Design and synthesis of N-vinylacetamide derivative with bulky group by nucleophilic substitution reaction

Article abstract of DOI:10.1016/j.molstruc.2009.11.012

Cyclohexyl, adamantyl, and triphenylmethyl groups were employed for the nucleophilic substitution reaction with N-vinylacetamide (NVA), in order to investigate the bulky substituents effects on molecular structures in N-vinyl monomers. Although normal alk

Full text of DOI:10.1016/j.molstruc.2009.11.012

Journal of Molecular Structure 964 (2010) 67–71
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Design and synthesis of N-vinylacetamide derivative with bulky group
by nucleophilic substitution reaction
Hiroharu Ajiro a,b, Chizuru Hongo a, Mitsuru Akashi a,b,
*
a Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
b The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclohexyl, adamantyl, and triphenylmethyl groups were employed for the nucleophilic substitution
reaction with N-vinylacetamide (NVA), in order to investigate the bulky substituents effects on molecular
structures in N-vinyl monomers. Although normal alkyl halides were known to produce N-substituted
NVA, alkyl halides with secondary and tertiary carbons did not occur nucleophilic substitution reaction.
On the contrary, triphenylmethyl group was introduced into b-position on NVA, accompanied with
hydrogen transfer. The refined crystal structure of b-triphenylmethyl-N-vinylacetamide revealed inter-
molecular linear hydrogen bonds and aromatic bulky triphenylmethyl group supported the structure.
Ó 2009 Elsevier B.V. All rights reserved.
Received 28 September 2009
Received in revised form 31 October 2009
Accepted 2 November 2009
Available online 10 November 2009
Keywords:
Crystal structure
Nucleophilic substitution
N-Vinylacetamide
1. Introduction
structural control [13]. Thus, it is meaningful to design and charac-
terize bulky substituents of N-vinylamides.
N-Vinylamides have been studied as vinyl monomers in which
the vinyl group is directly connected to a nitrogen atom. The un-
ique features of N-vinylamides are that they provide thermosensi-
tive polymers [1,2] and poly(vinylamine) [3,4] as a polycation, by
tuning substituents and hydrolysis. Among them, N-vinylaceta-
mide (NVA) [5,6] is one of the most investigated functional vinyl
monomers, which produces an amphiphilic and nonionic polymer.
The aforementioned chemical and physical characters were deter-
mined which functional substituent was introduced into nitrogen
atom on N-vinylamide. However, the detailed molecular structures
of N-vinylamides, such as conformations have not been discussed.
Bulky substituents in vinyl monomers play important role to
construct stereoregularities and higher order structures of poly-
mers, such as one-handed helical polymers [7]. Some of them were
applied as the stationary phase in column chromatography for
chiral separation of racemates [8], because they maintain the
conformation even in solution state, such as triphenylmethyl
methacrylate (TrMA) [9,10] and triphenylmethylmethacrylamide
(TrMAM) [11,12]. The configurations of their polymers were highly
controlled along polymer backbone (isotactic triad: mm >99%), be-
cause the bulkiness of triphenylmethyl (Tr) groups regulate the
direction of the growing reaction during polymerization. Similarly,
hydrogen bondings of amide groups could also contribute the
In this study, we compared the substituents bulkiness of
N-(4-methoxyphenyl)-N-vinylacetamide and N-(3-phenylpropyl)-
N-vinylacetamide [14], which produce vinyl polymers, to the other
bulky substituents, such as cyclohexyl group, adamantyl group,
and Tr group (Scheme 1). The single crystal structure of TrNVA
was also discussed.
2. Experimental
N-Vinylacetamide (NVA) (Showa Denko, Co. Ltd.), sodium
hydride 60% in oil (Wako Co. Ltd.), and triphenylmethylchloride
(Tokyo Chemical, Co. Ltd.) were purchased and used without fur-
ther purification. Tetrahydrofuran (THF) (Kanto Kagaku, Co. Ltd.)
and dimethylformaide (DMF) (Aldrich, Co. Ltd.) were used after
dehydrated with molecular sieves 4A.
The syntheses of N-vinylacetamide derivatives were shown in
Scheme 1. Typical procedure is described for b-TrNVA. In round
bottom glass flask attached three-way cock, sodium hydride
(336 mg, 8.4 mmol) was placed. Under nitrogen atmosphere, it
was washed three times by dry THF. After cooling down to 0 °C,
0.60 g of NVA in DMF (0.2 g/mL), which was dehydrated by molec-
ular sieve 4A, was slowly added. Triphenylmethylchloride was
introduced into the solution with slight heat generation. Then,
temperature increased to 45 °C to keep stirring for 24 h. The reac-
tion was terminated by several drops of water, and washed by
10 mL of ethyl acetate for three times with NaClaq. The organic
layer was combined to dry with MgSO4 overnight. The residue
* Corresponding author. Address: Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871,
Japan. Tel.: +81 6 6879 7356; fax: +81 6 6879 7359.
E-mail address: akashi@chem.eng.osaka-u.ac.jp (M. Akashi).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.11.012

68
H. Ajiro et al. / Journal of Molecular Structure 964 (2010) 67–71
Scheme 1. Nucleophilic substitution reaction with NVA.
was chromatographed on a column of silica gel with hexane–ethyl
acetate (90:10–50:50, v/v) to give the fractions containing b-TrNVA
(Rf = 0.64, hexane:ethyl acetate = 1:1). The fractions were collected
and evaporated under reduced pressure to give b-TrNVA (245 mg,
11%): 1H NMR (CD3CN, r.t.) d 1.89 (s, 3H, CH3AC@O), 6.26
(s, 1H, ACH@CHA), 6.28 (s, 1H, ACH@CHA), 7.08–7.11(m, 6H, aro-
having approximate dimensions of 0.1 Â 0.1 Â 0.1 mm was
mounted on a glass fiber. All measurements were made on a Riga-
ku RAXIS-RAPID Imaging Plate diffractometer with graphite mono-
chromated MoKa radiation. Cell constants and an orientation
matrix for data collection corresponded to a primitive orthorhom-
bic cell with a = 8.7612 (4), b = 22.7026 (8), c = 9.4513 (3) Å, Z = 4,
Dcalcd = 1.157 g cmÀ1. Based on the systematic absences of: 0kl,
k + l = 2n; h0l, h = 2n, packing considerations, a statistical analysis
of intensity distribution, and the successful solution and refine-
ment of the structure, the space group was determined to be Pna21.
The data were collected at a temperature 296 K to a maximum
2h value of 55.0°. Data were processed by the PROCESS-AUTO pro-
gram package. Of the 30149 reflections which were collected, 2287
were unique (Rint = 0.025). An absorption correction was not
applied. The data were corrected for Lorentz and polarization
effects. All calculations were performed using the teXsan crystallo-
graphic software package of Molecular Structure Corporation.
(1985 and 1999). The structures were all solved by direct methods
SIR92 [15] and expanded using Fourier techniques DIRDIF94. The
matic), 7.22–7.33 (m, 9H, aromatic), 8.31 (br, 1H, NAH); IR (cmÀ1
)
1646, 1550, 1528, 1488, 1368, 1291, 698; MS (FAB) m/z = (M+H)
calcd for C23H21NO 328.17, found 328.2. Elemental analysis was
calcd C: 84.37, H: 6.46, N: 4.28, found C: 83.94, H: 6.37, N: 4.21.
Crystallization was achieved with ethyl acetate evaporating
slowly over weeks. Transparent cube crystal was obtained after
washed with ethyl acetate. Details of data, data collection and
structure solution and refinement are available (Table S1 in Sup-
plementary Material). A colorless chunk crystal of C23H21ON
Table 1
Yields of NVA derivatives.a
RAX
N-Isomer (%)
b-Isomer (%)
1 [14]
2 [14]
3
4
5
85
98
0
0
0
0
0
0
0
11
a
Isolated yields.
Fig. 1. IR spectrum of b-TrNVA.
Fig. 2. Molecular structure of b-TrNVA (50% probability).

H. Ajiro et al. / Journal of Molecular Structure 964 (2010) 67–71
69
Table 2
Table 3
Selected torsion angles.
Hydrogen-bonding geometry (Å, °).
Angle (°)
DAHÁ Á ÁA
DAH
HÁ Á ÁA
1.87
1.95
DÁ Á ÁA
2.7931
2.826
DAHÁ Á ÁA
177
165
N
C20
O
C21
C21
C22
N
C20
N
N
C19
C22
C21
C23
172.9 (2)
172.5 (2)
À2.9 (3)
178.4 (2)
a
-NaphNVAa [18]
NAH1ÁÁÁO
0.93
0.89
b-TrNVAb
NAH21ÁÁÁO
Symmetry code:
C21
C22
a
1/2 À x, y À 1/2, z.
b
x + 1/2, Ày + 1/2, z.
non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were refined isotropically. The maximum and minimum
peaks of the final difference Fourier map corresponded to 0.23
and À0.17 eÀ/Å3, respectively. The crystallographic data for the
structures in this paper have been deposited with the Chembridge
Crystallographic Data Centre as supplementary publication No.
CCDC 715860.
Fig. 3. Crystal packing structure of b-TrNVA.

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H. Ajiro et al. / Journal of Molecular Structure 964 (2010) 67–71
various hetero atoms [22–24]. Both the bond lengths and the an-
3. Results and discussion
gles for NAH21Á Á ÁO were calculated to be typical hydrogen bond-
ing values (Table 3), but the length of the NAH21Á Á ÁO (2.826 Å)
3.1. Synthesis of N-substituted N-vinylacetamides
bond was slightly longer than the NAHÁ Á ÁO (2.793 Å) bond in
a-
NaphNVA [18], suggesting that the aforementioned C23AH18Á Á ÁO
hydrogen bond might be concerned (Fig. 3b). A 21 helix was ob-
served perpendicularly to the hydrogen bonding lines, due to the
linear hydrogen bonds, differing from usual dimer packing [19–
21]. Tr groups surrounded the hydrogen bonding lines and they
were present back to back to support the linear structures each
other. The directions of the hydrogen bonds build up alternatively,
forming aromatic regions intermolecularly. Unfortunately, vinyl
group position was far from each other, however, the single crystal
structure of b-TrNVA afforded important insights for molecular de-
sign for polymerization of N-vinyl monomers.
An electrophile is usually substituted with hydrogen on the
amide group of NVA in DMF solution when NVA is activated with
sodium hydride, such as N,N-5-oxanonamethylene-bis-N-vinylace-
tamide [16]. Therefore, N-substituted-N-NVA derivatives were ini-
tially expected. The results of the syntheses with various
alkylhalides were listed in Table 1. As the previous literature
[14], 4-methoxybenzyl chloride (1) and 3-bromopropylbenzene
(2) produced the polymerizable vinyl monomers in good yields,
however, cyclohexylchloride (3) and adamantylbromide (4) did
not react with NVA. It is suggested that the higher bulkiness of sec-
ondary carbon at halogen position prevent the substitution reac-
tion with an amide group.
Similarly, N-triphenylmethyl-N-vinylacetamide (N-TrNVA) was
not expected at first, but the substitution reaction has occurred.
The mass spectrum and elemental analysis of the purified com-
pound by silicagel chromatography were in good agreement with
the predicted structure (Fig. S1 in Supplementary material). How-
ever, the NAH bending vibration (1550 cmÀ1) remained in the IR
spectrum after the reaction (Fig. 1). These results imply that the
4. Conclusion
In conclusion, the bulky aromatic Tr group was introduced to
NVA, which influenced the substituted positions at the b-vinyl
proton of NVA, while no reactions were occurred with secondary
carbon at halogen position. The crystal structure of b-TrNVA
indicated that it crystallized in an orthorhombic system of
non-centrosymmetric space group Pna21. The phenyl rings of
the Tr groups flexibly adjusted the packing structure with a dif-
ferent plane angle among the phenyl rings. The C23AH18Á Á ÁO
hydrogen bonds are suggested to form chelating with amide
hydrogen bonds. In addition, the linear hydrogen bonds are dif-
ferent from the packing patterns that make a pair facing each
other with the amide groups, and this may be an advantage in
controlling the higher order structure when the compound is a
monomer to be polymerized. The demonstrated structural eluci-
dation of b-TrNVA in this study would contribute the molecular
design of N-vinyl monomers.
Tr group was substituted with an
a- or b-position vinyl group,
accompanied with hydrogen transfer [17].
3.2. Structural studies
Fig. 2 is the ORTEP representation of the obtained compound,
showing b-triphenylmethyl-N-vinylacetamide (b-TrNVA). In accor-
dance with the other analyses, the Tr group was substituted with a
hydrogen atom on the vinyl group of NVA. The nitrogen atom and
Tr group were placed at the trans-position of the vinyl group to
avoid intramolecular steric repulsion. The refinement (R-fac-
tor = 0.046) showed highly reliable structure.
Acknowledgment
First, angles of phenyl rings are examined, defining plane 1,
plane 2, and plane 3 with C1AC6, C7AC12, and C13AC18, respec-
tively (Table S1 in Supplementary material). Three phenyl rings
did not stand symmetrically. The angle was 75.52° between plane
1 and plane 2, although that between plane 2 and plane 3 was
99.52°.
The other end position, methyl group was also examined. The
calculated H18 position was located in the direction of adjacent
O atom. It is noteworthy that the H21, N, C22, C23, and H18 are
on the same plane, and the apparently longer distance of
C23AH18 (1.00 Å) near the other carboxyl group as compared to
the other C23AH19 (0.86 Å) and C23AH20 (0.86 Å) bonds, implies
the C23AH18Á Á ÁO hydrogen bond towards the oxygen atom of the
adjacent molecule.
It is known that the conjugation nature of carbonyl group and
unshared electron pair on nitrogen atom in amide group. Thus,
the further conjugation character with vinyl group was investi-
gated. The torsion angles of the amide were described in Table 2.
The carbonyl group and NAH are on almost the same plane, includ-
ing the adjacent vinyl group. The distance C21AN (1.397 (2) Å) was
shorter than the normal carbon–nitrogen length, whereas the CAN
of the similar crystal of 1-acetamido-1-(1-naphthyl)ethylene
This work was partly supported by the Kinki Regional Inoven-
tion Center. The authors are grateful for fruitful discussion with
Drs. N. Kanehisa, T. Kida, M. Matsusaki, T. Akagi.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2009.11.012.
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