J. Chem. Soc., Perkin Trans. 2, 1998 13 Elimination mechanisms in the anilinolysis of sulfamoyl chlorides in chloroform and acetonitrile William J. Spillane,* Francis A. McHugh and Padraig O. Burke Chemistry Department, National University of Ireland, Galway, Ireland The kinetics of the reaction of various sulfamoyl chlorides, R1R2NSO2Cl (R1 5 Ph, Me, c-C6H11, But, R2 5 H and R1 5 R2 5 Me and R1 5 R2 5 PhCH2) with anilines in chloroform and acetonitrile have been studied. Reaction is first order in both chloride and aniline and pseudo first order and second order rate constants have been determined for various chlorides and para- and meta-substituted anilines.Hammett Ò values vary from 24.76 to 22.63 for varying XC6H4NH2 depending on the halide, X. Substituents in XC6H4NHSO2Cl have only small effects on the rates. There is a ca. 106-fold rate difference between PhNHSO2Cl and (PhCH2)2NSO2Cl reacting with p-anisidine in chloroform at 25 8C. This finding, coupled with the observation of hydrogen/deuterium isotope effects, supports the operation of an elimination mechanism involving an N-sulfonylamine, [PhN]] SO2], as a transient species.In chloroform an E2-type mechanism is suggested, while in acetonitrile the activation parameters (DH, DS) may indicate a more E1cB-like E2 mechanism. For quite a few years there has been widespread interest in the kinetics and mechanism of reactions of sulfonyl halides in hydrolysis, alcoholysis (including phenolysis) and aminolysis processes (Scheme 1) leading to sulfonic acid, sulfonate ester and sulfonamide products, respectively.This area has been authoritatively reviewed.1 A number of mechanisms have been supported depending on substrate, reagents and solvents and these range from nucleophilic substitutions (SN) through addition–eliminations (SAN) to eliminations (E1, E2 and E1cB variants). Studies on the mechanism(s) of reaction of the related sulfamoyl halides R = RNH or R1R2N in 1 [reaction (1)] have not RSO2X 1 Y2 æÆ RSO2Y 1 X2 1 (1) been extensive despite their importance as intermediates in the pharmaceutical and agrochemical industries 2 and their utility in the synthesis of sulfamides.3 The hydrolysis of N,N-disubstituted sulfamoyl halides R1R2NSO2Cl has been controversial, with both SN1 and SN2 processes being favoured by different groups.4a–f The kinetics of halide exchange using a 36Cl label have been reported for N,Ndimethylsulfamoyl chloride.4g We could only find one piece of kinetic information on the reaction of a sulfamoyl halide with an amine, namely the rate of reaction of N,N-dimethylsulfamoyl chloride with piperidine in aqueous dioxane giving N,N-dimethyl-N9-piperidylsulfamide.4a This paucity of information on sulfamoyl group transfers to nitrogen centres prompted us to probe the kinetics and mechanism of such transfers using a series of anilines and a number of sulfamoyl chlorides. Results and discussion Preliminary studies using N-phenylsulfamoyl chloride and aniline at varying concentrations in chloroform showed that the UV kinetics were first order in chloride and in aniline.Second order rate constants were obtained from plots of kobs, the pseudo first-order rate constant, determined using excess amine from plots of kobs vs. [aniline]. The observed second order kinetics are compatible with the following mechanistic types: SN2, SAN, E2 and E1cB. However, the pronounced acidity of the N]H group in monosubstituted sulfamates compared to that of the C]H group in phenylmethylsulfonate esters, such as PhCH2SO2OC6H4CH3-p,5 which are well known to react via elimination mechanisms involving sulfenes,6 suggests that sulfamoyl halides will be very likely to involve elimination pathways in their decomposition.King has shown that the analogous phenylmethylsulfonyl halides, PhCH2SO2X react with aniline and other amines via an elimination path involving a sulfene.7 Williams 8 has determined the acidities of the aryl methylsulfamates, MeNHSO2OAr in 50% EtOH]H2O as being in the range 10.53 (Ar = C6H5) to 8.70 (Ar = m-NO2C6H4).We feel that the pKa of PhNHSO2Cl may be lower, ca. 7–8. This is based on comparison of this system with the sulfonamides shown. The pKa values of the latter have been determined in water.9 Comparison of the sp value for chlorine (0.227) with the s values for a series of C6H4X groups indicated that the electronic demands of Cl would probably be best matched by p-nitrophenyl, which has sp = 0.23. The pKa of PhNHSO2- C6H4NO2-p was found to be 7.50 in water and it is reasonable to consider that the pKa of phenylsulfamoyl chloride should be ca. 7–8 in H2O and ca. 9 in 50% EtOH.10 PhNHSO2Cl PhN _ SO2Cl 1 H1 PhNHSO2C6H4X PhN _ SO2C6H4X 1 H1 Evidence for an elimination mechanism The data in Table 1 support the operation of an elimination mechanism in the aminolysis of monosubstituted sulfamoyl chlorides, which are seen to react ca. 106 times more rapidly than disubstituted sulfamoyl chlorides. The latter probably react via bimolecular nucleophilic attack by the amine at the sulfur of the sulfamoyl centre. This test has also been used to show that monosulfamate esters, RNHSO2OR9 react by a Table 1 Second order rate constants for the reaction of some monoand disubstituted sulfamoyl chlorides R1R2NSO2Cl with p-anisidine in chloroform at 25 8C R1 Ph Bu Ph PhCH2 R2 HH Me PhCH2 k2/dm3 mol21 s21 10.3 13.9 1.3 × 1025 5.8 × 102614 J.Chem. Soc., Perkin Trans. 2, 1998 different mechanism to disulfamate esters R2NSO2OR9.8,11 Further support for an elimination mechanism possibly involving an N-sulfonylamine [PhN]] SO2], came from the reaction of N-phenyl sulfamoyl chloride (1, R = PhNH, X = Cl) with panisidine- ND2 (>90% D) (10 fold excess) in deuteriated chloroform. The product formed, N-phenyl-N9-p-anisylsulfamide, was fully deuteriated on both nitrogens.Had substitution taken place by amine attack at sulfur, a product containing only one deuterium would be expected, i.e. PhNHSO2NDC6H4OMe-p. Fig. 1 shows the 1H NMR spectra for the products of reaction when (a) non-deuteriated and (b) deuteriated materials were used. The possibility that the deuteriated anisidine might exchange with the starting sulfamoyl chloride or the product sulfamide seems unlikely since it is a weak base. This is supported by the fact that in our attempts to fully deuteriate panisidine, equilibration with DCl in D2O for two days at room temperature resulted in only ca. 40% incorporation of deuterium. We synthesised the fully deuteriated material by a phase transfer method instead (see Experimental section). Further support for an elimination mechanism comes from a ‘reverse’ isotope experiment in which we probed the hydrogen deuterium kinetic isotope effect by synthesising PhNDSO2Cl. Table 2 records the observed kH and kD values and the ratio kH/kD.The observation of these effects effectively rules out an (E1cB)rev mechanism and would point towards either an E2 or an (E1cB)irrev mechanism (Scheme 1). An (E1cB)rev mechanism involves a non-rate determining deprotonation equilibrium for which a kinetic isotope effect would not be expected. Substituent eVects Hammett Ò values. The effects of varying substituents both in aniline and in sulfamoyl chloride have been probed.The results for various anilines are displayed in Tables 3–5, Table 6 (runs 1–4) and Table 7 and for sulfamoyl chloride in Table 8 and Table 6 (runs 2, 5 and 6). For the seven anilines in Table 3, a Hammett r of 23.57 (correlation coefficient, r = 0.975; stand. error = 0.364) at 25 8C in chloroform was obtained, in excellent agreement with the r obtained from the more limited plot for the four anilines (runs 1–4) in Table 6 which gave a r of 23.54 (r = 0.997; stand. error = 0.181). Changing the sulfamoyl chloride from N-phenyl- or N-methyl- to p-methylphenyl- and p-chlorophenyl- gave r values of 24.76 (r = 0.99; stand.Scheme 1 ArNH2 + PhNHSO2Cl ArNH2 H Ph N SO2 .... .... d+ d– ....Cl d– k1 k2 ArNH3•Cl– + [PhN=SO2] PhNHSO2NHAr ArNH2 fast E2 + ArNH2 + PhNHSO2Cl ArNH3 + PhNSO2Cl + – k1 ArNH3Cl– + [PhN=SO2] PhNHSO2NHAr ArNH2 fast E1cB + –Cl– k2 Table 2 Kinetic isotope effects for the reaction of N-phenylsulfamoyl chloride with anilines (XC6H4NH2) in chloroform at 25 8C X p-OMe p-Me H kH a/dm3 mol21 s21 10.3 3.1 1.0 kD b/dm3 mol21 s21 3.9 3.5 0.78 0.86 0.19 kH/kD 2.6 2.9 4.0 3.6 5.3 a From Table 3.b Using PhNDSO2Cl (97% D by 1H NMR spectroscopy) and CDCl3. error = 0.171) for the six anilines in the Table reacting with N-phenylsulfamoyl chloride. Large negative r values, usually in the range of 22.0 to 22.9 for the aminolysis of sulfonyl halides are common1 and more negative values have been reported. The reaction of phenylmethanesulfonyl halides with anilines (involving an elimination pathway with a sulfene intermediate 7 and a substrate that may be viewed as the carbon analogue of phenylsulfamoyl chloride) gives r values of ca. 23.50 for variation of the aniline base with a number of ring-substituted phenylmethanesulfonyl Table 3 Second order rate constants for the reaction of N-phenylsulfamoyl chloride with anilines (XC6H4NH2) in chloroform at 25 8C X p-OMe p-OEt p-Me Hm -OMe p-Cl p-Br l/nma 305 305 294 287 287 314 298 k2/dm3 mol21 s21 10.3 7.8 3.1 1.0 0.39 0.31 0.08 log k2 1.014 0.892 0.495 0.002 20.412 20.507 21.1 sb 20.2688 20.24 20.17 0.0 0.115 0.227 0.232 pKa c 5.34 5.20 5.08 4.60 4.23 3.98 3.86 a Analytical wavelength used.b D. H. McDaniel and H. C. Brown, J. Org. Chem., 1958, 23, 458. 0.23 for p-nitrophenyl (see text) from C. Hansch and A. J. Lee, Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley-Interscience, New York, 1979, p. 128. c Refs B66, H16 (for p-OEt) and F14 (for p-CN in Table 7), D. D. Perrin, Dissociation Constants of Organic Bases in Aqueous Solution, Butterworths, London, 1965. Table 4 Pseudo-first order rate constants for the reaction of p-methylphenylsulfamoyl chloride with anilines (XC6H4NH2) in chloroform at 25 8Ca X p-OMe p-OEt p-Me Hm -OMe p-Cl kobs/s21 0.88 0.65 0.17 0.67 0.012 0.003 log kobs 20.56 20.187 20.769 21.187 21.921 22.511 s 20.268 20.24 20.17 0 0.115 0.227 a [Aniline] 6 × 1024 mol dm23, [sulfamoyl chloride] 3.75 × 1025 mol dm23.Table 5 Pseudo first order rate constants for the reaction of pchlorophenylsulfamoyl chloride with anilines (XC6H4NH2) in chloroform at 25 8Ca X p-OMe p-OEt p-Me Hm -OMe p-Cl kobs 0.71 0.52 0.41 0.12 0.07 0.04 log kobs 20.150 20.282 20.384 20.907 21.186 21.45 s 20.268 20.24 20.17 0.0 0.115 0.227 a Concentrations of reactants as in Table 4 footnote. Table 6 Pseudo-first order rate constants for the reaction of sulfamoyl chlorides (RNHSO2Cl) with anilines (XC6H4NH2) in chloroform at 20 8Ca Run 123456 R Me c-C6H11 Ph X Hp -OMe p-Cl p-CN p-OMe p-OMe l/nm 287 311 299 270 305 305 kobs/1023 s21 0.34 3.2 0.04 0.0017 b 18.0 34.6 a [Aniline] 12 × 1024 mol dm23, [sulfamoyl chloride] 0.75 × 1024 mol dm23.b Estimated (see Experimental section).J. Chem. Soc., Perkin Trans. 2, 1998 15 chlorides.12 The r values of 23.57 (phenylsulfamoyl chloride) and 23.54 (methylsulfamoyl chloride) are strikingly close to this value for the related phenylmethanesulfonyl chloride system.Changing from chloroform to acetonitrile produces a lower r value of 23.09 and this would be expected on the basis of the change to a more polar solvent: the relative permittivities (e) of chloroform and acetonitrile are 4.81 and 35.9, respectively. 13 For phenylmethanesulfonyl chloride the r values were measured in MeOH–CH3CN mixtures varying from 100% MeOH (e = 32.7 13) to 50% MeOH (v/v). These r values determined here indicate that the anilines play a major role by proton abstraction in an E2 transition state or in the first step (k1) of an (E1cB)irrev mechanism (Scheme 1).The much lower and higher r values measured for p-chlorophenyland p-methylphenylsulfamoyl chlorides of 22.63 (Table 5) and 24.76 (Table 4), respectively can be understood in terms of relative acid strength. The p-chloro compound should be more acidic than the parent sulfamoyl chloride and a diminished role can be envisaged for the anilines since the N–H is already weakened.However, in the p-methyl compound the hydrogen of the N–H bond should be more tightly held and consequently the bases will have a greater role. In Table 8 the effects of a limited study of the variation of rates with varying substitutent in XC6H4NHSO2Cl are presented. In chloroform the reaction is virtually insensitive to changing substituent and interestingly a similar result was obtained in the hydrolysis in aqueous dioxane at 29 8C of the sulfamoyl azides (RNHSO2N3, R = Ph, p-ClC6H4 and p- MeOC6H4), which gave rates of 8.75, 6.68 and 8.68 (×102 min21) respectively.14 In acetonitrile in our system there is a notable increase in rate with a change from an electrondonating to an electron-withdrawing substituent (Table 8).Also, it is noticeable that the rates are considerably faster in acetonitrile: kCH3CN/kCHCl3 for p-Me, H and p-Cl being respectively 19.5, 20.1 and 41.4.The more polar solvent facilitates reaction and in the case of p-chlorophenylsulfamoyl chloride a 40-fold acceleration is found. The extra rate enhancement for the chloro compound may well be due to the fact that in either an E2 or (E1cB)irrev mechanism the chloro substituent will stabilise an intermediate N-sulfonylamine, whereas a p-methyl group or the unsubstituted parent compound would not provide such stabilisation; hence their 20-fold acceleratory action may be due simply to the change to the more polar solvent.In Table 6 an approximately tenfold acceleration is noted from runs 2, 5 and 6 for a change in sulfamoyl chloride in the Table 7 Second order rate constants for the reaction of Nphenylsulfamoyl chloride with anilines (XC6H4NH2) in acetonitrile at 25 8C X p-Me Hm -OMe p-Cl p-CN p-NO2 k2/dm3 mol21 s21 89.1 20.3 11.2 2.68 0.28 0.08 log k2 1.95 1.31 1.05 0.428 20.55 21.12 sa 20.17 0 0.115 0.227 0.66 0.778 pKa a 5.08 4.60 4.23 3.98 1.74 1.00 a For s and pKa values see Table 3 footnotes b and c.Table 8 Second order rate constants for the reaction of parasubstituted phenylsulfamoyl chlorides (XC6H4NHSO2Cl) with aniline at 25 8C in chloroform and with aniline in acetonitrile a Chloroform Acetonitrile X p-OMe p-Me Hp -Cl k2/dm3 mol21 s21 0.98 0.88 1.01 0.84 X p-Me Hp -Cl k2/dm3 mol21 s21 17.1 20.3 34.8 reaction with p-anisidine in chloroform at 20 8C. These data gave a very poor Taft plot when log kobs was plotted vs.s*. The rate constants do, however, increase with increasing s*. Brønsted ‚ values. Brønsted b values have been determined for the data in Tables 3 and 7 using pKa values measured in water (see Table 3, footnote c). In CHCl3 at 25 8C the bnuc for aniline attack is 1.27 (n = 0.982, stand. error = 0.11) and in CH3CN at 25 8C the value is 0.685 (n = 0.980, stand. error = 0.076). These Brønsted coefficients could be substantially in error since the rate data in the Tables should of course be plotted using pKa values measured in the same solvents in which the rates were measured.At least, however, it may be taken that the bnuc values for the reaction are reasonably positive. In agreement with this, bnuc values of ca. 1.2 have been reported for the anilinolysis of phenylmethanesulfonyl chloride in 100% MeOH, 80% and 50% MeOH–CH3CN (v/v) 12 and of ca. 0.6–1.1 for the elimination reaction of 2-arylethylquinuclidinium ions, ArCH2CH2 1X in 60% DMSO–H2O (v/v).15 Using pKa values for anilinium ions, determined in dimethyl sulfoxide (DMSO),16 an approximate straight line is obtained when they are plotted against those determined in water. The values for p-Cl and p-NO2 are available in DMSO,16 and the other four pKa values in DMSO required for the data in Table 7 were obtained by interpolation (for m-OMe and p-CN) and by a slight extrapolation (for p-Me and H).A plot of log k2 values in Table 7 vs. these pKa values gave a slope of 0.62 (r = 0.976, stand.error = 0.069). Since the relative permittivity of DMSO (e = 46.5 13) is closer to that of acetonitrile (e = 35.9) than H2O (e = 78.3 13) such a plot may be more meaningful and seems to point to a reasonable degree of proton transfer in the slow step of the elimination. Activation data Table 9 contains DH‡ and DS‡ values for the reaction of phenylsulfamoyl chloride with anilines in chloroform and acetonitrile. The lower enthalpies in acetonitrile are immediately clear and the ca. 20-fold times faster reaction in this solvent has been referred to above. Acetonitrile, being more polar than chloroform, can provide greater stabilisation of the transition state. However, the lower enthalpies may indicate a shift to a more E1cB type mechanism, where proton removal is an important process occurring in the transition state. The enthalpies associated with proton dissociation of various anilinium ions in water lie in the range of ca. 16–30 kJ mol21.17 Some data for different temperatures are plotted in Fig. 2. The entropy data for acetonitrile compared to that for chloroform may also indicate a move to a mechanism with a greater charge build-up in the transition state and thus a somewhat greater change in entropy on going from ground state reactants to activation complex. The evidence in support of E2 or (E1cB)irrev mechanisms has been given above. A priori the involvement of an NTable 9 Activation parameters for the reaction of N-phenylsulfamoyl chloride with anilines in chloroform and acetonitrile Solvent CHCl3 a CH3CNd Substituent p-OMe p-OEt p-Me Hb m-OMeb p-Cl c Hm -OMe p-Cl DH‡/kJ mol21 24.3 ± 4 23.2 ± 2 23.4 ± 4 30.2 ± 2 53.6 ± 5 50.5 ± 7 17.7 ± 9 26.5 ± 3 37.3 ± 1 DS‡/J K21 mol21 2141.7 ± 12 2151.9 ± 5 2154.5 ± 12 2143.5 ± 6 273.2 ± 2 285.1 ± 23 2160.4 ± 1 2136.2 ± 7 2112.0 ± 1 a Temperature range 298–313 K (four temperatures). b Temperature range 298–313 K (three temperatures).c Temperature range 298–317.5 K (three temperatures).d Temperature range 298–314 K (four temperatures).16 J. Chem. Soc., Perkin Trans. 2, 1998 sulfonylamine is very likely. The general conditions for generation of an N-sulfonylamine 18 correspond to the reaction conditions used in this work. The likely mechanistic possibilities are shown in Scheme 1. The reaction may involve a central E2 type mechanism where departure of chloride and removal of the amino hydrogen in the sulfamoyl chlorides may both be concerted, or an (E1cB)irrev mechanism where a negative charge is first deposited on nitrogen prior to carbon–chlorine bond cleavage. In acetonitrile an E1cB-like E2 mechanism is proposed and in chloroform the mechanism may be shifted to a more E2 type.Experimental Solvents and starting materials Chloroform was refluxed over PCl5 for 12 h and fractionally distilled a number of times until a satisfactory low water content, which was determined by a Dean–Stark apparatus, was obtained.The solvent used in kinetic runs was distilled weekly and stored in an opaque container. Pyridine was left to stand for 24 h over KOH and then refluxed over fresh KOH, following which it was fractionally distilled. The first and last 10% of the distillate were discarded. Benzene stock solution was stored over CaCl2 and was refluxed and fractionally distilled over CaH2. It was stored over sodium wire. Acetonitrile was refluxed and distilled over CaH2 and stored in a dark container.Light petroleum was fractionally distilled and stored over sodium wire at least 72 h before use. Anilines. All liquid amines were refluxed over KOH and then fractionally distilled through an efficient Vigreux column, being sure to discard the first and last 15% of the distillate. All solid amines were sublimed or distilled under reduced pressure using a Kugel–Rohr distillation unit. All amines were stored under a nitrogen atmosphere at ca. 5 8C. Sulfamoyl chlorides. These were prepared by the method of Kloek and Leschinsky,19 except for N-methylsulfamoyl chloride, which was prepared by the method of Weiss and Schulze.20 Deuteriated materials. p-Anisidine-ND2 was prepared as follows: p-anisidine (0.5 g, 4.1 mmol) was dissolved in CDCl3 (10 ml) together with tetramethylammonium chloride (0.022 g, 0.2 mmol). To this was added 10 ml of D2O and sodium deuteroxide (0.008 g, 0.2 mmol); the reaction mixture was stirred for 24 h following which time the organic and aqueous layers were separated and the aqueous layer was replaced with a fresh batch of 10 ml of D2O, and the procedure was repeated.The layers were then separated and the chloroform was removed under vacuum. The deuteriated amine was purified by bulb to bulb distillation. The percentage of deuterium was determined by 1H NMR spectroscopy to be 94%. PhNDSO2Cl was prepared in >97% yield as follows: phenylsulfamoyl chloride (4.0 g, 0.021 mol) was added slowly to a solution of 15 ml of D2O containing NaOD (0.021 mol).This solution was heated to 40 8C for 2 h to ensure the complete hydrolysis of the chloride to the sulfamic acid. The D2O was removed under vacuum and the remaining sulfamate salt was recrystallised from 4: 1 CH3CN–D2O. The percentage of deuterium incorporated into the sodium phenylsulfamate salt was estimated by 1H NMR spectroscopy to be 98%. This was then reacted in the usual way in [2H6]benzene with phosphorus pentachloride to form the N-deuteriated phenylsulfamoyl chloride.Preparation of N-phenyl-N9-p-anisylsulfamide Non-deuteriated material. N-Phenylsulfamoyl chloride (0.25 g, 0.0013 mol) was dissolved in dry chloroform (50 ml) and p-anisidine (0.32 g, 0.0026 mol) was added. The solution was stirred for 2 h at room temperature, by which time complete reaction had occurred. The p-anisidine hydrochloride which forms precipitated from solution and was filtered off; removal of the solvent under vacuum gave crude product sulfamide (0.341 g, 94%).This was flash chromatographed to yield the pure product (87%). dC 55.190, 114.186, 117.919, 121.904, 122.490, 128.929, 130.667, 138.433, 155.831 ppm. 1H NMR spectrum in [2H6]DMSO, see Fig. 1(a). Deuteriated material. This reaction was conducted as in the previous experiment, except that a 10 : 1 molar ratio of p-anisidine-ND2 to phenylsulfamoyl chloride was used. The product sulfamide was redissolved in [2H6]DMSO (in CDCl3 the 1H NMR signals for the amino hydrogens fall under the aromatic peaks) and its 1H NMR spectrum was recorded, see Fig. 1(b). Two deuterium atoms, one on each of the nitrogens, are indicated and thus the reaction product is PhNDSO2NDC6H4OMe- p. Kinetic measurements The reactions between various aromatic amines and the sulfamoyl chlorides were carried out at 25 ± 0.2 and 20 ± 0.2 8C unless otherwise stated in the text and were monitored by UV spectroscopy using a Shimadzu 260 instrument. Reactions were generally followed by monitoring the decrease in absorbance of the amine peak at a suitable wavelength (see Tables 3 and 6).The reactions were started by the addition of 1 ml of a sulfamoyl chloride stock solution to an equal volume of the appropriate amine solution equilibrating in a quartz cuvette in the sample holder of the instrument. The initial sulfamoyl chloride concentration was 3.75 × 1025 mol dm23 (runs at 25 8C) and 0.75 × 1024 mol dm23 (runs at 20 8C).Amine concentrations varied from 4.5 × 1024 mol dm23 to 24 × 1024 mol dm23. Plots of |At 2 A•| as a function of time were found to be linear for over 90% reaction (>3 half lives). From 15 to 20 points were used in each plot. Second order rate constants were determined from plots of kobs as a function of amine concentration, the best line being determined by least-squares analysis. Some typical plots are shown in Fig. 2.Rate constants (Tables 1–8) were accurate to within ±5% based on replicate runs. The reaction of p-cyanoaniline in CHCl3 with MeNHSO2Cl was extremely slow and the spectral changes were very small (thus the method of initial rates was not used). The pseudo first-order Fig. 1 1H NMR spectra for (a) PhNHSO2NHC6H4OCH3-p and (b) PhNDSO2NDC6H4OCH3-pJ. Chem. Soc., Perkin Trans. 2, 1998 17 rate constant for this reaction, kobs (Table 6), was estimated as follows: (i) MeNHSO2Cl (1.0 × 1024 mol dm23) was reacted with p-anisidine (4.0 × 1024 mol dm23) in chloroform at 20 8C, a half-life of 4.6 min being observed; (ii) the sulfamoyl chloride (0.025 mol dm23) was reacted with p-cyanoaniline (0.1 mol dm23) in chloroform at 20 8C, a half-life of 35 min being observed; the reaction was performed in 100 ml of solution, with appropriate dilution of sample in chloroform prior to absorbance readings.The above results (i) and (ii) indicate that p-cyanoaniline is 1902 (35/4.6 × 250) times less reactive than panisidine towards N-methylsulfamoyl chloride.Thus an estimated rate constant for the reaction of N-methylsulfamoyl chloride (0.75 × 1024 mol dm23) and p-cyanoaniline (12.0 × 1024 mol dm23) in chloroform at 20 8C is 1.003 × 1024 min21 (0.190 76/1902 min21) or 0.001 67 × 1023 s21. Product runs Since the reaction of sulfamoyl chlorides with amines is a well documented synthetic route to unsymmetrical sulfamides, extensive product studies were not carried out.TLC analysis, to ensure that clean reactions were occurring, was performed, however. Bearing in mind the careful drying of the solvents and amines which was carried out the formation of sulfamic acids by reaction of H2O with the sulfamoyl chlorides would be negligible. Product runs with N-methylsulfamoyl chloride (5 mmol) and with aromatic amine (10 mmol) in chloroform (2 ml) were carrried out by refluxing for 40 min. The usual work-up for sulfamides gave from the appropriate amine the following: Nmethyl- N9-phenylsulfamide, 71%, mp 80–81 8C, N-methyl- Fig. 2 Plots of pseudo first order rate constants as a function of amine concentration at four different temperatures for the reaction of phenylsulfamoyl chloride (3.75 × 1025 mol dm23) with p-ethoxyaniline (4.5– 12 × 1024 mol dm23) in chloroform N9-p-anisylsulfamide, 96%, mp 86–87 8C and N-methyl-N9-pchlorophenylsulfamide, 97%, mp 112–113 8C. The yields are yields of crude product.A product run with phenylsulfamoyl chloride (0.25 g, 1.3 × 1023 mol) and p-anisidine (0.32 g, 2.6 × 1023 mol) in CHCl3 (50 ml) was carried out at room temperature over 2 h and 94% crude sulfamide was formed. After purification an 87% yield of pure sulfamide giving C, H and N microanalyses within ±5% and good 13C and 1H NMR spectra (see above) was obtained. Sulfamides were purified by recrystallisation using EtOH–H2O (50/50 v/v) or flash chromatography. 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