Reactions of (benzamidomethyl)triethylammonium chloride with some inorganic nucleophiles in aqueous media

Article abstract of DOI:10.3390/11040279

A variety of benzamidomethyl derivatives were prepared in water under alkaline conditions (pH>9) via reaction of (benzamidomethyl)triethylammonium chloride (1) with different inorganic nucleophiles. Reaction of 1 with hydroxylamine did not give the expect

Full text of DOI:10.3390/11040279

Molecules 2006, 11, 279-285
molecules
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Full Paper
Reactions of (Benzamidomethyl)triethylammonium Chloride
with Some Inorganic Nucleophiles in Aqueous Media
Emil Popovski 1,*, Jane Bogdanov 1, Metodija Najdoski 1 and Evamarie Hey-Hawkins 2
1
Institute of Chemistry, Faculty of Natural Sciences & Mathematics, Sts. Cyril and Methodius
University, PO Box 162, 1000 Skopje, Macedonia; E-mails: jbb15@psu.edu,
metonajd@iunona.pmf.ukim.edu.mk
2
Faculty of Chemistry and Mineralogy, University of Leipzig, Johannsallee 29, D-04103 Leipzig,
Germany; E-mail: hey@rz.uni-leipzig.de
* Author to whom correspondence should be addressed; E-Mail: emilp@iunona.pmf.ukim.edu.mk
Received: 3 March 2006 / Accepted: 9 April 2006 / Published: 10 April 2006
Abstract: A variety of benzamidomethyl derivatives were prepared in water under
alkaline conditions (pH>9) via reaction of (benzamidomethyl)triethylammonium chloride
(1) with different inorganic nucleophiles. Reaction of 1 with hydroxylamine did not give
the expected mono(benzamidomethyl)-hydroxylamine (3) but rather gave N,N-
di(benzamidomethyl)hydroxylamine (2). Reactions of 1 with sodium azide and potassium
cyanide gave benzamidomethyl azide (4a) and benzamidomethyl cyanide (4b)
respectively. Potassium thiocyanate and sodium iodide reacted with 1, and the anion-
exchanged products (benzamidomethyl)triethylammonium isothiocyanate (5a) and
(benzamidomethyl)triethylammonium iodide (5b) were thus obtained. Cyanamide and
potassium cyanate reacted readily with 1 and both gave the same mixture of
di(benzamidomethyl)amine (7) and tri(benzamidomethyl)amine (8). All the reactions
occurred smoothly, under mild conditions, to give the products in moderate to high yields.
Keywords: Benzamidomethylation, inorganic nucleophiles, aqueous medium
Introduction
Quaternary ammonium salts have been used extensively in preparative organic chemistry. Their
properties have been thoroughly studied and they have been found to be superb phase-transfer
catalysts in terms of stability, toxicity and cost [1]. Our previous research has shown that

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(benzamidomethyl)-triethylammonium chloride (1) is an excellent benzamidomethylating agent, both
in non-aqueous and in aqueous media (pH > 9) [2,3]. We were especially interested in
benzamidomethylation of phenols, thiols, amines and dithiocarbamates in aqueous media using 1,
because of the mild reaction conditions, high yields and simple isolation of products [3]. In the course
of this work, we have also carried out reactions of 1 with ammonia obtaining a mixture of
di(benzamidomethyl)amine and tri(benzamido-methyl)amine [3]. Our intention was to further explore
the reactions of 1 in aqueous media with other inorganic nucleophilic compounds.
O
-
Cl
C2H5
C
+
N
H
CH2
N
C2H5
C2H5
1
Results and Discussion
The reactions of 1 with aqueous solutions of hydroxylamine always gave N,N-
di(benzamidomethyl)-hydroxylamine (2) as a colorless precipitate, regardless of the mole ratio of
reactants and the rate and mode of addition (normal vs. inverse, Scheme 1).
Mono(benzamidomethyl)hydroxylamine (3) was not obtained even when a two or three-fold excess of
hydroxylamine was used. This phenomenon is comparable to our previous finding that primary
amines give dibenzamidomethyl derivatives with 1 [3].
Scheme 1.
OH
N
O
O
NH2OH
1
N
H
N
H
H2O, TEA
2
The probable explanation of this phenomenon is that 3 is indeed formed but is rapidly
benzamidomethylated by 1. Another plausible explanation is that 3, under the reaction conditions,
undergoes self-alkylation to give the observed product, N,N-di(benzamidomethyl)hydroxylamine (2)
(along with hydroxylamine).
OH
N
O
H
N
H
3

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281
Benzamidomethyl azide (4a) and benzamidomethyl cyanide (4b) were obtained in the reactions of
1 with concentrated aqueous solutions of sodium azide and potassium cyanide, respectively (Scheme
2). It is interesting to note that an unfamiliar phenomenon was observed in the infrared spectra of
compound 4b. Thus, whereas the infrared spectra of 4a showed two intense bands at 2125 cm-1 and
2085 cm-1 characteristic of the azide group [4], in the infrared spectra of 4b, however, the C≡N band
(~2100 cm-1) was not observed [4]. The structure of 4b was confirmed based on other spectroscopic
methods (1H-NMR, 13C-NMR), as well as elemental analysis and comparison of its melting point [5-7].
In our previous work devoted to this peculiar phenomenon, we have interpreted such behavior as a
purely molecular (not a solid state) effect. Such experimental findings were also supported by our
preliminary ab initio studies of several molecular systems, which indicated rather small dipole moment
changes in the course of excitation of the CN vibrational mode. The absence of C≡N band, has been
further confirmed by preparation of series of related derivatives and recording their IR spectra. Both
experimental and theoretical data suggest that under the measurement conditions the C≡N band will
not be observed [8].
Scheme 2.
-
Et
Y
-
-
Z
+
Y
BAM
N
Et
BAM
Z
1
Et
4
5
PhCONHCH2 = BAM
N3
4a) Z =
4b) Z =
5a)Y = SCN
C
N
I
5b) Y =
Attempts to synthesize benzamidomethyl isothiocyanate (BAM-NCS) and N-(iodomethyl)-
benzamide (BAM-I) using the reaction of 1 with potassium thiocyanate and sodium iodide respectively
in aqueous solutions were unsuccessful. We were curious to see, in the case of the reaction of the
potassium thiocyanate (a well studied ambident nucleophile) [9] with 1, whether S or N alkylation
would take place. To our surprise, instead of the expected nucleophilic reaction, simple anion-
exchange occurred and (benzamidomethyl)triethylammonium thiocyanate (5a) and (benzamido-
methyl)triethylammonium iodide (5b) were obtained (Scheme 2). All doubts about the identity of 5a
were removed by comparison of the IR bands and 13C-NMR chemical shift of the SCN anion with the
commercially available tetrabutylammonium thiocyanate [10]. It has been established that anions are
less nucleophilic in water than in dipolar aprotic media [11]. This diminished nucleophilicity in water
and the fact that thiocyanate ion and iodide ion are soft nucleophiles (Lewis bases) [12] with affinity
for soft cations (i.e., tetralkylammonium cations) can be used to rationalize the observed results.
Additionally, it has been reported that the thiocyanate anion has a large affinity for quaternary

Molecules 2006, 11
282
ammonium cations [13]. The physicochemical data and yields for the derivatives 2-5b are given in
Table 1 and the NMR data is given in Table 2.
Table 1. Physicochemical data of compounds 2-5b.
Calc./found
H
FTIR (KBr) / cm-1
Yield
%
M.p.
oC
Compound
C
N
νNHa Amide I Amide II
Other
2
63
48
73
96
65
140-143
62
64.2
64.0
5.7
5.9
14.0
13.8
3315
3262
1639
1628
1549
1540
4a
4b
5a
5b
54.5
54.3
4.6
4.2
31.8
31.6
3299
1645
1640
1671
1678
1528
1538
1545
1523
2125 and
2085 ν(N3)
143-144b 67.5
67.7
5.0
5.3
17.5
17.3
3244
absence of
ν(C≡N) bond
127-128
61.4
61.3
7.9
8.2
14.3
14.0
3229
3180
2039
ν(SCN ¯ )
165
46.4
46.1
6.4
6.6
7.7
7.5
3207
3178
a For compound 2 νNH = (νNH and νOH)
b Ref. [5] = 144 oC; Ref. [6] = 141-143 oC: Ref. [7] = 146-148 oC
As an aside, the water solubility of the (benzamidomethyl)triethylammonium salts is dependant on
the counter-ion. For instance, the chloride 1 is the most soluble, the iodide 5b is partially soluble, and
the isothiocyanate 5a is insoluble in water at room temperature.
The reaction of cyanamide with 1 and the reaction of potassium cyanate with 1 in aqueous solution
(pH > 9) gave the same mixture of two products: di(benzamidomethyl)amine (7) and tri(benzamido-
methyl)amine (8) (Scheme 3). These products were previously prepared by a different route and fully
characterized in our laboratories [3]. Based on the known chemistry of cyanamide [14], we postulate
that di(benzamidomethyl)cyanamide (6) is formed first, and is rapidly hydrolyzed under the reaction
conditions to give 7. A portion of 7 reacts with the remaining of 1 to give 8.
It is known that reactions of electrophiles, such as alkyl halides, with cyanate anion give alkyl
isocyanates (R-NCO) almost exclusively [15]. In the case of the reaction between 1 and potassium
cyanate the benzamidomethyl isocyanate (9) is the most likely intermediate and is hydrolyzed under
the reaction conditions to the amine 10 (via the intermediacy of the N-substituted carbamic acid which
decomposes to give an amine and carbon dioxide) [15]. The primary amine 10 reacts with the rest of
the unreacted 1 to give a mixture of 7 and 8.
Conclusions
In summary, (benzamidomethyl)triethylammonium chloride (1) displays an interesting reactivity in
aqueous media (pH>9), depending on the nature of the nucleophiles. With hard nucleophiles it gives

Molecules 2006, 11
283
substitution products, some of which, depending on their nature, subsequently hydrolyze. With soft
nucleophiles anion exchange takes place.
Scheme 3.
BAM
BAM
potas sium
cyanat e
NH2CN
1
N
CN
BAM NCO
6
9
-
-
OH
H2O
OH
H2O
BAM
BAM
N
1
1
7
N
H
BAM
BAM NH2
+
BAM
BAM
7
8
10
Table 2. NMR data for compounds 2-5b.
1H-NMR (DMSO-d6; δ in ppm)
13C-NMR (DMSO-d6; δ in ppm)
Comp.
2
CONH
Aromatic
NHCH2
Other
166.81 C=O; 60.00 CH2; Ar: 134.25;
131.34; 128.27; 127.38
s(t), 8.87
2H
m, 7.94-7.46
10H
d, 4.32
4H, J 4.2
s, 8.28, 1H
OH
t, 9.55
1H, J 6.0
m, 7.91-7.49
5H
d, 4.74
2H, J 6.3
-
167.35 C=O; 55.53 CH2;
Ar: 133.06; 132.14; 128.65; 127.49
4a
4b
t, 8.87
1H, J 4.9
m, 7.90-7.46
5H
d, 4.34
2H, J 5.6
-
166.79 C=O; 117.75 C≡N; 27.85 CH2;
Ar: 132.94; 132.02; 128.59; 127.45
5a
t, 9.40
1H, J 7.0
m, 7.96-7.53
5H
d, 4.74
2H, J 7.2
q, 3.23, 6H,
3 × CH2, J 7.2
168.64 C=O; 129.73 SCN; 59.68 N-
CH2-N; 50.10 N-CH2-C; 7.36 CH3
Ar: 132.61; 132.52; 128.45; 128.32
t, 1.27, 9H
3 × CH3, J 7.1
5b
t, 9.38
1H, J 7.0
m, 7.96-7.52
5H
d, 4.74
2H, J 7.0
q, 3.23, 6H,
3 × CH2, J 7.0
168.61 C=O; 59.69 N-CH2-N;
50.08 N-CH2-C; 7.39 CH3
t, 1.26, 9H
Ar: 132.62; 132.52; 128.42; 128.14
3 × CH3, J 7.0

Molecules 2006, 11
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Acknowledgements
We are grateful to Deutscher Akademischer Austausch Dienst (DAAD) for financial support. We
also appreciate the technical support and hospitality from the Faculty of Chemistry and Mineralogy at
the University of Leipzig.
Experimental Section
General
Melting points were determined on a Reichert heating plate and were uncorrected. C,H elemental
analysis was carried out with Coleman Model 33. N elemental analysis was carried out by the Dümas
method. NMR spectra were recorded on a Bruker 400 MHz instrument using DMSO-d6 as solvent and
tetramethylsilane as internal standard. Infrared spectra (KBr pellets) were measured on a Perkin-Elmer
System 2000 FT IR. All the reagents and solvents were obtained from commercial sources and were
used without further purification. (Benzamidomethyl)triethylammonium chloride (1) was obtained as
described in our previous work [2].
N,N-Di(benzamidomethyl)hydroxylamine (2).
A solution of hydroxylamine hydrochloride (0.289 g; 4.16 mmol) in water (10 mL) was added to a
solution of 1 (2.690 g; 9.93 mmol) in water (30 mL). Triethylamine (0.7 mL) was added in one portion
and colourless crystals started to form after several seconds. The mixture was stirred for 1 h at room
temperature and filtered. Purification was performed by recrystallization from ethanol.
Benzamidomethyl azide (4a).
A solution of sodium azide (0.337 g; 5.20 mmol) in water (10 mL) was added to a solution of 1
(1.867 g; 6.70 mmol) in water (10 mL). Several drops of triethylamine were added (pH > 9). The
mixture was stirred at room temperature and crystals were obtained after 3 h by cooling in ice bath.
The product was filtered off and air-dried to give colorless crystals (from water).
Benzamidomethyl cyanide (4b).
A solution of potassium cyanide (0.874 g; 13.43 mmol) in water (20 mL) was added in small
portions to a solution of 1 (3.826 g; 13.43 mmol) in water (30 mL). The mixture was stired for 2-3 h at
room temperature. White lumps formed, which were broken up with a glass rod. Colourless crystals
were collected by filtration and purification was performed by dissolving the product in dioxane and
precipitating with a few drops of cold water.
(Benzamidomethyl)triethylammonium thiocyanate (5a, colorless crystals from acetone) and iodide (5b,
colorless crystals obtained by washing the precipitate with dioxane, cold water and acetone) were
synthesized as described for 4b and 4a, respectively.

Molecules 2006, 11
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Sample Availability: Samples of the compounds are available from authors.
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