10.1071/CH12405_AC CSIRO 2013 Australian Journal of Chemistry 2013, 66(2), 213-217

Supplementary Material

Monoliths for Flow Chemistry: Produced via Visible Light-Initiated

Radical Generation

Farhan R. Bou-Hamdan,a Kathleen Krüger, a Klaus Tauer,a D. Tyler McQuadea,c and

Peter H. Seebergera,b

aMax Planck Institute of Colloids and Interfaces Am Mühlenberg 1, 14476 Potsdam (Germany)

bInstitute of Chemistry and Biochemistry, Freie Universität Berlin Arnimallee 22, 14195

Berlin (Germany)

cDepartment of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306 USA.

1.General Information (S2)

2.Procedures and Spectroscopic Data (S4)

3.SEM images and pictures of monoliths (S8)

4.FT-IR Spectra (S17)

5.1H and 13C-NMR Data of All Compounds (S20)

S2

1. General Information

All chemicals were reagent grade and used as supplied except where noted. DCM, 2-Propanol and THF

were HPLC grade. N-methyl-4-aminopyridine was purchased from Alfa Aesar. Irgacure® 819 was

obtained as a gift from BASF, Basel-Switzerland. Hunig’s base, 4,4’-azobis(4-cyanovaleric acid) and

cysteamine hydrochloride was purchased from Sigma Aldrich. Styrene was obtained from Acros

Chemicals and distilled under reduced pressure prior to use. Divinylbenzene was purchased from Alfa

Aesar and passed through a pad of grade III neutral alumina prior to use. FEP tubing (fluorinated ethylene

polymer) was purchased from IDEX Health & Science 1520, natural color, outside diameter (OD) 1/8 in

and inside diameter (ID) 1.55 mm).[1] The term “concentrated under reduced pressure” refers to the

removal of solvents and other volatile material using a rotary evaporator while maintaining a water bath

temperature under 30 °C. The compounds purified over silica gel were further concentrated by the removal

of residual solvent under high vacuum (<0.2 mbar). FEP tubing was selected for its high transmittance and

stability in the UV-vis light range,[2] its flexibility and its high chemical resistance. The temperature in the

polymerization zone during the reaction is estimated to range from 25 to 30 °C, based on temperature

measurements taken around the reaction vial. For safety reasons, the experiments were conducted inside a

fume hood covered with aluminum foil to partially block the intense irradiation of the lamps.

1H NMR spectra were recorded on a Varian 400-MR (400 MHz) spectrometer at ambient temperature. The

proton signal of residual non-deuterated solvent (δ 7.26 ppm for CHCl3) was used as an internal reference

for 1H spectra. Data are reported as follows: chemical shift in parts per million (δ, ppm), multiplicity (s =

singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, qn = quintet and m = multiplet), coupling

constants reported in Hertz (Hz) and integration. 13C spectra were recorded on a Varian VXR-300

spectrometer (at 100 MHz) at ambient temperature. Chemical shifts are reported in parts per million (δ,

ppm). The carbon signal of deuterated solvent (δ 77.16 ppm for CDCl3) was used as an internal reference

for 13C spectra.

Infrared (IR) spectra were recorded as thin films on a Perkin-Elmer 1600 ATR-FTIR spectrophotometer.

GC-MS measurements were performed on a Varian Saturn 2100T GC-MS equipped with a Varian

FactorFour capillary column (Cat. Number: CP8944, VF-5ms, 30 m X 0.25 mm ID, DF 0.25) at the Freie

Universität Berlin, Mass Spectrometry Core Facility. High-resolution mass spectra (HRMS) were recorded

S3

with an Agilent 6210 ESI-TOF mass spectrometer at the Freie Universität Berlin, Mass Spectrometry Core

Facility. 17 W PAR 38 cold white LED lamps, illumination angle 120° were purchased form Conrad (Best-

Nr. 574897 - 62).[3] The intensity spectrum of the LED lamp was recorded with a photonic multichannel

analyzer C10027 (Hamamatsu, Japan). SEM was carried out with a Gemini Leo 1550 microscope. N2

adsorption experiments were conducted at 77K on a Quadrasorb machine from Quantachrome instruments.

Samples were outgassed under reduced pressure overnight at 80 °C. Analytical thin layer chromatography

(TLC) was performed on Kieselgel 60 F254 glass plates precoated with a 0.25 mm thickness of silica gel.

The TLC plates were visualized with UV light and by staining with Hanessian solution (ceric sulfate and

ammonium molybdate in aqueous sulfuric acid) or anisaldehyde dip. Column chromatography was

perfomed using Kieselgel 60 (230-400 mesh) silica gel.

S4

2. Experimental Procedures and Spectroscopic Data

Preparation of 6-methacrylamidohexanoic acid (1)

HN

OH

O

OH2N

OH

O , EtNiPr2 (2 equiv.)

DCM:MeOH (10:1), rt, 4 h

O

ON

O

O

To a cooled suspension (0 °C) of caproic acid (1.00 g, 7.62 mmol, 1.50 equiv.) in DCM:MeOH (10:1, 55

mL) was added Hunig’s base (1.97 g, 15.25 mmol, 3.0 equiv.) and N-methacryloxysuccinimide (0.93 g,

5.08 mmol, 1.0 equiv.) and the mixture was allowed to warm up to room temperature and stirred for an

additional 4 h. The reaction mixture was then cooled down to 0oC, acidified by the dropwise addition of

H2SO4 (1M, 15 mL) and extracted with DCM (3X). The combined organic phases were washed with H2O,

brine, dried over Na2SO4 and concentrated to afford 6-methacrylamidohexanoic acid (0.55 g, 54%) as a

colorless oil and was used directly in the following step without any purification. 1H NMR (400 MHz,

CDCl3) 1H NMR (400 MHz, cdcl3) δ 5.84 (bs, 1H), 5.69 – 5.64 (dq, J = 1.0, 1.0 Hz, 1H), 5.34 – 5.31 (dq, J

= 1.5, 1.0 Hz, 1H), 3.32 (td, J = 7.1, 6.0 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1.96 (dd, J = 1.5, 1.0 Hz, 3H),

1.72 – 1.62 (m, 2H), 1.62 – 1.52 (m, 2H), 1.45 – 1.35 (m, 2H).

Preparation of 2,5-dioxopyrrolidin-1-yl 6-methacrylamidohexanoate (1)

HN

OH

O

O

N-hydroxysuccinimide (1,25 equiv.)

DCC (1.5 equiv.), DCM, rt, 14 h1

HN

O

O

O

N

O

O

To a cooled solution (0 °C) of crude 6-methacrylamidohexanoic acid (0.55 g, 2.74 mmol, 1.00 equiv.) and

N-hydroxysuccinimide (0.40 g, 3.43 mmol, 1.25 equiv.) in DCM (0.1 M, 28 mL) was added DCC (0.85 g,

4.11 mmol, 1.5 equiv.) and the mixture was allowed to warm up to room temperature and stirred at room

temperature for 14 h. The reaction mixture was filtered and concentrated. The residue was dissolved in

minimal DCM and filtered through a cotton pad to remove the residual dicyclohexyl urea product and the

process was repeated a second time. The oily residue was purified by column chromatography (5% then

S5

15% then 25% acetone in DCM) to afford (1) (0.72 g, 89%) as a colorless oil which solidified upon

standing in the freezer. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, cdcl3) δ 5.91 (bs, 1H), 5.71 –

5.64 (dq, J = 1.0, 1.0 Hz, 1H), 5.31 (dq, J = 1.5, 1.0 Hz, 1H), 3.33 (dt, J = 7.0, 6.0 Hz, 2H), 2.84 (d, J = 3.0

Hz, 4H), 2.63 (t, J = 7.2 Hz, 2H), 1.96 (dd, J = 1.5, 1.0 Hz, 3H), 1.79 (dt, J = 14.8, 7.3 Hz, 2H), 1.64 – 1.55

(m, 2H), 1.52 – 1.42 (m, 2H). 13C NMR (100 MHz, cdcl3) δ 169.3, 168.6, 168.6, 140.3, 119.4, 39.4, 31.0,

29.1, 26.0, 25.7, 24.4, 18.9; IR-thin film (ν, cm-1) 3352 (b), 3004, 2942, 2964, 1814, 1780, 1729, 1655,

1607, 1532, 1460, 1433, 1363, 1202, 1073, 1059, 927, 872, 820; HRMS–ESI: M+Na, calc. 319.1270,

meas. 319.1278.

Preparation of N-allyl-N-methyl-4-aminopyridine

a) BuLi (1.1 equiv.), THF, 0 °C, 1 h

b) allylBr (1.2 equiv.), THF, 0 °C, 30 minN

NH

N

N

To a cooled solution (0 °C) of N-methyl-4-aminopyridine (2.0 g, 18.49 mmol, 1.00 equiv.) in THF (0.1 M,

28.0 mL) was added a solution of n-BuLi in hexanes (1.60 M, 12.7 mL, 20.34 mmol, 1.10 equiv.) dropwise

and the mixture was stirred at 0 °C for 1 h. Allyl bromide (2.7 g, 22.19 mmol, 1.20 equiv.) was then added

and the reaction mixture was stirred for an additional 30 min. Water (50 mL) was added and mixture was

extracted with EtOAc (3X). The combined organic phases were washed with brine, dried over Na2SO4 and

concentrated to afford N-allyl-N-methyl-4-aminopyridine (2.50 g, 91%) as a light yellow oil. 1H NMR (400

MHz, CDCl3) 1H NMR (400 MHz, cdcl3) δ 8.21 – 8.16 (m, 2H), 6.50 – 6.44 (m, 2H), 5.83 – 5.72 (m, 1H),

5.16 (ddt, J = 10.3, 1.5, 1.5 Hz, 1H), 5.10 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H), 3.92 (ddd, J = 4.8, 3.2, 1.6 Hz,

2H), 2.96 (d, J = 1.6 Hz, 3H); 13C NMR (100 MHz, cdcl3) δ 153.7, 150.0, 132.1, 116.7, 106.8, 53.8, 37.3;

IR-thin film (ν, cm-1) 3644 – 2750 (b), 3086, 3033, 3006. 2984, 2910, 1644, 1600, 1541, 1515, 1455, 1435,

1386, 1354, 1228, 1213, 1123, 989, 921, 801; HRMS–ESI: M+H, calc. 149.1079, meas. 149.1074.

Preparation of N-allyl-N-methyl-4-aminopyridinium p-toluenesulfonate

p-TsOH•H2O (1.0 equiv.)

EtOAc, 0 °CN

N

N

N

SO3H

•

S6

To a cooled solution (0 °C) of N-methyl- N-allyl-4-aminopyridine (1.33 g, 8.97 mmol, 1.00 equiv.) in

EtOAc (15.0 mL) was added a solution of p-TsOH in EtOAc (35.0 mL, 8.97 mmol, 1.00 equiv.) dropwise

and the mixture was stirred at 0 °C for 5 min. The product was collected by filtration and washed with

Et2O to afford N-allyl-N-methyl-4-aminopyridinium p-toluenesulfonate (2.41 g, 84%) as a browm solid. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, cdcl3) δ 8.24 (bs, 2H), 7.86 – 7.79 (m, 2H), 7.16 (m,

2H), 6.76 (bs, 2H), 5.78 (ddt, J = 17.2, 10.3, 4.8 Hz, 1H), 5.28 (ddd, J = 10.4, 1.6, 0.9 Hz, 1H), 5.11 (ddd, J

= 10.4, 1.8, 1.2 Hz, 1H), 4.10 (dt, J = 4.7, 1.8 Hz, 2H), 3.17 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz,

cdcl3) δ 157.4, 142.8, 140.0, 139.9, 129.4, 128.9, 126.2, 118.3, 107.2, 54.8, 38.7, 21.4.

Preparation of N-(3-((2-aminoethyl)thio)propyl)-N-methyl-4-aminopyridine (2)

HSCH2CH2NH2 • HCl (7.0 equiv.)

4,4'-azobis(4-cyanovaleric acid) (0.2 equiv.)H2O, 80 °C, 18 h N

N

N

N

SO3H

•S

NH2

2 N-allyl-N-methyl-4-aminopyridinium p-toluenesulfonate (1.0 g, 3.15 mmol, 1.00 equiv.), cysteamine

hydrochloride (2.5 g, 22.07 mmol, 7.00 equiv.) and 4,4’-azobis(4-cyanovaleric acid) (0.177 g, 0.63 mmol,

0.20 equiv.) were dissolved in degassed water under an atmosphere of argon and the mixture was heated at

80 °C for 18 h. The reaction mixture was then cooled down to 0oC, basified by the dropwise addition of

NaOH (20% w/w, 10 mL) and extracted with EtOAc (4X). The combined organic phases were washed

with NaOH, H2O, brine, dried over Na2SO4 and concentrated to afford N-(3-((2-aminoethyl)thio)propyl)-

N-methyl-4-aminopyridine (2) (0.60 g, 84%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) 1H NMR

(400 MHz, cdcl3) δ8.22 – 8.17 (m, 2H), 6.52 – 6.47 (m, 2H), 3.45 (t, J = 7.3 Hz, 2H), 2.96 (s, 3H), 2.87 (t,

J = 6.4 Hz, 2H), 2.61 (t, J = 6.3 Hz, 2H), 2.53 (t, J = 6.9 Hz, 2H), 1.91 – 1.81 (m, 2H), 1.43 (bs, 2H); 13C

NMR (100 MHz, cdcl3) δ 153.4, 150.1, 106.6, 50.1, 41.2, 37.7, 36.6, 29.2, 26.7; IR-thin film (ν, cm-1) 3352

(b), 3361 (b), 3091, 3038, 2997, 2918, 2861, 1659, 1596, 1540, 1519, 1465, 1437, 1391, 1369, 1279, 1228,

1107, 992, 803; HRMS–ESI: M+H, calc. 226.1378, meas. 226.1380.

S7

General procedure for the preparation of the monolith in glass vial

A solution of styrene (60 mol%, 28% v/v), divinylbenzene (40 mol%, 22% v/v), Irgacure® 819 (1 mol%)

and porogen (50% v/v) was loaded into a 15.0 or a 6.6 mm glass vial, and the container was placed

between two LED lamps, placed 20 cm apart, and irradiated for 5 h. The glass vial was removed and the

monolithic structure was extensively washed with MeOH to remove the porogen and any residual non-

polymeric material, resulting in a rigid white monolith. Physical properties of the monoliths were evaluated

by visual and qualitative mechanical inspection, SEM and resistance to flow (back-pressure

measurements).

General procedure for the preparation of the monolith (Omnifit column or FEP tuning)

A solution of styrene (60 mol%, 28% v/v), divinylbenzene (40 mol%, 22% v/v), Irgacure® 819 (1 mol%)

and porogen (50% v/v) was loaded into a 1.55 mm FEP tubing or 10.0 X 6.6 mm Omnifit glass column,

sealed at both ends, and the container was placed between two LED lamps, placed 20 cm apart, and

irradiated for 5 h. The column endings were then replaced with a set of fritted end pieces and extensively

washed with DCM (R2+ unit set to a flow rate of 1.0 mL min−1 for 2 h) to remove the porogen and any

residual non-polymeric material, resulting in a rigid white monolith that completely filled the glass column.

Physical properties of the monoliths were evaluated by visual and qualitative mechanical inspection, SEM

and resistance to flow (back-pressure measurements).

S8

A. 1-Dodecanol, 15.0 mm glass vial, 2 X 17 W LED lamps:

Picture

SEM images

S9

B. 1-Dodecanol:THF, 15.0 mm glass vial, 2 X 17 W LED lamps:

SEM images

S10

BET measurements: Surface area = 197 m2g-1

0 20 40 60 80 100 120

0,000

0,002

0,004

0,006

0,008

0,010

0,012

0,014

0,016

0,018

dV(r

) (cc

/A/g

)

Half pore width (A)

S11

C. THF, 15.0 cm glass vial, 2 X 17 W LED lamps:

SEM images

S12

D. i-Propanol, 6.6 mm glass vial, 2 X 17 W LED lamps:

SEM images

S13

E. 1-Dodecanol, 1.55 mm FEP tubing, 2 X 17 W LED lamps:

SEM images

S14

F. 1-Dodecanol, 1.55 mm FEP tubing, Hannovia 450 W medium pressure Hg lamp:

G. 1-Dodecanol, 6.6 mm glass vial, two standard fluorescent tubes (Osram L 18W, light

color 840, lumilux, cool white):

Procedure for the preparation of the DMAP-functionalized monolith in an Omnifit column

A solution of styrene (50 mol%, 20% v/v), divinylbenzene (40 mol%, 20% v/v), N-hydroxysuccinimidyl

ester 1 (10 mol%), Irgacure® 819 (1 mol%) and i-PrOH (50% v/v) was loaded into a 10.0 X 6.6 mm

Omnifit glass column, sealed at both ends, and the container was placed between two LED lamps, placed

20 cm apart, and irradiated for 5 h. The column endings were then replaced with a set of fritted end pieces

and extensively washed with DCM (R2+ unit set to a flow rate of 1.0 mL min−1 for 2 h) to remove the

porogen and any residual non-polymeric material, resulting in a rigid white monolith that completely filled

the glass column. The NHS-monolith was then treated with a solution of 2 (3 equiv. relative to NHS) and

Hunig’s base (3 equiv.) in DCM at a flow rate of 500 µL/min for 16 hours at room temperature using a

closed loop to minimize the amount of 2 needed to maximally functionalize the column. The monolith was

then washed with DCM for 2 hours at a flow rate of 1 mL/min and directly used in acylation studies.

S15

General procedure for the continuous flow acylation of 1-phenylethanol.

A Vapourtec R series flow reactor system[4] was set up. With the pump set to flow at the required flow rate,

a solution of 1-phenylethanol (0.5 mmol, 1 equiv.), Ac2O (0.75 mmol, 70 µL, 1.5 equiv.), DIPEA (0.75

mmol, 130 µL, 1.5 equiv.) in DCM (0.25 M) was loaded into the reactor via a 2 mL injection loop. The

system was configured to collect 5 mL of the product solution in a single vessel containing MeOH (2.5

mmol, 100 µL, 5 equiv.). An aliquot of the product solution was diluted 100-fold and analyzed by GC-MS.

The concentrations of 1-phenylethanol and 1-phenethylacetate were calculated using the GC calibration

curves shown below. Background acylation is below detection limits.

GC-MS calibration curves

A. 1-Phenylethanol: retention time = 6.60 min, Area = 3.06 * 108 (Concentration), R2 = 0.994

B. 1- -phenethylacetate: retention time = 7.64 min, Area = 1.37 * 108 (Concentration), R2 =

0.998

0,0000 0,0005 0,0010 0,0015 0,00200

50000100000150000200000250000300000350000400000450000500000550000600000650000700000

1-Phenylethanol 1-Phenethylacetate

Area

Concentration (M)

S16

Catalysis Results

Run Flow Rate

(mL/min)

Residence

Time (min)

5 mol% DMAP 10 mol% DMAP Calculated Conversion (%)

Area SM Area Product Area SM Area Product 5 mol% 10 mol%

1 2.4 0.5 154473 56259 111135 89806 14 27 2 1.2 1 144968 99961 77605 135843 24 44 3 0.6 2 94630 148585 46371 182172 41 64 4 0.3 4 57546 147725 22042 255783 53 84 5 0.15 8 37243 212843 1000 327442 72 99

0 1 2 3 4 5 6 7 8 90

10

20

30

40

50

60

70

80

90

100

(5 mol%) (10 mol%)

Conv

ersio

n (%

)

Residence Time (min)

S17

1. IR Spectra

4000 3500 3000 2500 2000 1500 100080

85

90

95

Tran

smitta

nce (

%)

Wavenumber (cm-1)

IR Spectrum of the Unfunctionalized PS Monolith

S18

4000 3500 3000 2500 2000 1500 100090

92

94

96

98Tr

ansm

ittan

ce (%

)

Wavenumber (cm-1)

IR Spectrum of the NHS-functionalized PS Monolith

S19

4000 3500 3000 2500 2000 1500 100086

88

90

92

94

Tran

smitt

ance

(%)

Wavenumber (cm-1)

IR Spectrum of the DMAP-functionalized PS Monolith

S20

2. 1H and 13C-NMR Data

-00.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.50.0f1 (ppm)

2.19

4.19

3.08

2.00

1.96

0.95

0.97

0.91

1H NMR, CDCl3

HN

OH

O

O

S21

-00.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.50.0f1 (ppm)

2.06

3.16

2.07

3.02

2.00

4.12

1.97

1.05

0.98

0.89

1, 1H NMR, CDCl3

HN

O

O

O

N

O

O

S22

010203040506070809010011012013014015016017018019000f1 (ppm)

1, 13C NMR, CDCl3

HN

O

O

O

N

O

O

S23

-00.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.50.0f1 (ppm)

2.98

2.00

1.97

0.94

1.97

1.92

1H NMR, CDCl3

N

N

S24

010203040506070809010011012013014015016017018019000f1 (ppm)

13C NMR, CDCl3

N

N

S25

-00.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.50.0f1 (ppm)

2.85

3.03

2.00

1.01

0.99

0.97

2.01

1.95

1.90

1.96

1H NMR, CDCl3

N

N

·SO3H

S26

010203040506070809010011012013014015016017018019000f1 (ppm)

13C NMR, CDCl3

N

N

·SO3H

S27

-00.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.50.0f1 (ppm)

2.08

2.03

1.99

2.00

2.01

3.00

2.06

2.13

2.06

2, 1H NMR, CDCl3

N

N SNH2

S28

010203040506070809010011012013014015016017018019000f1 (ppm)

2, 13C NMR, CDCl3

N

N SNH2

S29

[1] http://www.idex-hs.com

[2] (a) A. M. S. Galante, O. L. Galante and L. L. Campos, Nucl. Instrum. Meth. A, 2010, 619, 177; (b) B. D. A. Hook, W. Dohle, P. R.

Hirst, M. Pickworth, M. B. Berry and K. I. Booker-Milburn, J. Org. Chem., 2005, 70, 7558.

[3] http://www.conrad.de

[4] http://www.vapourtec.co.uk/