Macromolecules
Article
Scheme 1. Reaction Mechanism of the Nucleophile-Initiated Thiol-Michael Addition Reaction
(m, 4H), 2.04 (m, 4H), 1.66 (m, 2H), and 1.54 (m, 2H). 13C NMR
(400 MHz, CDCl3) δ 145.6, 100.6, 67.1, 48.6, 27.0, 24.5, 23.3, and
22.9.
these reactions.11 Most recently, the Michael addition reaction
facilitated by photolatent tertiary amines was found to be
highly efficient; however, most photolatent tertiary amines are
associated with limited solubility and stability of the
formulations of low polarity which then leads to non-
orthogonality of the reaction.12,13
1-(1-Cyclohexen-1-yl)pyrrolidine (Enamine 2). Brown liquid.
1
Yield 99%; H NMR (400 MHz, CDCl3) δ 4.28 (t, 1H), 2.98 (m,
4H), 2.18 (m, 2H), 2.09 (m, 2H), 1.83 (m, 4H), 1.67 (m, 2H), and
1.54 (m, 2H). 13C NMR (400 MHz, CDCl3) δ 143.4, 93.6, 47.6, 27.6,
27.1, 25.3, 25.0, 24.5, 23.4, and 23.0.
1-(1-Cyclopent-1-yl)pyrrolidine (Enamine 4). Brown liquid. Yield
97%; 1H NMR (400 MHz, CDCl3) δ 4.07 (s, 1H), 3.10 (m, 4H), 2.47
(m, 2H), 2.37 (m, 2H), and 1.88 (m, 6H). 13C NMR (400 MHz,
CDCl3) δ 149.5, 92.1, 48.9, 48.6, 46.9, 33.0, 30.8, 25.5, 25.2, 25.0,
23.3, and 23.0.
Herein, a series of enamines are investigated for their
potential as nucleophilic catalysts for the thiol-Michael
addition. It is proposed that enamines are capable of
overcoming some of these limitations of the thiol-Michael
“click” reaction, while also mitigating the formation of
potentially toxic and otherwise undesirable byproducts.
Enamines have been extensively used in organocatalysis for
transformations such as the aldol, Mannich, Michael-addition,
and Diels−Alder reactions.14−18 Chiral amines have also been
extensively studied as asymmetric organocatalysts for similar
transformations.19 The strong nucleophilic character of
enamines has been demonstrated and studied in regards to
reactivity toward Michael acceptors, acceptor-activated aryl
halides, and electron-deficient dienes. More importantly, Mayr
et al. demonstrated that the nucleophilicity of enamines is
tailored by modulating the ring size and electron density of the
corresponding enamine.20
Herein, the potential of a series of enamines formed from
different amines and cyclic ketones of varying ring sizes to act
as a catalyst for the thiol-Michael “click” reaction was
investigated. A detailed kinetic study with systematically
varying enamine structures led to successful employment in
the thiol-Michael reaction. Furthermore, enamines were
generated in situ by the reaction of a photocleaved amine
with equimolar amounts of cyclic ketone present in a monomer
mixture of a stoichiometric ratio of monofunctional thiol and
acrylate. The amine, formed after irradiation, preferentially
reacts with ketones to form an enamine over deprotonation of
the thiol, which would further catalyze the reaction. The
success of utilizing enamines to catalyze the reaction was
further extended to bulk network polymerization.
Synthesis of 1-(9-Fluorenylmethoxycarbonyl)-diethylamine
(Fmoc-DEA). To a round-bottom flask equipped with a magnetic
stir bar was added the corresponding amine (14.1 mmol) and
fluorenylmethyloxycarbonyl chloride (14.1 mmol) in dichloro-
methane (0.3 M) at 0°C. The reaction was then allowed to slowly
warm to room temperature and stirred overnight. The mixture was
diluted with dichloromethane and transferred to a separatory funnel
and washed with water, saturated aq. ammonium chloride, brine, and
dried over Na2SO4. The solvent was removed under reduced pressure,
and the product was purified by column chromatography to yield
1
colorless viscous liquid. Yield 70%; H NMR (400 MHz, CDCl3):
7.78 (d, J = 7.89 Hz, 2H), 7.61 (d, J = 7.67 Hz, 2H), 7.42 (dd, J =
7.24 Hz, 2H), 7.34 (dd, J = 7.56 Hz, 2H), 4.48 (d, J = 6.5 Hz, 2H),
4.28 (t, J1 = 7.3 Hz, J2 = 6.76 Hz, 1H), 3.27 (m, 4H), and 1.07 (m,
6H). 13C NMR (400 MHz, CDCl3): 155.80, 144.30, 141.42, 127.62,
127.02, 119.95, 66.93, 47.53, 41.82, 41.27, 13.92, and 13.53.
2-(2-Nitrophenyl)propoxycarbonyl Pyrrolidine (NPPOC-Pyr). To
a round-bottom flask equipped with a magnetic stir bar was added
pyrrolidine (14.1 mmol) and 2-(2-nitrophenyl)propyl chloroformate
(14.1 mmol) in dichloromethane (0.3 M) at 0 °C. Triethylamine
(28.2 M) was then added dropwise to the solution. The reaction was
then allowed to slowly warm to room temperature and stirred
overnight. The mixture was diluted with dichloromethane and
transferred to a separatory funnel and washed with water, saturated
aq. ammonium chloride, brine, and dried over Na2SO4. The solvent
was removed under reduced pressure to afford clean products. Yield
1
90%; H NMR (400 MHz, CDCl3) δ 7.75 (m, 1H), 7.56 (m, 2H),
7.37 (m, 1H), 4.23 (m, 2H), 3.72 (m, 1H), 3.17 (m, 4H), 1.82 (m,
4H), and 1.37 (d, 2H). 13C NMR (400 MHz, CDCl3) δ 154.7, 150.5,
137.8, 132.5, 128.3, 127.3, 124, 69.1, 46.0, 33.5, 25.4, and 17.9.
HRMS-ESI+ (m/z) [M + H]+ calculated at 279.1345, found
279.1371.
MATERIALS AND METHODS
■
Materials. Butyl 3-mercaptopropionate (BMP), n-hexyl acrylate
(HA), imidazole (Im), cyclohexanone (CyHex), cyclopentanone
(CyPent), 2-(2-nitrophenyl)propyl chloroformate (NPPOCl), pyrro-
lidine (Pyr), morpholine (Mor), diethylamine (DEA), pentaerythritol
tetrakis(3-mercaptopropionate) (PETMP), trimethylolpropane tria-
crylate (TMPTA), anhydrous toluene, and anhydrous dichloro-
methane were purchased from Sigma-Aldrich. Sulfuric acid (H2SO4)
was purchased from fisher scientific. NPPOC-DEA was synthesized
according to the previously reported procedure.21 All other chemicals
were of reagent grade and used without further purification.
Characterization. 1H NMR and 13C NMR spectra were recorded
on a Bruker 400 MHz NMR spectrometer. Proton chemical shifts are
expressed in parts per million (δ). The δ scale was referenced to
deuterated solvents, indicated in the respective measurement.
Real-Time Fourier Transform Infrared (FT-IR) Spectroscopy.
Reaction kinetics were analyzed using a FT-IR spectrometer (Nicolet
8700) in transmission mode to monitor real-time functional group
conversions. Samples were interposed between two NaCl windows
and placed into a horizontal transmission apparatus. Irradiation was
performed using a mercury-lamp (Acticure 4000) with a 365 nm band
gap filter after 1 min and continued for 60 min. The light intensity was
kept at 50 mW/cm2, which was measured by an International Light.
Inc., model IL 1400A radiometer. By measuring the IR peak area
decreasing at 3100 and 2560 cm−1, the real-time functional group
conversions of vinyl and thiol groups were monitored and calculated
as the ratio of the real-time peak area to the peak area of the initial
spectra. The real-time analysis to compare enamines with amine
Methods. General Synthesis of Enamines (1, 2, 4). To a round-
bottom flask equipped with a magnetic stir bar and Dean−Stark
apparatus was added an equimolar amount of the corresponding
amine and ketone in toluene (0.5 M). A catalytic amount of sulfuric
acid was added, and the reaction was heated to reflux overnight. The
reaction was then concentrated under reduced pressure to afford
enamines, which was then used without further purification.
4-Cyclohexen-1-ylmorpholine (Enamine 1). Brown liquid. Yield
98%; 1H NMR (400 MHz, CDCl3) δ 4.66 (t, 1H), 3.73 (m, 4H), 2.77
1694
Macromolecules 2021, 54, 1693−1701