Efficient and continuous monoacylation with superior selectivity of symmetrical diamines in microreactors

Article abstract of DOI:10.1039/c1lc20765b

Efficient and continuous monoacylation of symmetrical diamines performed in microreactors yielded superior selectivity to that predicted by statistical considerations. It is highly valuable that the kinetically controlled product in high yields was achieved without any special catalyst at ambient temperature.

Full text of DOI:10.1039/c1lc20765b

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Efficient and continuous monoacylation with superior selectivity
of symmetrical diamines in microreactor
Ram Awatar Maurya, Phan Huy Hoang and Dong-Pyo Kim*
National Creative Research Center of Applied Microfluidic Chemistry, Chungnam National University,
Daejeon, 305-764, South Korea, and Graduate School of Analytical Science and Technology, Chungnam
National University, Daejeon, 305-764, South Korea
General: Sylgard 184 silicone elastomer (dimethyl siloxane oligomer) and curing agent were
purchased from Dow Corning (Midland, MI, USA). PFA tubing (id = 500 micron) and T-
shaped micromixer were purchased from Upchurch Scientific. Unless otherwise specified, all
reagents and chemicals were purchased from Sigma-Aldrich and were used as such without
1
further any purification. Common solvents were purchased from Daejung Chemicals. H
13
NMR and C NMR spectra were recorded on a JEOL JNM-AL 400 spectrometer. Proton
(400 MHz) and carbon (100 MHz) chemical shifts are reported in ppm (  ) relative to TMS
as internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, dd = doublet and doublet dt = doublet and triplet, m =
multiplet, quint = quintet), coupling constants (Hz) and integration. PHD 2000 HARVARD
infuse/withdraw syringe pumps, glass syringes, JAC Ultrasonic (330W), PFA tubing and T-
shape micromixer (Upchurch Scientific) were used for experiments. All the compounds were
1
13
known and were characterized by comparing their H and C NMR spectra with literature
values.
Continuous capillary microreactor experiments: In our experiments, we took T- shaped
micromixers where due to the channel bends the laminar flow is disturbed, vortices are
generated, and first transient effects are observed, which dramatically enhance the mixing
quality.1 In order to further enhance mixing, the T-micromixer and tubing were immerged in
an ultrasonic bath. The typical schematic diagram of reaction set-up in microreactor is shown
in figure 1. A PFA capillary microreactor (inner diameter = 500m) was used for this study.

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Figure 1. Length of capillary micrreactor dipped in ultrasonic bath(330W) = 50 cm (effective volume = 0.098
ml); length of capillary microreactor outside ultrasonic bath = 10 cm
Fabrication of the microchannel for droplet generation and merging experiment: The
microfluidic devices for droplet generation and merging were fabricated using the facile non-
lithographic embedded template method, as developed by our own group.2 Briefly a
framework for channel formation was assembled using commercially available tubing. All the
tubings were purchased from Upchurch Scientific (Oak Harbor, WA). A perfluoralkoxyalkane
(PFA) tubing (OD 1.5mm, ID ~508 m) was connected to both the ends of a polyetherether
ketone (PEEK) tubing with an OD of ~510 m. For creation of the perpendicular side
channels for injection, PEEK (OD 360m, ID 100m) were connected with the surface of
PEEK tubing. This scaffold was then placed on the double sided tape (3M, St. Paul, MN) and
subsequently a mixture of PDMS pre-polymer and curing agent (10:1) was poured in a Petri
dish and cured at 60°C for several hours.
Typical experimental procedure for monoacylation of symmetrical diamines
with acid chloride in microreactor under ultrasonic irradiation in glacial AcOH: The T-
micromixer and microreactor tubing were immerged in an ultrasonic bath (330W). Acid
chloride (1 mmol in 20 ml of glacial AcOH) and diamine (1 mmol in 20 ml of glacial AcOH)
were taken in separate syringe and pumped through a syringe pump. The temperature of
0
ultrasonic bath was set to 60 C. After completion, the reaction mixture was evaporated to
dryness to yield crude. The crude was stirred with 30 ml of concentrated ammonia for 2 h
then it was extracted with dichloromethane (25 ml x 6). The dichloromethane layer was dried
over anhydrous MgSO4 and concentrated to yield crude which was purified by silica-gel
column chromatography using methanol/chloroform as eluent with increasing polarity to
yield the desired monoacylated product.

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Typical experimental procedure for monoacylation of symmetrical diamines
with N-hydroxy succinimide esters in microreactor under ultrasonic irradiation: The T-
micromixer and microreactor tubing were immerged in an ultrasonic bath (330W). N-
hydroxy succinimide ester (1 mmol in 20 ml of methanol) and symmetrical diamine (1 mmol
in 20 ml of methanol) were taken in separate glass syringes and pumped by a syringe pump
with flow rate of 200 L/min. Ultrasonic irradiation resulted to increase in the temperature of
0
ultrasonic bath hence the temperature of ultrasonic bath was maintained below 25 C by
addition of ice at certain intervals. The reaction mixture was collected in 20 ml of 0.1N HCl.
After completion the resulting methanol-water solution was concentrated, basified with
ammonia and extracted with dichloromethane (15 ml x 6). The organic layer was dried over
anhydrous MgSO4, concentrated under reduced pressure to yield crude which was purified by
silica-gel column chromatography using methanol/chloroform as eluent in increasing polarity
to yield the desired products.
Typical experimental procedure for mono acylation of diamines with PhCOSu
in flask: Diamine (1 mmol in 20 mM in MeOH) was placed in a round bottom flask and
PhCOSu (1 mmol in 20 ml MeOH) was added drop-wise to it over a period of 90 min. The
reaction mixture was further stirred for 30 min at room temperature. The products were
isolated and purified as aforementioned.
1H and 13C NMR data of compounds
N-(3-aminopropyl)benzamide (3aa):
O
N
NH2
H
1H NMR (DMSO-d6, 400 MHz) : 1.70-1.78 (m, 2H), 2.69-2.84 (m, 2H), 3.26-3.43 (m, 2H),
13
4.67 (bs, 2H), 7.38-7.48 (m, 3H), 7.88 (d, J = 7.32 Hz, 2H), 8.86 (s, 1H); C NMR (CDCl3,
100 MHz) : 31.45, 39.31, 40.71, 126.99, 128.52, 131.40, 134.34, 167.82.
N,N'-(propane-1,3-diyl)dibenzamide (4aa):
O
O
N
N
H
H
1H NMR (CDCl3 + DMSO-d6, 400 MHz) : 1.83 (qui, J = 6.10 Hz, 2H), 3.50 (dd, J = 6.10 &
12.20 Hz, 4H), 7.40-7.51 (m, 6H), 7.90 (d, J = 7.32 Hz, 4H), 8.12 (s, 2H); 13C NMR (DMSO-
d6, 100 MHz) : 29.59, 37.68, 127.40, 128.29, 131.08, 134.61, 166.37.

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N-(2-aminoethyl)benzamide (3ba):
O
NH2
N
H
1H NMR (CD3OD, 400 MHz) : 2.80 (t, J = 6.59 Hz, 2H), 3.42 (t, J = 6.59 Hz, 2H), 4.79 (s,
13
3H), 7.37-7.50 (m, 3H), 7.79 (d, J = 7.07 Hz, 2H); C NMR (CD3OD, 100 MHz) : 42.06,
43.58, 128.32, 129.54, 132.66, 135.67, 171.52.
N,N'-(ethane-1,2-diyl)dibenzamide (4ba):
O
H
N
N
H
O
1H NMR (DMSO-d6, 400 MHz) : 3.44 (s, 4H), 7.37-7.52 (m, 6H), 7.84 (d, J = 7.01 Hz, 4H),
13
8.61 (s, 2H); C NMR (DMSO-d6, 100 MHz) : 38.99, 127.16, 128.23, 131.11, 134.46,
166.51.
N-(4-aminobutyl)benzamide (3ca):
H
N
H2N
O
1H NMR (DMSO-d6, 400MHz) δ: 1.41-1.58 (m, 4H), 2.62 (t, J = 6.83 Hz, 2H ), 3.23-3.28 (m,
2H) 3.49 (bs, 2H), 7.42-7.53 (m, 3 H), 7.83-7.86 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) :
25.41, 26.42, 29.00, 40.52, 127.05, 128.13, 130.89, 134.60, 165.97.
N,N'-(butane-1,4-diyl)dibenzamide (4ca):
O
H
N
N
H
O
1H NMR (DMSO-d6, 400 MHz) : 1.54-1.63 (m, 4H), 3.23-3.36 (m, 4H), 7.43-
13
7.54 (m, 6H), 7.83-7.86 (m, 4H), 8.50 (s, 2H); C NMR (DMSO-d6, 100 MHz) δ: 26.67,
39.62, 127.04, 128.14, 130.92, 134.59, 166.05.
N-(6-aminohexyl)benzamide (3da):
O
NH2
N
H
1H NMR (CD3OD, 400 MHz) : 1.24-1.60 (m, 6H), 2.57-2.60 (m, 2H), 3.32-3.35 (m, 2H),

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13
7.37-7.42 (m, 2H), 7.44-7.49 (m, 1H), 7.75-7.78 (m, 2H); CNMR (CD3OD, 100 MHz) :
27.69, 27.91, 30.49, 33.64, 40.94, 42.44, 128.24, 129.54, 132.53, 135.92, 170.15.
N,N'-(hexane-1,6-diyl)dibenzamide (4da):
O
H
N
N
H
O
1H NMR (DMSO-d6, 400 MHz) : 1.21-1.36 (m, 4H), 1.40-1.55 (m, 4H), 3.22-3.32 (m, 4H),
7.41-7.52 (m, 6H), 7.81-7.83 (m, 4H), 8.45 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) : 26.18,
29.06, 39.42, 127.03, 128.14, 130.89, 134.64, 166.00.
N-2-aminocyclohexyl)benzamide (3ea):
O
NH
NH2
1H NMR (CDCl3, 400MHz) δ: 1.19-1.41 (m, 4H), 1.71-1.83 (m, 2H), 1.85 (s, 2H), 1.96-2.13
(m, 2H), 2.46-2.53 (m, 1 H), 3.67-3.75 (m, 1H), 6.43 (d, J = 8.04 Hz, 1H), 7.40-7.51 (m, 3 H),
13
7.80 (d, 7.07 Hz, 2H); C NMR (CDCl3, 100 MHz,) δ: 25.06, 32.52, 35.50, 55.48, 56.63,
126.98, 128.52, 131.43, 134.71, 167.90.
N,N'-(cyclohexane-1,2-diyl)dibenzamide (4ea):
O
NH
NH
O
1H NMR (DMSO-d6, 400 MHz) δ: 1.37-2.04 (m, 8H), 3.93-4.01 (m, 2H), 7.37-7.51 (m, 6H),
7.69-7.72 (m, 2H), 7.84-7.85 (m, 2H), 8.23 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ:
24.91, 31.82, 53.30, 117.35, 128.74, 131.13, 135.10, 166.73.
N-(2-aminoethyl)-2-phenylacetamide (3bb):
H
N
H2N
O
1H NMR (DMSO-d6, 400 MHz)  2.87-3.22 (m, 4H), 3.39 (s, 2H), 7.18-7.30 (m, 5H), 8.11 (s,

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1H); 13C NMR (DMSO-d6, 100 MHz) : 38.62, 41.34, 42.52, 126.42, 128.29, 129.12, 136.45,
169.50.
N,N'-(ethane-1,2-diyl)bis(2-phenylacetamide) (4bb):
O
H
N
N
H
O
1H NMR (DMSO-d6, 400 MHz) : 3.09 (d, J = 5.12 Hz, 4H), 3.38 (s, 4H), 7.19-7.31 (m,
10H), 8.07 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) : 38.38, 42.32, 126.25, 128.12, 128.94,
136.26, 170.24.
N-(2-aminoethyl)cinnamamide (3bc):
O
NH2
N
H
1H NMR (CDCl3, 400 MHz) : 1.61 (bs, 2H), 2.89 (t, J = 5.85 Hz, 2H); 3.42 (dd, J = 5.85 &
11.70 Hz, 2H), 6.47 (d, J = 15.61 Hz, 1H), 6.73 (s, 1H), 7.31-7.35 (m, 3H), 7.45-7.50 (m, 2H),
13
7.60 (d, J = 15.61 Hz, 1H); C NMR (CDCl3, 100 MHz)  , 37.51, 52.22, 120.37, 127.77,
128.71, 129.64, 134.65, 141.03, 165.94.
(2E,2'E)-N,N'-(ethane-1,2-diyl)bis(3-phenylacrylamide) (4bc):
O
H
N
N
H
O
1H NMR (DMSO-d6, 400 MHz) : 3.37 (s, 4H), 6.58 (d, J = 15.61 Hz, 1H), 6.73 (s, 1H),
13
7.31-7.35 (m, 3H), 7.43-7.50 (m, 2H), 7.60 (d, J = 15.61 Hz, 1H), 8.28 (s, 2H); C NMR
(CDCl3 + DMSO-d6, 100 MHz) : 28.33, 122.42, 127.86, 129.54, 129.67, 135.37, 139.41,
166.22.
Phenyl(piperazin-1-yl)methanone (3fa):
O
N
NH
1H NMR (CDCl3, 400 MHz) : 1.74 (s, 1H); 2.80-2.94 (m, 4H), 2.39-2.76 (m, 4H), 7.40 (m,
13
5H); C NMR (CDCl3, 100 MHz) : 43.15, 45.93, 46.44, 48.95, 126.97, 128.65, 129.61,
135.82, 170.41.
piperazine-1,4-diylbis(phenylmethanone) (4fa):

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O
N
N
O
13
1H NMR (CDCl3, 400 MHz) : 3.40-3.90 (m, 8H), 7.37-7.50 (m, 10H); C NMR (CDCl3,
100 MHz) : 41.50, 47.45, 127.00, 128.59, 130.00, 135.10, 170.55..
(E)-3-phenyl-1-(piperazin-1-yl)prop-2-en-1-one (3fe):
O
N
NH
1H NMR (CDCl3, 400 MHz) : 1.94 (s, 1H); 2.87-2.91 (m, 4H), 3.63-3.71 (m, 4H), 6.87 (d, J
13
= 15.4 Hz, 1H), 7.33-7.40 (m, 3H), 7.52-7.54 (m, 2H), 7.66 (d, J = 15.4 Hz, 1H); C NMR
(CDCl3, 100 MHz)  43.29, 45.89, 46.54, 47.09, 117.10, 127.70, 128.76, 129.56, 135.24,
142.64, 165.46.
piperazin-1-yl(thiophen-2-yl)methanone (3ff):
O
S
N
HN
1H NMR (CDCl3, 400 MHz) : 1.96 (s, 1H), 2.86-2.88 (m, 4H), 3.68-3.71 (m, 4H), 7.02 (dd,
J= 3.66 & 5.12 Hz, 1H), 7.26 (dd, J = 0.98 & 3.66 Hz, 1H), 7.37 (dd, J = 1.22 & 5.12 Hz,
1H); 13C NMR (CDCl3, 100 MHz) : 46.14, 126.61, 128.41, 129.16, 137.06, 163.41.
1-tosylpiperazine (3fg):
NH
O
N
S
O
1H NMR (CDCl3, 400 MHz) : 1.52 (s, 1H), 2.43 (s, 3H), 2.90-3.08 (m, 8H), 7.32-7.35 (m,
13
2H), 7.59-7.65 (m, 2H); C NMR (DMSO-d6, 100 MHz) : 21.50, 45.31, 46.88, 127.83,
129.60, 132.41, 143.61.
1-(piperazin-1-yl)ethanone (3ff):
O
N
NH
13
1H NMR (CDCl3, 400 MHz) : 1.83 (s, 3H), 2.52 (s, 1H), 3.15-3.42 (m, 8H); C NMR

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(CDCl3, 100 MHz) : 21.33, 42.18, 45.52, 46.13, 47.22, 169.17.
2-phenyl-1-(piperazin-1-yl)ethanone (3fi):
NH
N
O
1H NMR (CDCl3, 400 MHz) : 1.84 (s, 1H); 2.58-2.61 (m, 2H), 2.73-2.75 (m, 2H), 3.34-3.37
13
(m, 2H), 3.53-3.57 (m, 2H), 3.69 (s, 2H), 7.18-7.23 (m, 3H), 7.26-7.31 (m, 2H); C NMR
(CDCl3, 100 MHz) : 40.76, 42.82, 45.68, 46.00, 47.28, 126.61, 128.52, 135.12, 169.27.
(1,4-diazepan-1-yl)(phenyl)methanone (3gd):
O
N
HN
1H NMR (CDCl3, 400 MHz) : 1.66 (m, 1H), 1.79-1.92 (m, 2H), 2.79-3.01 (m, 4H), 3.38-
13
3.45 (m, 2H), 3.72-3.79 (m, 2H), 7.33-7.38 (m, 5H); C NMR (CDCl3, 100 MHz) : 31.54,
45.15, 47.70, 48.40, 50.59, 126.36, 128.35, 129.15, 136.99, 171.58.
1-(1,4-diazepan-1-yl)-2-phenylethanone: (3gi):
O
N
HN
1H NMR (CDCl3, 400 MHz) : 1.65-1.78 (m, 2H), 2.32 (s, 1H), 2.73-2.92 (m, 4H), 3.36-3.63
(m, 4H), 3.72 (s, 2H), 7.21-7.33 (m, 5H); 13C NMR (CDCl3, 100 MHz) : 30.80, 40.91, 44.91,
48.40, 49.91, 51.18, 126.68, 128.60, 128.71, 135.20, 170.63.
1-tosyl-1,4-diazepane (gg):
O
HN
N S
O
1H NMR (CDCl3, 400 MHz) : 1.79-1.89 (m, 2H), 2.42 (s, 3H), 2.83-2.96 (m, 4H), 3.29-3.39
(m, 4H), 7.29-7.31 (m, 2H), 7.63-7.69 (m, 2H); 13C NMR (CDCl3, 100 MHz) : 21.48, 31.13,
47.26, 50.08, 50.97, 51.50, 126.83, 129.82, 135.97, 143.52.
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