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Molecules 2006, 11(4), 279-285; doi:10.3390/11040279

Reactions of (Benzamidomethyl)triethylammonium Chloride with Some Inorganic Nucleophiles in Aqueous Media
Institute of Chemistry, Faculty of Natural Sciences & Mathematics, Sts. Cyril and Methodius University, PO Box 162, 1000 Skopje, Macedonia
Faculty of Chemistry and Mineralogy, University of Leipzig, Johannsallee 29, D-04103 Leipzig, Germany
Author to whom correspondence should be addressed.
Received: 3 March 2006 / Accepted: 9 April 2006 / Published: 10 April 2006


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.
Benzamidomethylation; inorganic nucleophiles; aqueous medium


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 (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.
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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.
Scheme 1.
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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).
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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 [5,6,7]. 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.
Scheme 2.
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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 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.
Table 1. Physicochemical data of compounds 2-5b.
CompoundYield %M.p. oCCalc./foundFTIR (KBr) / cm-1
CHNνNHaAmide IAmide IIOther
3299164515282125 and 2085 ν(N3)
324416401538absence of ν(C≡N) bond
167115452039 ν(SCN ¯ )
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.


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 substitution products, some of which, depending on their nature, subsequently hydrolyze. With soft nucleophiles anion exchange takes place.
Scheme 3.
Scheme 3.
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Table 2. NMR data for compounds 2-5b.
Table 2. NMR data for compounds 2-5b.
Comp.1H-NMR (DMSO-d6; δ in ppm)13C-NMR (DMSO-d6; δ in ppm)
2s(t), 8.87
m, 7.94-7.46
d, 4.32
4H, J 4.2
s, 8.28, 1H
166.81 C=O; 60.00 CH2; Ar: 134.25; 131.34; 128.27; 127.38
4at, 9.55
1H, J 6.0
m, 7.91-7.49
d, 4.74
2H, J 6.3
-167.35 C=O; 55.53 CH2;
Ar: 133.06; 132.14; 128.65; 127.49
4bt, 8.87
1H, J 4.9
m, 7.90-7.46
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
5at, 9.40
1H, J 7.0
m, 7.96-7.53
d, 4.74
2H, J 7.2
q, 3.23, 6H,
3 × CH2, J 7.2
t, 1.27, 9H
3 × CH3, J 7.1
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
5bt, 9.38
1H, J 7.0
m, 7.96-7.52
d, 4.74
2H, J 7.0
q, 3.23, 6H,
3 × CH2, J 7.0
t, 1.26, 9H
3 × CH3, J 7.0
168.61 C=O; 59.69 N-CH2-N;
50.08 N-CH2-C; 7.39 CH3
Ar: 132.62; 132.52; 128.42; 128.14

Experimental Section


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.


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.

References and Notes

  1. Jones, R. A. Quaternary Ammonium Salts: Their Use in Phase-Transfer Catalysed Reactions; Academic Press: San Diego, 2001; pp. 1–8. [Google Scholar]
  2. Popovski, E.; Klisarova, L.; Vikic-Topic, D. Simple Method for Benzamidomethylation of Phenols in Water Solution. Synth. Commun. 1999, 29, 3451–3458. [Google Scholar] [CrossRef]
  3. Popovski, E.; Klisarova, L.; Vikic-Topic, D. Benzamidomethylation with (Benzamidomethyl)-triethylammonium Chloride. 2. A Simple Method for Benzamidomethylation of Thiols, Amines and Carboxylic acids. Molecules 2000, 5, 927–936. [Google Scholar]
  4. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identification of Organic Compounds, 5th ed.; Wiley: New York, 1991; p. 126. [Google Scholar]
  5. Klages, A. Ueber Das Methylenamino-acetonitril. Chem Ber 1903, 36, 1506–1512. [Google Scholar] [CrossRef]
  6. Martin, A. R.; Ketcham, R. Heterocyclic Ring-Closure Reactions. I. A Novel Oxazole Synthesis from S,S'-Dialkyl or Diaryl Dithiooxaldiimidates and Aromatic Aldehydes. J. Org. Chem. 1966, 31, 3612–3615. [Google Scholar]
  7. Sun, Y. Z.; Martell, A. E.; Welch, M. J. Synthesis of a New Diaminodithiol Bifunctional Chelator for Radiolabeling Biomolecules with Indium(III). Tetrahedron 2000, 56, 5093–5103. [Google Scholar] [CrossRef]
  8. Popovski, E. unpublished results.
  9. Loos, R.; Kobayashi, S.; Mayr, H. Ambident Reactivity of the Thiocyanate Anion Revisited: Can the Product Ratio be Explained by the Hard Soft Acid Base Principle? J. Am. Chem. Soc. 2003, 125, 14126–14132. [Google Scholar] [CrossRef]
  10. The IR band (KBr disk) of the SCN anion of tetrabutyilammonium thiocyanate is at 2059 cm–1 which is comparable to 2039 cm-1 of 5b. The 13C-NMR chemical shift (CDCl3) of the SCN anion of tetrabutylammonium thiocyanate is at 129.73 ppm vs. 130.94 ppm for 5b. The spectral data for tetrabutylammonium thiocyanate were obtained from: SDBS Integrated Spectral Data Base System for Organic Compounds., National Institute of Advanced Industrial Science and Technology, 2/22/2006.
  11. Ritchie, C. D. Cation Anion Combination Reactions .23. Solvent Effects on Rates and Equilibria of Reactions. J. Am. Chem. Soc. 1983, 105, 3573–3578. [Google Scholar]
  12. Pearson, R. G.; Songstad, J. Application of Principle of Hard and Soft Acids and Bases to Organic Chemistry. J. Am. Chem. Soc. 1967, 89, 1827–1836. [Google Scholar] [CrossRef]
  13. Ohtani, N.; Murakawa, S.; Watanabe, K.; Tsuchimoto, D.; Sato, D. Thiocyanation of Alkyl Halides with Alkyl Thiocyanates in the Presence of Quaternary Phosphonium Halides. J. Chem. Soc.-Perkin Trans. 2 2000, 1851–1856. [Google Scholar]
  14. Noller, C. R. Chemistry of Organic Compounds, 2nd ed.; Saunders: Philadelphia, 1957; pp. 320–321. [Google Scholar]
  15. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed.; Wiley: New York, 1992; pp. 429, 886. [Google Scholar]
  • Sample Availability: Samples of the compounds are available from authors.
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