3 mixing devices. We define, after Johnson et al., that 4% hydrolysis of DMP is the point at which the time scale of mixing is equal to the reaction half-life. There are two sources of energy available to aid in mixing the two solutions for reaction. The first is the mechanical energy from the magnetic stir bars, and the second is the inertial energy from the flowing liquids. As the flow rate is increased, additional energy is provided for mixing. Thus, better mixing takes place even while a shorter residence time in the reactor is obtained. The converse is not immediately obvious but is very important; slower flow rates in a mixing device will allow longer residence time, but probably do so at the cost of poorer mixing. or a very fast reaction, this has very negative consequences because obviously complete reaction requires thorough mixing of the two streams. Benzaldehyde Preparation Reactor Setup: Solutions of bromobenzene & butyl lithium were pumped via syringe pump into one of the following reactors to create reactor 1: (a) a stainless steel T-mixer with a 0.02" through hole distributed by UpChurch Scientific connected to 300 ul of 1/16" OD, 0.04" ID PA tubing, or (b) a multilaminar mixer possessing 50 µm channels, fabricated by the Institut für Mikrotechnik Mainz, GmbH connected to 300 ul of 1/16" OD, 0.04" ID PA tubing, or (c) the MDAT mixer, created by joining a stainless steel T-mixer with a 0.02" through hole to a 30 mm 1/4"

6 SI-6 OD, 3.2 mm ID HPLC column, distributed by Restek (Cat# 25124) filled with two stirbars with a total void volume of 300 ul. The outlet of reactor one and the DM solution (pumped by syring pump) were connected to reactor two, which had the same reactor options as reactor one. The outlet of reactor two was connected to a collection flask with 1/16" OD, 0.02" ID PA tubing. All reactors and tubing were submerged in CO 2 /acetone bath to hold the internal temperature below - 70 C. Continuous preparation of benzaldehyde: A 1M solution of omobenzene in TH, 2.5M solution of BuLi in hexanes and a 2.0M solution of DM in TH were pumped at a ratio of 1.0:0.44:1.0 ml/min (1 eq to 1.1 eq to 2 eq) to achieve varying residence times in reactor 1 and 2. HPLC Method (Ascentis Express C18, 10 cm x 4.6, 2.7 µm; 1.8 ml/min, 210 nm, 40 C). Mobile Phase A: 0.1% H 3 PO 4 in water; Phase B: MeCN. Run gradient, from 10% B to 95% B over 6 min. Retention times as noted below: Compound R t (min) omobenzene 4.78 Benzaldehyde 2.06 Organometallic batch reactions: Batch preparation of 5-bromo-3-chloro-2-fluorobenzaldehyde (2a) & 6-bromo-2- chloro-3-fluorobenzaldehyde (3a). To a solution of 1.36 ml (9.55 ml) of diisopropyl amine in 7 ml of TH cooled to -15 C was added dropwise 3.98 ml of a 2.5 M solution of butyllithium in hexanes (9.55 mmol) keeping the internal temperature < -10 C. The solution of LDA was stirred at this temperature for 20 min and then cooled to -75 C and

7 SI g (9.55 mmol) of 4-bromo-2-chloro-1-fluorobenzene (1a) was added dropwise. The reaction was allowed to proceed for 45 min and was quenched with 1.05 ml (14.32 mmol) of DM and allowed to warm to -20 C. The reaction mixture was diluted with sat. ammonium chloride and extracted with 20 ml of MTBE. The organic layer was washed with brine and dried over MgSO 4. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography eluting with hexane. The first product eluted from the column (1.16 g, 51%) was identified as 5-bromo-3-chloro-2- fluorobenzaldehyde (2a) which was isolated as a colorless solid: 1 H NMR (CD 3, 400 MHz) δ 7.82 (m, 1H), 7.89 (m, 1H), (s, 1H); 13 C NMR (CD 3, 100 MHz) δ (d, J = 4 Hz), (d, J = 18 Hz), (d, J = 10 Hz), 129.7, 138.6, (d, J = 261 Hz), (d, J = 6 Hz); 19 NMR (CD 3, 376 MHz) δ Anal. Calcd. or C 7 H 3 O: C, 35.41; H, ound: C, 35.39; H, The second product to elute from the column (1.11 g, 49%) was identified as 6-bromo-2-chloro-3-fluorobenzaldehyde (3a) which was obtained as a colorless solid: 1 H NMR (CD 3, 400 MHz) δ 7.23 (dd, 1H, J = 8.8, 8.0 Hz), 7.59 (dd, 1H, J = 8.8, 4.5 Hz), (s, 1H); 13 C NMR (CD 3, 100 MHz) δ (d, J = 4 Hz), (d, J = 23 Hz), (d, J = 20 Hz), 132.8, (d, J = 7 Hz), (d, J = 252 Hz), (d, J = 3 Hz); 19 NMR (CD 3, 376 MHz) δ Anal. Calcd. or C 7 H 3 O: C, 35.41; H, ound: C, 35.63; H, HPLC Method (Zorbax Eclipse C18 Plus, 50 x 4.6 µm, 1.8 µm; 1.5 ml/min, 210 nm, 25 C). Mobile Phase A: 0.1% H 3 PO 4 in water; Phase B: MeCN. Run gradient, from 10% B to 95% B over 5min, hold 5min. Retention times as noted below: Compound R t (min) 4-bromo-2-chloro-1-fluorobenzene (1a) bromo-3-chloro-2-fluorobenzaldehyde (2a) 3.83

8 SI-8 6-bromo-2-chloro-3-fluorobenzaldehyde (3a) 3.49 Batch preparation of 3-bromo-5-chloro-2-fluorobenzaldehyde (2b) & 2-bromo-6- chloro-3-fluorobenzaldehyde (3b). To a solution of 1.36 ml (9.55 ml) of diisopropyl amine in 7 ml of TH cooled to -15 C was added dropwise 3.98 ml of a 2.5 M solution of butyllithium in hexanes (9.55 mmol) keeping the internal temperature < -10 C. The solution of LDA was stirred at this temperature for 20 min and then cooled to -75 C and 2.00 g (9.55 mmol) of 2-bromo-4-chloro-1-fluorobenzene (1b) was added dropwise. The reaction was allowed to proceed for 7 min and was quenched with 1.05 ml (14.32 mmol) of DM and allowed to warm to -20 C. The reaction mixture was diluted with sat. ammonium chloride and extracted with 20 ml of MTBE. The organic layer was washed with brine and dried over MgSO 4. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography eluting with hexane. The first product eluted from the column (1.16 g, 51%) was identified as 3-bromo-5-chloro-2- fluorobenzaldehyde (2b) which was isolated as a colorless solid: 1 H NMR (CD 3, 400 MHz) δ (m, 2H), (s, 1H); 13 C NMR (CD 3, 100 MHz) δ (d, J = 22 Hz), (d, J = 11 Hz), (d, J = 2 Hz), (d, J = 4 Hz), 139.2, (d, J = 259 Hz), ((d, J = 6 Hz); 19 NMR (CD 3, 376 MHz) δ Anal. Calcd. or C 7 H 3 O: C, 35.41; H, The second compound to elute from the column was identified as 2-bromo-6-chloro-3-fluorobenzaldehyde (3b) which was obtained as a colorless solid: 1 H NMR (CD 3, 400 MHz) δ 7.22 (dd, 1H, J = 8.8, 8.0 Hz), 7.62 (dd, 1H, J = 8.8, 4.5 Hz), (s, 1H); 13 C NMR (CD 3, 100 MHz) δ 119.2, (d, J = 23 Hz), (d, J = 20 Hz), 132.6, 133.2, (d, J = 250 Hz), 189.3; 19 NMR

9 SI-9 (CD 3, 376 MHz) δ Anal. Calcd. or C 7 H 3 O: C, 35.41; H, ound: C, 35.63; H, HPLC Method (Zorbax Eclipse C18 Plus, 50 x 4.6 µm, 1.8 µm; 1.5 ml/min, 210 nm, 25 C). Mobile Phase A: 0.1% H 3 PO 4 in water; Phase B: MeCN. Run gradient, from 10% B to 95% B over 5min, hold 5min. Retention times as noted below: Compound R t (min) 2-bromo-4-chloro-1-fluorobenzene (1b) bromo-5-chloro-2-fluorobenzaldehyde (2b) bromo-6-chloro-3-fluorobenzaldehyde (3b) 3.50 low Reactor Setup B: 1/16" OD, 0.04" ID 316 stainless-steel (SS) tubing was used; all MDATs and SS tubing reactors were submerged in CO 2 /acetone bath to hold the internal temperature below 78 C. Solutions A & B were flowed into an MDAT connected to 1000µm ID SS tubing (R 1, variable length & volume) to form reactor 1 with residence time τ 1. The end of this tubing was connected to a 2 nd MDAT through which solution C was introduced, and the resultant mixture aged via passage through SS tubing (R 2, variable length & volume), for τ 2. The end of this tubing was connected to a 3 rd MDAT through which solution D was introduced, and the resultant mixture aged via passage through SS tubing (R 3, variable length & volume), for τ 3. The output solution was collected into vials pre-charged with 12% water-acoh / MTBE mixture in order to immediately halt the reaction. Commercial n-butyllithium (2.5M in hexane) was used as received; solutions of ipr 2 NH, 1 and DM were prepared in volumetric flasks from inhibitor-free anhydrous TH (< 200ppm water by Karl-ischer titration).

10 SI-10 Organometallic flow reaction: Stock solutions were pumped through the reactor described above (R 1 = R 2 = R 3 = 0.5mL) at optimized flow-rates (as detailed in Table 2) and collected onto a flask precharged with 12% water-acoh / MTBE mixture. After collection was complete, the biphasic mixture was separated and the organic layer washed twice with water, followed by saturated NaHCO 3. The solution was passed through solka-floc; concentrated in vacuo to afford a slowly crystallizing oil. Analysis was performed by HPLC analysis versus standards prepared from materials isolated by the batch reactions. 2a CHO

11 SI-11 2a CHO 2a CHO

12 SI-12 OHC 3a OHC 3a

13 SI-13 OHC 3a 2b CHO

14 SI-14 2b CHO 2b CHO

15 SI-15 OHC 3b OHC 3b

16 SI-16 OHC 3b