Synthesis of 2-d-acrylamide

Article abstract of DOI:10.1002/jlcr.3603

2-d-Acrylamide was synthesized via the 2-step procedure starting from acrylonitrile and deuterium oxide. This procedure affords 2-d-acrylamide in 99.9% chemical purity and 98.4% isotopic enrichment.

Full text of DOI:10.1002/jlcr.3603

Synthesis of 2-d-acrylamide
Alexey V. Salina,*, Rashid Z. Musinb
aA.M. Butlerov Institute of Chemistry, Kazan Federal University
Kremlevskaya str. 18, Kazan 420008, Russia
bA.E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Scientific Center of Russian Academy of Sciences
Arbuzov str. 8, Kazan 420088, Russia
*Tel.: +7432337416; fax: +7432387901; E-mail: salin555@mail.ru
Abstract
2-d-Acrylamide was synthesized via the two-step procedure starting from
acrylonitrile and deuterium oxide. This procedure affords 2-d-acrylamide in
99.9% chemical purity and 98.4% isotopic enrichment.
Keywords: deuterium-labelled acrylamide, deuterium-labelled acrylonitrile,
electron-deficient alkenes, hydration
Introduction
Isotopically labelled acrylamides have been broadly used as internal
standards in liquid chromatography coupled with mass spectrometry (LC-MS)
for quantifying acrylamide in food1 and for quantitative proteomic experiments
based on alkylation of cysteine-containing peptides by acrylamide2. While
13
2,3,3-d3-acrylamide, d5-acrylamide, 1-13C-acrylamide and C3-acrylamide are
commercial products, 2-d-acrylamide is unavailable. The need of this
isotopomer for mechanistic studies of reaction of tertiary phosphines with
electron-deficient alkenes3-12 has prompted us to develop a synthetic protocol
for its preparation. Herein, we report a two-step procedure for laboratory
synthesis of 2-d-acrylamide starting from acrylonitrile and using D2O as the
deuterium source.
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Procedure
A general method for preparation of α-deuterated electron-deficient
alkenes involves the H/D-exchange between the alkene and D2O (or MeOD) in
16
the presence of a base, typically a tertiary amine13-15 or Ca(OD)2 . However,
this method is not applicable for synthesis of 2-d-acrylamide due to very slow
reaction rate and the presence of exchangeable amide protons in the alkene. In
this context, hydration of 2-d-acrylonitrile might provide a more appropriate
way for selective incorporation of deuterium to the α-position of acrylamide. 2-
d-Acrylonitrile is commercially available and alternatively can be easily
prepared by method reported previously by Fishbein and Jencks13 (Scheme 1).
In an oven-dried 250 mL round-bottom flask, 15.0 mL (12.09 g, 0.228
mol) of acrylonitrile (freshly distilled over CaH2), 80.0 mL (88.45 g, 4.423 mol)
D2O (99.8 atom % D) and 5.0 mL (3.64 g, 0.036 mol) of triethylamine (freshly
distilled over CaH2) were mixed. The mixture was stoppered and magnetically
stirred for 48 h at room temperature. Then, concentrated hydrochloric acid was
added to bring the pH of the aqueous phase to 5. The biphasic solution was
distilled from the flask equipped with a 20 cm fractional distillation head, and
the 2-d-acrylonitrile/water azeotrope was collected (bp 70-72oC). The distillate
was first dried over anhydrous magnesium sulfate overnight, decanted, and
finally distilled over CaH2 to give 11.15 g (0.206 mol, 90% yield) of 2-d-
25
20
acrylonitrile (bp 77oC, nD =1.3882, nD =1.3911). According to GC-MS
analysis, 2-d-acrylonitrile was isolated with 99.9% chemical purity and was
98.7% deuterated. 2-d-Acrylonitrile obtained from this method was used for the
preparation of 2-d-acrylamide.
Hydration of nitriles is usually carried out with strong acids such as
H2SO4 at high temperature. Although this procedure does not lead to the loss of
deuterium by exchange17, the carbon-carbon double bond of acrylonitrile does
not fully tolerate such drastic reaction conditions that decreases the yield of the
desired product. To improve the synthetic outcome of the hydration reaction we
screened other catalytic systems suitable for laboratory application. Unactivated
neutral alumina previously proposed for hydration of some aliphatic and
aromatic nitriles18, was found to be insufficient for hydration of 2-d-
acrylonitrile: anticipated 2-d-acrylamide was formed only in a trace amount.
Copper compounds for a long time have been known as useful catalysts
for hydration of nitriles. In 1978, Nakamura and co-workers showed that the
catalytic activity of copper catalyst can be substantially increased by treating it
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with a vanadate19. They found that high conversion of acrylonitrile to
acrylamide can be achieved using a three-component catalytic system: cuprous
chloride, sodium metavanadate and copper powder. We were pleased to find
that application of this catalyst for 2-d-acrylonitrile resulted in efficient
hydration (Scheme 2), and the reaction was not complicated by H/D-exchange.
Into a 50 mL round-bottom flask, cuprous chloride (0.32 g, 3.25 mmol),
sodium metavanadate tetrahydrate (0.63 g, 3.25 mmol) and copper powder (0.31
g, 4.9 mmol) were added, and then the flask was filled with water (20.0 mL).
After magnetically stirring at room temperature for 5 min, 2-d-acrylonitrile
(1.22 g, 22.6 mmol) was added. The mixture was stoppered and the hydration
was carried out at 80oC for 1 h under continuous stirring. Then, the mixture was
evaporated under reduced pressure, and the residue was extracted with hot ethyl
acetate (3×10 mL). The extract was filtered and concentrated under reduced
pressure. Purification by column chromatography (20 cm×2.5 cm) on silica gel
(60 Å), eluent – ethyl acetate (Rf=0.8), followed by sublimation at 1 mmHg
provided 1.22 g of 2-d-acrylamide as colorless crystals (16.9 mmol, 75% yield),
mp 84-85oС. GC-MS analysis showed 99.9% chemical purity and 98.4%
isotopic enrichment for the isolated 2-d-acrylamide.
The Raman, IR, NMR and MS spectra confirm the assignment of the
structure to 2-d-acrylamide. In the Raman spectrum, the frequency of C–H
stretching vibration at 3035 cm-1 shifts to 2270 cm-1 upon the deuteration. In the
IR spectrum, this vibration is not active. (For the copies of Raman and IR
1
spectra, see Supporting Information, pages S9,S10). In the H NMR spectrum,
the signal of methine proton at 5.71 ppm does not appear. Signal of the carbon
13
atom attached to deuterium in the C{1H} NMR spectrum is seen as a 1:1:1
1
triplet at 130.0 ppm with coupling constant JСD=24.6 Hz. (For the copies of 1H
13
and C{1H} NMR spectra, see Supporting Information, page S12). In electron
impact mass spectrum (Figure 1), 2-d-acrylamide shows diagnostic intensive
peak of molecular ion at m/z 72. A weak peak at m/z 71 is a composite of the
[M-1]+ peak and a peak of molecular ion from residual nondeuterated
acrylamide. Loss of NH2 from molecular ion yields characteristic fragmentary
peak of α-deuterated acryloyl cation at m/z 56 (Figure 1).
In conclusion, an efficient procedure for the preparation of 2-d-
acrylamide was developed. The 2-d-acrylamide obtained by this method has
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high chemical purity and isotope enrichment necessary for mechanistic studies
based on measuring kinetic isotope effects. In this context, a synthetic way to 2-
d-acrylamide is strongly desired, since an access to other α-deuterated electron-
deficient alkenes (except for 2-d-acrylonitrile) is very limited. For example, 2-d-
methyl acrylate, another potentially useful candidate, can be obtained only in
87% deuterated form and typically contains up to 2% hard-to-remove aromatic
impurities14 making it unsuitable for kinetic investigations using UV
spectroscopy. The utility of the 2-d-acrylamide for studying kinetic isotope
effects was recently demonstrated in phospha-Michael addition of tertiary
phosphines to electron-deficient alkenes12.
1
2-d-Acrylonitrile. NMR Н:  (ppm) 6.02-6.08 (m, 1Н, =СНAHB), 6.15-6.20
13
1
(m, 1Н, =СНAHB). NMR С{1H}:  (ppm) 107.2 (t, JСD=26.9 Hz, =CD–),
116.8 (s, CN), 137.1 (s, =CH2). Raman ν, cm–1: 3119 (w), 3032 (m), 2275 (m),
2227 (s), 1595 (s), 1397 (m), 1162 (w), 904 (w), 864 (w), 664 (w), 558 (w), 239
(m). IR ν, cm–1: 3118 (w), 3030 (w), 2274 (w), 2225 (s), 1594 (s), 1395 (s),
1161 (m), 967 (s), 903 (w), 861 (m), 661 (s). EI MS, m/z: 54 (100%), 53
(59.2%), 52 (34.9%), 51 (21.1%), 27 (58.2%), 26 (32.9%), 18 (16.9%).
1
2-d-Acrylamide. NMR Н:  (ppm) 5.70-5.76 (m, 1Н, =СНAHB) overlapped
with 5.75 (broad s, 1Н, NН), 6.09 (broad s, 1Н, NН), 6.27-6.32 (m, 1Н,
13
1
=СНAHB). NMR С{1H}:  (ppm) 127.3 (s, =CH2), 130.0 (t, JСD=24.6 Hz,
=CD–), 168.0 (s, CONH2). Raman ν, cm–1: 3157 (w), 3107 (m), 3005 (s), 2270
(s), 1668 (m), 1623 (s), 1589 (s), 1425 (s), 1148 (s), 966 (m), 886 (s), 837 (m),
807 (w), 620 (w), 503 (m), 305 (m). IR ν, cm–1: 3343 (s), 3165 (s), 1667 (s),
1633 (s), 1608 (s), 1411 (s), 1352 (s), 1137 (s), 959 (s), 878 (m), 831 (s), 805
(s), 656 (s), 621 (s), 500 (s). EI MS, m/z: 72 (79.8%), 71 (4.2%), 56 (74.4%), 44
(100%), 29 (12.7%), 27 (37.7%), 26 (14.7%).
Acknowledgement. This research was supported by a grant of Russian
Foundation for Basic Research (project 15-33-20067 a).
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Figure 1. Electron impact mass spectrum of 2-d-acrylamide
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D
D2O
CN
CN
Et3N, rt, 48 h
90%
Scheme 1. Preparation of 2-d-acrylonitrile
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D
D
H2O
CuCl/NaVO3/Cu
80oC, 1 h
CN
CONH2
75%
Scheme 2. Hydration of 2-d-acrylonitrile
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