Synthesis of propiolamide and 1H, 13C and 15N NMR spectra of formamide, acetamide and propiolamide

Article abstract of DOI:10.1002/(SICI)1097-458X(199709)35:9<571::AID-OMR140>3.0.CO;2-K

A high-yield synthesis and purification of propiolamide is described. The structure and purity of the compound were confirmed by ¹H, ¹³C and ¹⁵N NMR studies. Natural abundance ¹³C and ¹⁵N chemical shift measurements in 3.0 M acetonitrile solutions are reported along with ¹H-¹H, ¹H-¹⁵N and ¹H-¹³C spin coupling constants. Polarization transfer techniques were used for the ¹⁵N and ¹³C measurements. The propiolamide NMR parameters were compared with those for 3.0 M solutions of formamide and acetamide in acetonitrile solution. Measurements at 298 and 278 K indicated that for all three compounds there is still significant rotation about the carbon-nitrogen bond at room temperature.

Full text of DOI:10.1002/(SICI)1097-458X(199709)35:9<571::AID-OMR140>3.0.CO;2-K

MAGNETIC RESONANCE IN CHEMISTRY, VOL. 35, 571È576 (1997)
1
13
15
Synthesis of Propiolamide and H, C and N
NMR Spectra of Formamide, Acetamide and
Propiolamide
Thomas D. Ferris, Peter T. Lee and Thomas C. Farrar*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA
A high-yield synthesis and puriÐcation of propiolamide is described. The structure and purity of the compound were
conÐrmed by 1H, 13C and 15N NMR studies. Natural abundance 13C and 15N chemical shift measurements in 3.0
M acetonitrile solutions are reported along with 1H–1H, 1H–15N and 1H–13C spin coupling constants. Polarization
transfer techniques were used for the 15N and 13C measurements. The propiolamide NMR parameters were com-
pared with those for 3.0 M solutions of formamide and acetamide in acetonitrile solution. Measurements at 298 and
2
78 K indicated that for all three compounds there is still signiÐcant rotation about the carbon–nitrogen bond at
room temperature. ( 1997 by John Wiley & Sons, Ltd.
Magn. Reson. Chem. 35, 571È576 (1997) No. of Figures: 6 No. of Tables: 2 No. of References: 18
Keywords: NMR; 1H NMR; 13C NMR; 15N NMR; formamide; acetamide; propiolamide
Received 30 December 1996; revised 28 March 1997; accepted 9 April 1997
tance as a model compound for the study of hydrogen
INTRODUCTION
bonding, solution structure and molecular dynamics.
Recent single-crystal x-ray studies have shown that
propiolamide is a planar molecule consisting of non-
symmetric dimers with the two monomer units slightly
non-planar.8 Owing to the high degree of conjugation
caused by the carbonyl and acetylenic bonds and the
lone pair on the nitrogen, one might expect that the
electronic structure of formamide and propiolamide
would be di†erent and lead to signiÐcant di†erences in
the barrier to rotation about the CwN bond and to
substantial di†erences in the NMR chemical shifts and
spin coupling constants. To test this supposition, we
carried out NMR measurements on formamide, acet-
amide and propiolamide (Fig. 1) in 3.0 M solutions of
Amide compounds have been the subject of many spec-
troscopic and theoretical investigations for several
decades. Because of its small size and its role as a model
compound for hydrogen bonding in peptides and pro-
teins, formamide has been extensively studied.1h3 Until
recently, however, little was known about the structures
or dynamics of formamide and related compounds in
the liquid state. Recent advances in NMR relaxation
methods and the ability to carry out accurate calcu-
lations of NMR parameters such as the chemical shift
tensor and the quadrupole coupling tensor have made it
possible to obtain detailed insight into the structure of
simple liquids.4,5 The work reported here is part of an
ongoing e†ort to learn more about how electronic
structure, steric e†ects and intermolecular interactions
between solvent and solute a†ect the liquid structure.
Since formamide and its derivatives serve as building
blocks for peptides and proteins, an understanding of
these apparently simple systems gives insight into
protein and peptide structure and the roles played by
steric, hydrophobic and hydrogen bonding interactions
in inÑuencing their structure. Recent theoretical and
experimental work with N-methylformamide6 and N-
methylacetamide7 show clearly that the presence of the
methyl groups signiÐcantly alters the liquid structure.
Propiolamide is an important model compound since it
presents a large blocking group on the carbonyl carbon.
In addition, it is the immediate precursor in the synthe-
sis of cyanoacetylene, a compound of signiÐcant impor-
acetonitrile-d . Measurements were made at both 298
3
and 278 K. Spectra are shown only for the lower tem-
perature where the spectral resolution is much better
owing to the slower rotation about the CwN bond.
EXPERIMENTAL
Materials
Formamide (99]%), acetamide, acetonitrile and
acetonitrile-d were obtained from Aldrich Chemical.
3
*
Correspondence to: T. C. Farrar.
Figure 1. Structures of propiolamide (left), formamide (center)
and acetamide (right). Tables of chemical shifts and coupling con-
stants follow the labeling shown here.
Contract grant sponsor: National Science Foundation; Contract
grant number: CHE-9500735.
(
1997 by John Wiley & Sons, Ltd.
CCC 0749È1581/97/090571È06 $17.50

5
72
T. D. FERRIS, P. T. LEE AND T. C. FARRAR
The acetonitrile and deuterated acetonitrile were dried
over molecular sieve material before use. The for-
mamide and acetamide were used as received.
dard WALTZ decoupling and RINEPT ] pulse
sequences were used to collect coupling information.
Both proton and carbon chemical shifts were referenced
to internal TMS. The times required to record the nitro-
gen spectra were about 15 min and those for the carbon
spectra were about 20 min. Solutions of approximately
Synthesis of propiolamide
3
.0 M concentration in acetonitrile were used in 5.0 mm
Propiolamide was synthesized by the addition of ethyl propiolate
o.d. NMR tubes to obtain spectra of all three com-
(
99%, Aldrich) to liquid ammonia (99.99]%, Aldrich) through a
pounds. The digital resolution values for 13C, 1H and
modiÐed procedure of Murahashi et al.9 A 50 ml volume of liquid
ammonia was collected in a dry, three-necked reaction Ñask that was
submerged in a dry-iceÈacetonitrile eutectic bath at [55 ¡C. Previous
methods involved a dry-iceÈethanol bath, but the synthesis is simpli-
Ðed by using a warmer eutectic bath such as acetonitrile because the
ethanol formed in the reaction becomes very viscous at lower tem-
peratures and interferes with stirring as the reaction proceeds. A dry-
iceÈethanol bath could be used if it was maintained at [55 ¡C. Using
a syringe, 20 ml (0.197 mol) of ethyl propiolate, injected through a
septum, was added dropwise to the liquid ammonia.
1
5N spectra were 0.898, 0.179 and 0.061 Hz per point,
respectively.
RESULTS AND DISCUSSION
Nitrogen spectra
The resulting mixture was stirred at [55 ¡C for 9 h. At this point
the dry-iceÈacetonitrile bath was replaced with a 30 ¡C water-bath
and dry nitrogen was cycled through the system to remove the
remaining ammonia; the removal took about 20 min. Quick removal
of the ammonia at the higher temperature is a necessary condition for
a high yield.10 Flushing with dry nitrogen was continued until the
ethanol was completely removed. This procedure left a yellow solid
material. The solid was dissolved in cold anhydrous diethyl either,
leaving behind a yellowÈorange oil as an impurity. The ether solution
was decanted and the ether evaporated in a dry nitrogen atmosphere.
This procedure removed most, but not all, of the impurities.
The Ðnal step in puriÐcation was accomplished by placing the solid
propiolamide in a round-bottomed Ñask connected to a water-cooled
condensing column, which was in turn attached to a vacuum line. The
water condenser was cooled to 15 ¡C by cold tap water and the propi-
olamide was slowly heated to the boiling point under reduced pres-
sure (approximately 80 ¡C at 0.1 Torr). Using this procedure, white
crystals formed on the inside of the condensing column. Caution
should be used with this procedure since propiolamide sublimes under
vacuum, even at room temperature.
Final recrystallization was accomplished by dissolving the solid in
an excess of anhydrous diethyl ether, adding hexane until the solution
started to cloud, and Ðnally slowly evaporating the ether to produce
white needles which precipitated out in the remaining hexane. The
needles were dried under partial vacuum. The Ðnal product had a
melting point of 61.2È62 ¡C; this compares well with the literature
value of 61È62 ¡C.11 The overall yield was 83%. At higher tem-
perature (around 80 ¡C) in an open container, propiolamide poly-
merizes to a brown viscous oil. Propiolamide is very soluble in diethyl
ether, water and acetone. It is slightly soluble in chloroform (7 g l~1)
and insoluble in hexane and carbon tetrachloride.
The natural abundance 15N NMR spectra for propi-
olamide, formamide and acetamide are shown in Fig.
2
(A), (B) and (C), respectively. The spectrum of propi-
olamide is a doublet of doublets arising from the spin
coupling with the two non-equivalent amide protons
which are cis and trans to the carbonyl R group (where
R \ H, CH or CyCH). The spin coupling constants
3
are Jtrans \ 91.2 Hz and Jcis \ 89.2 Hz. Spin coupling of
NH
NH
the 15N with the acetylenic proton is so small that it is
not resolved.
The 15N spectrum of formamide is a doublet of doub-
lets of doublets. The long-range protonÈnitrogen coup-
ling from the carbonyl proton to the nitrogen is 15.3
Hz. The cis and trans NH coupling constant are 87.9
and 90.3 Hz, respectively. As can be seen, there is a sub-
stantial (about 2 ppm) change to lower Ðeld in the nitro-
gen chemical shift of propiolamide relative to
formamide. The spectrum of acetamide is a doublet of
doublets of quartets. The long-range coupling to the
methyl protons is 1.2 Hz. Here the nitrogen chemical
shift is to higher Ðeld (lower frequency) relative to for-
mamide.
Owing to the partial double bond character of the
CwN bond, formamide is a planar, essentially rigid
molecule at room temperature, as evidenced by the fact
that one clearly observes two well deÐned peaks for the
two amide protons. However, the linewidths can be nar-
rowed substantially by working at lower temperature.
For this reason, the spectra were obtained at 278 K. At
room temperature (298 K), the linewidths in the 15N
spectrum of formamide are 1.6 Hz; at 278 K the line-
widths are 0.5 Hz. The chemical shift data are sum-
marized in Table 1 and the coupling constant data in
Table 2.
Warning. Propiolamide is a vesicant. Contact (especially
in the ether solution) causes irritation lasting for several
days. Propiolamide is also hygroscopic and slowly sub-
limes in air. In a dry nitrogen atmosphere, it is stable
indeÐnitely. In aqueous solutions, it is known that pro-
piolamide undergoes slow proton exchange;12 however,
it does not otherwise react at any appreciable rate.
NMR measurements
The natural abundance 15N NMR measurements were
made on a Bruker AM500 spectrometer operating at
Carbon spectra
50.68 MHz and 298 K. The spectrometer digital
resolution was 0.0625 Hz. RINEPT ] pulse sequences13
were used to obtain both chemical shift and coupling
information. Acetonitrile was used as a reference for the
nitrogen chemical shift.14 13C and 1H measurements
were made at 298 K on a Bruker AC300 spectrometer
operating at 74.51 and 299.87 MHz, respectively.
Carbon chemical shift data were obtained using stan-
The 13C chemical shifts of the three compounds (Table
1) were measured using composite pulse (WALTZ)
decoupling. With no attached protons, the two interior
carbons of propiolamide, (C and C in Fig. 1) have very
long relaxation times, but with appropriate changes in
the delay times of the RINEPT ] sequence, good
quality spectra can still be obtained in about 10 min.
a
b
(
1997 by John Wiley & Sons, Ltd.
MAGNETIC RESONANCE IN CHEMISTRY, VOL. 35, 571È576 (1997)

SYNTHESIS OF PROPIOLAMIDE
573
Figure 2. 15N RINEPT ½spectra of propiolamide (A), formamide (B) and acetamide (C) in 3.0 M acetonitrile. Chemical shifts are referenced
to external acetonitrile; 64 scans were taken with a relaxation delay of 5 s.
The di†erence in shifts between the carbonyl carbons in
the three samples (Table 1) is substantial and is attrib-
uted to increased electron density from the delocal-
plane of the molecule into the n* antibond in propi-
CO
olamide.
The 13C proton-coupled spectra for propiolamide,
formamide and acetamide are shown in Fig. 3(A), (B)
and (C), respectively. The doublet and the doublet of
doublets at about 75 ppm in the propiolamide spectrum
are due to the acetylenic carbon nuclei. The doublet
ization of the acetylenic n bond perpendicular to the
CC
Table 1. Chemical shifts (ppm) of various nuclei for amide
systems at room temperature (298 K) in acetonitrile
solution (3 M)a
(
J
B 256 Hz) is due to the terminal carbon (C , Fig.
HCc
c
1
) and the doublet of doublets is due to C , which is
b
coupled to H1 and to H3. The peak at about 150 ppm is
Propiolamide
Acetamide
Formamide
due to the carbonyl carbon, C . The protonÈcarbon
a
N
C
É269.1
154.9
77.8
75.4
6.6
É273.3
174.3
22.6
—
É271.5
164.8
—
spin coupling constants (Table 2) were determined by
use of RINEPT ] pulse sequences. The assignment of
a
C
C
the H3ÈC coupling was determined by decoupling
b
c
b
—
the H3 proton resonance during the coupled
H3
H2
H1
6.4
6.5
RINEPT ] sequence. The result of this experiment was
6.9
6.7
6.6
5
8.1
a collapse of a doublet of doublets into a single doublet
3.3
1.9
with an H1ÈC coupling constant of 49.6 Hz. Decoup-
b
a 15N chemical shifts are referenced to external acetonitrile. 13C
and 1H shifts are referenced to internal TMS. Numerical subscripts
refer to protons (3 ¼trans ; 2 ¼cis ; 1 ¼terminal/methyl) and letters
refer to carbon (a ¼carbonyl, etc.).
ling the other amide proton, H2, had no observable
e†ect on the 13C spectrum.
Proton spectra
The proton spectra for all three compounds (Figs 4È6)
show very broad peaks for the amide protons due to
spin coupling to the nitrogen-14; the nitrogen-14 has a
very short relaxation time owing to quadrupole relax-
Table 2. Coupling constants (Hz) at 298 K for amide systems
in 3.0 M acetonitrile solutiona
Propiolamide
Acetamide
Formamide
ation. This results in short T values for the protons
J
J
J
J
J
J
J
J
J
J
91.2
89.2
—
89.5
87.9
1.2
90.3
87.9
15.1
—
H3N
2
(
due to scalar relaxation13) and broad lines, since
H2N
H1N
H1Cc
H1Cb
H3Cb
H1Ca
H1H2
H1H3
H2H3
1/(nT ) \ *l , where *l is the proton linewidth at
2
1@2
1@2
256.0
49.2
10.2
5.6
—
its half maximum height. The fact that the broad proton
linewidths are due to interaction with the rapidly relax-
ing nitrogen nucleus, rather than rotation about the
CwN bond, is clearly demonstrated by the fact that the
proton lines are narrow (about 1 Hz) in the nitrogen-15-
containing molecules. The chemical shifts (Table 1) for
the amide protons are similar for all three compounds
and in the same general range as for most substituted
amides. The acetylenic proton chemical shift is typical
of other acetylenic compounds.
128.0
7.0
—
—
—
189.9
1.6
—
—
—
0.7
13.5
2.7
2.2
2.9
a Data were obtained using RINEPT ½pulse sequences. Numerals
refer to protons (3 ¼trans ; 2 ¼cis ; 1 ¼terminal/methyl) and letters
refer to carbons (a ¼carbonyl, etc.).
(
1997 by John Wiley & Sons, Ltd.
MAGNETIC RESONANCE IN CHEMISTRY, VOL. 35, 571È576 (1997)

5
74
T. D. FERRIS, P. T. LEE AND T. C. FARRAR
Figure 3. Coupled 13C NMR spectra of propiolamide (A), formamide (B) and acetamide (C) in 3.0 M acetonitrile. Carbon chemical shifts
are referenced to internal TMS; 128 scans were taken with a relaxation delay of 15 s.
Figure 4. Proton NMR spectra of propiolamide in 3.0 M acetoni- trile. Expanded sections show the satellite lines arising from the 1H–1H,
1
H–13C and 1H–15N spin coupling interaction. Chemical shifts are referenced to internal TMS; 32 scans were taken with a relaxation delay of
s.
5
Figure 5. Proton NMR spectra of acetamide in 3.0 M acetonitrile. Expanded sections show the satellite lines arising from the 1H–1H,
H–13C and 1H–15N spin coupling interaction; 32 scans were taken with a relaxation delay of 5 s.
1
(
1997 by John Wiley & Sons, Ltd.
MAGNETIC RESONANCE IN CHEMISTRY, VOL. 35, 571È576 (1997)

SYNTHESIS OF PROPIOLAMIDE
575
Figure 6. Proton NMR spectra of formamide in 3.0 M acetonitrile. Expanded sections show the satellite lines arising from the 1H–1H,
H–13C and 1H–15N spin coupling interaction; 32 scans were taken with a relaxation delay of 5 s.
1
Figure 4 shows the proton spectrum for propiolamide
is a very weak and DMSO is a very strong hydrogen
with expanded sections for the amide protons and for
the terminal acetylene proton. Superimposed on the
sides of the broad amide proton peaks are doublets of
doublets which arise from the 0.37% of the molecules
containing nitrogen-15. The doublet of doublets on the
broad low-frequency peak (the cis-amide proton) arises
bonding solvent. One might therefore have expected to
see substantial solvent-dependent changes in the chemi-
cal shifts and/or spin coupling constants of the amide
protons. There is almost no solvent change in the amide
proton of acetamide which is cis to the oxygen. There is
a shift of about 0.7 ppm for the proton which is trans to
the oxygen. This is what is to be expected on the basis
of recent experimental and theoretical work on chemi-
cal shifts in amides.4
from the interaction with the nitrogen-15 (J
\
2
NH
Jcis \ 89.2 Hz) and with the trans-amide proton
NH
(
J
\ 2.2 Hz). A similar doublet of doublets is seen
3
2
H H
on the high-frequency proton (the trans-amide proton)
peak from which we obtain J
There is a substantial change (0.5È0.7 Hz) in the
geminal protonÈproton coupling of the propiolamide
compared with formamide and acetamide. The other
spin coupling constants change relatively little. Simi-
larly, there are substantial changes in the carbonyl
carbon chemical shifts of propiolamide, acetamide and
formamide, but relatively little change for the other
nuclei. A theoretical natural bond order analysis (NBO)
is being carried out for these three molecules and will be
reported later.
Propiolamide is easily synthesized in high yield and
puriÐed by the method described here. All of the NMR
spectra indicate that the product is of high purity. The
carbon chemical shift data indicate that the extended
conjugation in propiolamide leads to a signiÐcant
shielding of the carbonyl carbon. The high-resolution
satellite Ðne structure of the proton spectra of all three
compounds is well resolved and provides accurate data
for proton spin coupling to all of the NMR-active
nuclei.
\ Jtrans \ 91.2 Hz. The
3
NH
NH
Ðne structure on the acetylenic proton gives information
about the various carbonÈhydrogen coupling constants
with J \ 256.0, J
\ 49.2 and J
\ 5.6 Hz.
CH
CCH
CCCH
Figure 5 shows the proton spectrum of acetamide.
Here, in a similar fashion, the Ðne structure on the low-
frequency amide peak is a doublet of quartets with
J
J
\ Jcis \ 87.9, J
\ Jtrans \ 89.5, J \ 2.9 and
2
3
NH
NH
NH
NH
HH
\ 0.7 Hz. The Ðne structure on the high-
1
3
H CNH
frequency (the cis-amide) proton peak is a doublet of
doublets, since the coupling of the cis-amide proton to
the methyl protons is too small to be resolved.
Figure 6 shows the spectrum of formamide. For both
amide protons, the Ðne structure is a doublet of doub-
lets with J
\ 90.3, J
\ 87.9, J
\ 2.7, J
\
3
2
2 3
1 2
NH
NH
\ 13.5 Hz. These results are summarized
3
H H
H H
1
.6 and J
1
H H
in Table 2.
CONCLUSION
The data for the scalar couplings and the chemical shifts
which we obtained here are in amazingly good agree-
ment with the earlier results for the spin coupling con-
stants in N-methylacetamide reported by DeMarco and
Acknowledgements
We thank the National Science Foundation, Grant No. CHE-
9
500735, for support of this research. The 500 and 300 MHz NMR
Llina

s,15 especially considering the fact that DeMarco
spectrometers used for part of this research were purchased with the
aid of NSF Grant No. CHE-8306121 and NIH Grant No. NIH 1 S10
RR-2388-01. We thank Mr Mark Wendt for a number of helpful dis-
cussions and comments.
and Llina

sÏs spectra were obtained as 0.6 M solutions in
dimethyl sulfoxide (DMSO) and the spectra reported
here were for 3.0 M solutions in acetonitrile. Acetonitrile
(
1997 by John Wiley & Sons, Ltd.
MAGNETIC RESONANCE IN CHEMISTRY, VOL. 35, 571È576 (1997)

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T. D. FERRIS, P. T. LEE AND T. C. FARRAR
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