Saccharin Reaction with Cyanide

Letters in Organic Chemistry, 2011, 8, 315-319

315

Saccharin Reaction with Cyanide Gabi Drochioiu*,a, Calin Deleanub, Elena Rusub and Ionel Mangalagiua a

Faculty of Chemistry, Al. I. Cuza University of Iasi, 11 Carol I, Iasi-700506, Romania

b

Petru Poni Institute of Macromolecular Chemistry, Iasi, 41 A Grigore Ghica Voda Alee, Iasi- 700487, Romania Received October 16, 2010: Revised March 31, 2011: Accepted March 31, 2011

Abstract: A novel reaction between saccharin (1,2-benzisothiazole-3(2H)-one-1,1-dioxide, o-sulfobenzimide, or obenzoic sulfimide) and cyanide to afford an unexpected compound, 2-(cyanosulfonyl)benzamide, has been described. Cyanide ion proved to attack the sulfonyl group of o-sulfobenzimide over 170 ºC to open the ring and to add to form a new C-S bond. This is an unexpected reaction, as the leading theory of chemical reaction predicts cyanide to be too weak to react with sulfonyl groups. The spectroscopic data and the elemental analyses confirm the structure of the resulted compound and support the mechanism of reaction. The reaction pathway is important from the theoretical point of view, however it might serve both preparative and analytical purposes.

Keywords: Saccharin, cyanide, 2-(cyanosulfonyl)benzamide, reaction mechanism. INTRODUCTION Driven by remarkable advances in the understanding of structure and reaction mechanisms, organic synthesis is increasingly directed to producing newly designed and bioinspired molecules [1]. This is also the case of the chemistry of saccharin derivatives and their use in medical and agrochemical fields [2-4]. Thus, saccharin moiety has been identified in various classes of biologically active compounds, nevertheless, saccharin and sodium saccharin used as sweeter are excreted unchanged in the urine without accumulation [5]. Sodium saccharin is not carcinogenic for the urinary bladder in several onegeneration studies in male and female rats or in mice. Calcium saccharin did not produce tumors. Imide group in the saccharin molecule is an interesting functionality, due to its wide presence in the natural and pharmacologically products [6-10]. However, no direct reaction between cyanide and o-sulfobenzimide or its N-substitutes was described in the literature. Besides, a nucleophylic attack of cyanide ion to SO2 or C=O groups seems to be improbable at ordinary temperature. So far, a facile synthesis of sulfonyl cyanides using p-toluenesulfonyl chloride and sodium cyanide at 70 °C was investigated by Pews and Corson [11]. However, this is not the case of saccharin and the reaction produces cyanogen, thiocyanatobenzene, and other by-products. Previously, we found an interesting reaction between cyanide and ninhydrin (1H-indene-1,2,3-trione) at room temperature and proved a nucleophylic attack of cyanide toward a C=O group to form an instable intermediate [1217]. The intermediate, 2,3-dihydro-1-hydroxy-2,3-dioxo1H-indene-1-carbonitrile, once formed gave a stable compound, 1,2,3-trihydroxy-2H-indene-2-carbonitrile. A reaction between C=O group in amides and cyanide ion to *Address correspondence to this author at the Faculty of Chemistry, Al. I. Cuza University of Iasi, 11 Carol I, Iasi-700506, Romania; Tel: +40232201279; Fax: +40232201313; E-mail: [email protected]

1570-1786/11 $58.00+.00

afford stable cyanohydrines is not possible at the ordinary temperature because the amino group in amides hinders this reaction due to electron shifting. However, it is well known that cyanide easily reacts with aldehydes and ketones at the C = O group, even if they are weak nucleophylic agents [18, 19]. Consequently, we considered that it is possible to react imide C=O or SO2 groups with cyanide to produce reaction intermediates which result in stable final compounds. Upon heating a mixture of saccharin with cyanide over 100 °C, under nitrogen, we found an unexpected reaction pathway, in which S-N bound was attacked. Therefore, we refer here to the formation of stable and separable cyanide derivatives starting from saccharin. One of them, 2-(cyanosulfonyl)benzamide, has been confirmed by their preparation in crystalline form. Other reaction products have also been isolated and characterized spectroscopically and by elemental analyses. The experimental details and possible mechanisms of reaction are discussed below in connection with the electron density of saccharin, which offers a plausible explanation for the observed reaction pathway. RESULTS We hypothesized that the adduct which results in the reaction between cyanide and saccharin derivatives, which undergoes a thermal degradation to produce various compounds (Fig. (1)). The reaction between cyanide and o-benzoic sulfimide resulted in the formation of several compounds, of which 2(cyanosulfonyl)benzamide (1) was the most important because it confirmed our hypothesis. To explain the formation of 2(cyanosulfonyl)benzamide, we supposed that CN group attacked nucleophylically one of the S = O groups to open the cycle. The reaction mechanism for the formation of 2(cyanosulfonyl)benzamide involves several steps: nucleophilic attack of cyanide ion on sulfur atom, and finally complex processes of oxidative-hydrolysis rearrangements in the acidic media. Whereas all carbon atoms in the benzene ring are

© 2011 Bentham Science Publishers Ltd.

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Drochioiu et al.

O

O N

R

R

+ KCN N

S O

O

S O

O

CN O-K+

N-Alkyl-o-benzoic sulfimide

R

+ H2O - KOH

S

N H CN

O O N-Alkyl-2-(cyanosulfonyl)benzamide

Fig. (1). Cyanide reaction with o-benzoic sulfimide.

negatively charged (Fig. (2)), the heteroatoms in the lateral ring have the charge in the range from – 0.792 (N8 atom) to 1.404 au (S7 sulfur atom) as revealed by Singh et al. [20]. The C and S atoms have comparable electronegativities. Both carbon-oxygen and sulfur-oxygen bonds are highly polarized because of the difference in electronegativity between oxygen (3.44), carbon (2.55) and sulfur (2.58), respectively. Oxygen is far more electronegative than carbon and sulfur and so has a strong tendency to pull electrons in a carbon-oxygen bond and sulfur-oxygen towards itself. Electrostatic charges (Fig. (2)) on each of the atoms in saccharin determined from an ab initio calculation [20] reveal that the C and S atoms associated with the five member ring are all positively charged with the bulk of the negative charge residing on the two oxygen atoms attached to the sulfur atom. These electron densities facilitate attack by a nucleophile. The nucleophilic C in the cyanide adds to the electrophilic S in the polar sulfonimide group and a partial withdrawal of the electron density from the S(O)O exposes to attack by negatively charged nucleophile occurs. The relatively low yield of (1) was explained by thermal degradation of the intermediate compounds with the formation of a polymeric mass as well as some by products such as 2-sulfobenzoic acid and 2-carbamoylbenzenesulfonic acid. 2-(Cyanosulfonyl)benzamide (yield 16 %, m.p. over 300 °C, black-brown crystals) proved to H 13 H 14 C

C 3

2 C

O 12 C9

4 C C 7 N 1 S 8 H 17 H 5 C6 15 O O11 H 16 10 Atom

Charge (au)

C2

-0.038

S7

1.404

N8

-0.792

C9

0.725

O10

-0.623

O11

-0.624

O12

-0.544

H17

0.452

Fig. (2). Electrostatic charges on the saccharin atoms may explain the reaction mechanism.

be soluble in dimethyl acetamide, cold NaOH, less soluble in K2CO3 solutions, insoluble in cold and hot toluene, chloroform, petroleum ether, acetone, glacial acetic acid. The structures of 2-(cyanosulfonyl)benzamide was proven by elemental and spectral analysis (IR, 1H NMR, 13C NMR, COSY) and mass spectrometry. Elemental (C, H, and N) analyses were compatible with the proposed structure for 2-(cyanosulfonyl)benzamide. The molecular weight of 210 Da was determined by mass spectrometry. The fragmentation schema was also in the best agreement with the proposed structure for 2(cyanosulfonyl)benzamide. The main fragments were found to be at 210 (molecular fragment), 209, 178, 150, 129, 120, 105, 92, and 77 units, respectively (Scheme 1). All signals were assigned to the expected fragments and the molecular weight of 2-(cyanosulfonyl)benzamide (MW 210) was confirmed. IR spectra were concordant with the established structure of 2-(cyanosulfonyl)benzamide. The peak at max = 1733 cm-1 was assigned to C=O bond. The corresponding C=O group in o-sulfobenzimide has a characteristic max at 1725 cm-1. In the IR spectrum of this compound, a doublet in the range from 2200 cm&1 to 2240 cm&1 appeared, which is related to the asymmetric stretching vibration of -C!N bond. This has been explained on the basis of Fermi resonance interaction of the fundamentals with the overtones or combination tones of certain low lying frequencies. There is also a significant dipole moment associated with the -C!N bond. The symmetric stretching frequencies appear in the region 1340-1180 cm&1 and the bending frequency is observed around 680 cm&1 for the -C!N group. The product displayed the carbonyl group stretching vibration associated with the bands at 1733 cm&1 and 1650 cm&1. The wavenumbers of the sulphonyl stretching, &1 for the SO2 mode are observed at 1340 and 1160 cm asymmetric and symmetric modes, respectively. The corresponding wavenumbers appear in the spectrum of free saccharin at 1360 and 1180 cm&1 and these shifts seem to be probably due to the charge redistribution. On the other hand, the sulphonyl stretching vibrations are observed at about 1260 and 1150 cm&1 for asSO2 and sSO2, respectively. The band at 3215 cm&1 due to the N-H vibration is not present in the spectrum of 2-(cyanosulfonyl)benzamide. In the IR spectrum of 1 the N-H vibration (from saccharin) at 3215 cm&1 and NH2 stretching vibration (from SO2NH2 group) at 3080 cm&1 were not present. CN group interaction with amide NH2 group may explain the splitting of IR signal at 2220 cm-1 (Fig. (3)). NMR spectra showed that a hydrogen bond between an oxygen atom in SO2 CN group and a hydrogen atom in amide group could stabilize the structure of 1. 1

The four aromatic protons gave characteristic signals in the H NMR spectrum in the range from " 7.889 to 8.121, with

Saccharin Reaction with Cyanide

Letters in Organic Chemistry, 2011, Vol. 8, No. 5

O

O O

O NH2 m/e 120 - CO

O O m/e 209 O

O NH2

NH2

m/e 92

N+ S O O m/e 209

NH+

S

O

NH2

NH

N

NH2+ m/e 120

317

NH+

CN CN S S O O O O m/e 210 m/e 209 2-(Cyanosulfonyl)benzamide - HNO

- NC-SO2 m/e 120

O N

NH2 m/e 92

CN S O m/e 150

S O m/e 150

CN

S O m/e 178

O N

- HCN

C4H3 m/e 51

m/e 92 m/e 65

- CO m/e 77

m/e 105

Scheme 1. Proposed fragmentation mechanism of 2-(cyanosulfonyl)benzamide

Fig. (3).

two coupling constants: J = 7.2 Hz and J = 7.6 Hz, respectively. Proton 2D COSY spectra of 2(cyanosulfonyl)benzamide in CDCl3 showed the signals of protons which are two or three bonds apart. Therefore, the cross signals between H1 and H2 protons and between H3 and H4 protons were observed. Thus, the proton at 8.11 ppm is next to the proton at 7.91 ppm. The two amide protons appeared at different chemical shift values. One of protons (Ha) generated a signal at " 7.835 ppm. The other one (Hb) may form a hydrogen bond with an oxygen atom in SO2 group and appeared therefore at " 7.965 ppm in the same area in which the peak for H4 was observed. H-C inverse long range shift correlation experiments confirmed thoroughly the chemical structure of 2-(cyanosulfonyl) benzamide. The heteronuclear couplings in the H,C-COSY spectrum showed the protons directly bound to carbon atoms. Thus, H1 which appeared at " 8.11 ppm was found

to be bound to the aromatic carbon C1 associated with a signal at " 120.87 in the 13C NMR spectrum. EXPERIMENTAL SECTION Flash column chromatography was performed with Merck silica gel (EM-9385-9, 230–400 mesh). Thin layer chromatography was performed on silica gel 60F254 plates (EM-5715-7, Merck). All chemicals were purchased from Merck (Darmstadt, Germany). Infrared spectra were measured on a JASCO FT/IR66oPlus Fourier spectrometer running a Spectra Manager Program. 1H NMR and 13C NMR spectra were recorded in DMSO and CDCl3 on a Bruker Avance DRX 400 (SWH 6410.256 Hz; Parameter Set: OH1-BBI (temp) XW3.5PL6) spectrometer. The mass spectra were acquired with a Vestec-2 instrument. Melting points were recorded on a Griffin apparatus and are uncorrected. Microanalytical data

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Letters in Organic Chemistry, 2011, Vol. 8, No. 5

were obtained with a Perkin Elmer 2410 Series II CHNS Analyzer. An equimolecular mixture of 650 mg of osulfobenzimide (saccharin) and 200 mg of potassium cyanide (poison!) was heated under nitrogen in a Kjeldahl flask at 130 °C for 1 hour. Gradually, the mixture has melted and became pale brown in color. Afterwards, upon increasing temperature up to 165-170 °C, the content of the flask became dark brown in color. After cooling, 5 ml of distilled water was added with stirring to dissolve the content of the Kjeldahl flask. A black-colored residue was found on the bottom of the flask, which could be a polymeric mass. The flask content was then centrifuged. The resulted solution was poured into a 100-mL Berzelius flask and an excess of 1M acetic acid solution added to neutralize it. No evolution of hydrocyanic acid was noticed. Nevertheless, the necessary precautions should be taken to prevent accidents. Flash chromatography (SiO2, hexanes/EtOAc) afforded 2-(cyanosulfonyl)benzamide as a black-brown crystals. H 13 H 14 C

4

C H 155

C 3

2 C

Drochioiu et al.

In conclusion, we have described a novel reaction pathway to form a C-S bond as well as the synthesis of a new compound, 2-(cyanosulfonyl)benzamide, starting from cyanide and o-sulfobenzimide. This may be a general, efficient and straightforward method for the preparation of N-alkyl derivatives of 2-(cyanosulfonyl)benzamide. ACKNOWLEDGEMENT The authors are grateful for mass spectra to Dr. Karin Popa. Financial support by CNMP Bucharest (Partnership Project PNII PC-2746, Contract 31-017/2007) is gratefully acknowledged. SUPPLEMENTARY MATERIAL Supplementary material is available on the publishers Web site along with the published article. REFERENCES

O12

[1]

C

[2]

Ha N 8 H b C 7 C6 1 S O 11 NC O 10 H 16

Fig. (4). The structure of 2-(cyanosulfonyl)benzamide may explain the shape of CN group in IR spectrum.

2-(Cyanosulfonyl)benzamide (1), also named 2carbamoylbenzenesulfonyl cyanide was obtained as blackbrown crystals, mp over 300 °C. IR: 3460, 3400 (N-H stretch), 3110, 3000 (C–H), 1650-1610 (NH) 1475, 1125 (C-N), 2240, 2210, and 680 (CN), 1733 (C=O amide), 1340, 1160 (SO2). 1H NMR (DMSO, 400 MHz): " 8.11 (d, J = 7.2 Hz, 1H1), 7.97 (m, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H4), 7.94 (m, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H2); 7.90 (d, J2 = 7.6 Hz, 1H3); 7.84 (s, 1Ha, NH2); 7.96 (s, 1Hb, NH2); 13C (CDCl3, 100 MHz) " 161.64 (C=O), 140.01, (C5), 134.94 (C2), 134.30 (C3), 128.36 (C6), 125.49 (CN), 124.5 (C4), 120.87 (C1) (Fig. (4)). Anal. Calcd for C8H6N2O3S (210.01): C, 45.71; H, 2.88; N, 13.33; S, 15.25. Found: C, 45.76; H, 2.91; N, 13.82; S, 15.16. Safely For safety reasons all of the experiments should be performed in an efficient hood in order to avoid contact with vapors. Cyanide is poisonous and must be treated with caution. To our knowledge, this is the first example of a cyanide reaction with o-sulfobenzimide. Though the yield was rather low under high temperature conditions, our results are encouraging. In addition to nitrogen protection, utilization of more elaborate methods of synthesis, such as that under microwave, may increase the yield and afford new compounds containing the C-N group.

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