Patai S., Rappoport Z. 1996 The chemistry of functional groups. The chemistry of amino, nitroso, nitro and related groups. Part 2 / 0893 948

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S- - -C˛ bond and that there will be little or no change in the stronger C˛- - -N bond when the para-substituent on the nucleophile changes.

A second observation is that the substituent effect is greater in the free ion reactions than in the ion-pair reactions, i.e. the (kH/kD)˛ (Table 14) changes by 15% in the free ion reactions but by only 7% in the ion-pair reactions. The corresponding change in the k14/k15 is 0.0007 in the free ion reaction but only 0.0005 in the ion-pair reactions. A possible explanation for this is that the change in charge on the nucleophilic sulfur atom with substituent is greater in the free ions than in the ion-pairs. A CNDO/2 calculation64 shows that the decrease in charge on the sulfur of the free ion is 0.0208 but is only 0.0171 for the ion-pair when the para-substituent is changed. Since the substituent effect on the negative charge on the sulfur atom is 22% greater for the free ion, it is not surprising that the substituent effect is greater in the free ion reactions.

Finally, the changes in transition state structure found in this study can be used to test the theories for predicting the substituent effects on the transition state structure. Unfortunately, Thornton’s Reacting Bond Rule65, the More O’Ferrall Jencks Energy Surface Method66,67 and the Pross Shaik Method68 all fail to predict the change in transition state structure that was found in this study. Only the Bell, Evans and Polanyi Principle69, which predicts an earlier transition state when a better nucleophile is used, and the Bond Strength Hypothesis61, which predicts there will be a significant change in the weaker S- - -C˛ reacting bond and little or no change in the stronger C˛- - -N reacting bond when the para-substituent in the nucleophile is changed, are consistent with the experimental results.

The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for the free ion and ion-pair reactions in Table 15 show how ion pairing affects the structure of the transition state for the SN2 reactions between benzyldimethylphenylammonium nitrate and sodium para-substituted thiophenoxides in methanol at 20 °C. The

TABLE 15. The secondary alpha deuterium and primary leaving

group nitrogen	kinetic isotope	effects	and	the	Hammett
values for	the ion-pair and	free	ion	SN 2	reactions

between benzyldimethylphenylammonium nitrate and sodium para-
substituted thiophenoxides in methanol at 20			°C
para-Substituent	Free ion		Ion-pair
	k14/k15		k14/k15
CH3O	1.0162	š 0.0005a	1.0161	š 0.0005a
H	1.0166	š 0.0008	1.0162	š 0.0010
Cl	1.0169	š 0.0005	1.0166	š 0.0003

		(kH/kD)˛		(kH/kD)˛
CH3O		1.271 š 0.013b		1.216 š 0.012b
CH3		1.237	š 0.008	1.213	š 0.013
H		1.222	š 0.013	1.207	š 0.008
Cl		.	.	.	.
	c	1 121	š 0 014d	1 150	š 0 009d
		0.85 š 0.14		0.84 š 0.11

a Standard deviation for the average kinetic isotope effect.

b The error in the isotope effect is 1/kD[ kH 2 C kH/kD 2 ð kD 2]1/2, where kH and kD are the standard deviations for the rate constants for the reactions of the undeuterated and deuterated substrates, respectively.

c The Hammett values were obtained by changing the para-substituent in the nucleophile.

d The standard error of coefficient of the value.

944 Kenneth C. Westaway

primary nitrogen leaving group kinetic isotope effects for the free ion and the ion-pair reactions (Table 15) are identical within the experimental error of the method. Although the incoming nucleophile sulfur kinetic isotope effects have not been measured, one can deduce how the S- - -C˛ bond changes with ion pairing by combining the information provided by the secondary alpha deuterium and the primary nitrogen kinetic isotope effects. The magnitude of the secondary alpha deuterium kinetic isotope effect is determined by the S- - -N distance in the SN2 transition state19 and, since the nitrogen isotope effects show that the C˛- - -N transition state bond is not changed by ion pairing, the change in the secondary alpha deuterium kinetic isotope effect caused by ion pairing must be due to a change in the S- - -C˛ transition state bond. Therefore, the secondary alpha deuterium kinetic isotope effects indicate that the free ion S- - -C˛ bond is significantly longer than the ion-pair S- - -C˛ bond when the nucleophile is the p-methoxythiophenoxide ion, is longer than the ion-pair S- - -C˛ bond when the nucleophile is the p-methylthiophenoxide ion, is slightly longer than the ion-pair S- - -C˛ bond when the nucleophile is thiophenoxide ion but is shorter than the ion-pair S- - -C˛ bond in the p-chlorothiophenoxide ion reaction. Finally, the identical Hammett values, found by changing the para-substituent on the nucleophile for the free ion and ion-pair SN2 reactions (Table 15), indicate that the change in charge on the nucleophilic sulfur atom in going to the transition state is identical for the free ion and ion-pair reactions, and therefore, that the S- - -C˛ transition state bond is not altered significantly when the nucleophile changes from a free ion to an ion-pair. The identical values for the free ion and ion-pair reactions may be observed because, on average, the S- - -C˛ bond for the free ion reaction is identical to the S- - -C˛ bond in the ion-pair reactions.

One explanation for the longer S- - -C˛ bond in the free ion transition state is that the sodium ion reduces the electron density on the sulfur atom64, making it a poorer nucleophile. This would lead to a more product-like transition state (vide supra). Unfortunately, this is not true for the p-chlorothiophenoxide ion reaction which has a shorter S- - -C˛ bond in the free ion transition state. Two other observations are obvious when one considers how ion-pairing affects the structure of the SN2 transition state. First, the major change in bonding occurs in the weaker S- - -C˛ bond and there is little or no change in the stronger C˛- - -N reacting bond as the Bond Strength Hypothesis61 predicts. The final observation is that the greatest change in transition state structure is found in the reaction with the best nucleophile, and the effect of ion-pairing becomes smaller as a more electron-withdrawing substituent is added to the nucleophile. This probably occurs because the decrease in the electron density on the sulfur atom, that occurs when a more electronwithdrawing substituent is added to the nucleophile, reduces the strength of the ionic bond between the solvent-separated sodium ion and the sulfur anion of the para-substituted thiophenoxide ion significantly. This means that the difference between the electron density on the sulfur atom of a free ion nucleophile and an ion-pair nucleophile will be smaller when a more electron-withdrawing substituent is on the nucleophile. As a result, the difference between the free ion and the ion-pair secondary alpha deuterium kinetic isotope effects should be smaller when a more electron-withdrawing group is added to the nucleophile. This trend is found when the nucleophile is the p-methoxythiophenoxide ion, the p-methylthiophenoxide ion and the thiophenoxide ion. Unfortunately, the effect of ion-pairing on the transition state for the p-chlorothiophenoxide ion reaction does not fit this trend.

The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects (Table 16) were determined for the ion-pair SN2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at 0 °C60 and in methanol at 20 °C64 to learn how a change in solvent affects the structure of the SN2 transition state.

Unfortunately, the isotope effects were measured at different temperatures. Applying an average temperature dependence of 0.008 per 20 °C to the secondary alpha deuterium

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TABLE 16. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for the ion-pair SN2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at 0 °C and in methanol at 20 °C

	Temp								Hammett
Solvent	(°C)	(kH/kD)˛			k14/k15				valuea
Methanol	20	1.215	š 0.012b		1.0162	š 0.0010c		0.84		š 0.11d
DMF	0	1.179	š	0.010	1.0200	š	0.0007		1.70	š	0.05
		e
DMF	20	1.17				e
					1.019

a The Hammett value was obtained by changing the para-substituent on the nucleophile.

b The error in the isotope effect is 1/kD[ kH 2 C kH/kD 2 ð kD 2]1/2, where kH and kD are the standard deviations for the rate constants for the reactions of the undeuterated and deuterated substrates,

respectively.

c Standard deviation of the average kinetic isotope effect. d The standard error of coefficient of the value.

eThe kinetic isotope effects are estimated at 20 ° C.

kinetic isotope effect of 1.179 found at 0 ° C in DMF70,71 suggests that this kinetic isotope effect would be approximately 1.17 at 20 °C. The temperature dependence of a nitrogen isotope effect would appear to be small1, i.e. a change of 20 ° C would change the isotope effect by less than one percent. Thus, the nitrogen isotope effect for the reaction in DMF would be 1.019 at 20 °C.

The larger secondary alpha deuterium kinetic isotope effect of 1.215 in methanol indicates that the S- - -N transition state distance is greater in methanol than it is in DMF. The primary leaving group nitrogen kinetic isotope effect, on the other hand, is smaller in methanol than in DMF, indicating that the C˛- - -N transition state bond is considerably shorter in methanol than in DMF. Because the transition state in methanol has a longer S- - -N distance but a shorter C˛- - -N bond, the S- - -C˛ bond must be much longer in methanol than in DMF. Therefore, an earlier transition state with a much longer S- - -C˛ and a shorter C˛- - -N bond is found in methanol (Figure 6).

The Hammett values found by changing the para-substituent on the nucleophile in DMF and methanol (Table 16) support this conclusion. The larger value in DMF indicates that the change in charge on the nucleophilic sulfur atom is greater on going from the reactant to the transition state in DMF. Therefore, the S- - -C˛ transition state bond is shorter in DMF than in methanol.

The earlier transition state in methanol can be rationalized as follows. The SN2 transition state for this reaction will primarily be solvated at the sulfur atom because the partial

In methanol:
δ−	δ+	δ+
S	Cα	N (kH/kD)α = 1.215
(Na+)				k14 /k15 = 1.0162
In DMF:
δδ−	δ+			δδ+
S	Cα			N (kH/kD)α = 1.17
+				k14 /k15 ≥ 1.019
(Na )

FIGURE 6. The relative transition state structures for the ion-pair SN 2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF and in methanol

946 Kenneth C. Westaway

positive charges on the alpha carbon and on the nitrogen atom are sterically hindered to solvation. The second assumption is that the structure of the transition state will depend on its stability in that solvent, i.e. that the transition state that is the most stable in each solvent will be found. An early transition state would be more stable than a product-like transition state in methanol, because solvation of the sulfur atom by hydrogen bonding would lower the energy of an early transition state where there is a greater negative charge on the sulfur atom, i.e. the solvent stabilizes an earlier transition state more than a late transition state. As a result, a transition state with a longer and weaker S- - -C˛ transition state bond would be expected in methanol. In DMF, a late, less ionic (dipolar) transition state which would be more strongly solvated by DMF, is expected.

Finally, the secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for the ion-pair SN2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate were measured at two different ionic strengths in DMF at 0 °C (Table 17)58. The larger secondary alpha deuterium and the smaller nitrogen leaving group kinetic isotope effect found in the high ionic strength reaction indicate that the S- - -N distance in the transition state is greater and that the C˛- - -N bond is shorter in the reaction at a high ionic strength. This means that the S- - -C˛ bond is longer in the transition state for the high ionic strength reaction. The earlier, more ionic, transition state is probably found at the high ionic strength because the more ionic transition state will be more stable (more highly solvated) in the more ionic solvent. The important observation, however, is that inert salts that are used to increase the ionic strength in reactions so that accurate rate constants can be measured, change the structure of the transition state markedly.

TABLE 17. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects and the relative transition state structures for the ion-pair SN 2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at different ionic strengths at 0 °C

		k14/k15	Relative transition
Ionic strength	(kH/kD)˛		state structure
	1.179 š 0.010a	1.0200 š 0.0007b	υυ	υυC
0.640			S- - -C- - -- - -N
	1.215 š 0.011a	1.0166 š 0.0004b	υ	υC
0.904			S- - -- - -C- - -N

a The error in the isotope effect is 1/kD[ kH 2 C kH/kD 2 ð kD 2]1/2, where kH and kD are the standard deviations for the rate constants for the reactions of the undeuterated and deuterated substrates, respectively.

bThe standard deviation for the average kinetic isotope effect.

V.REFERENCES

1.P. J. Smith and K. C. Westaway, in The Chemistry of the Functional Groups, Supplement F: The Chemistry of Amino, Nitroso and Nitro Compounds and Their Derivatives (Ed. S. Patai), Wiley, London, 1982, pp. 1261 1312.

2.L. Melander, Isotope Effects on Reaction Rates, Ronald Press, New York, 1960.

3.E. Caldin and V. Gold (Eds.), Proton Transfer Reactions, Chapman and Hall, London, 1975.

4.W. W. Cleland, M. H. O’Leary and D. B. Northrup (Eds.), Isotope Effects in Enzyme-catalyzed Reactions, University Park Press, Baltimore, 1977.

5.L. Melander and W. H. Saunders, Jr., Reaction Rates of Isotopic Molecules, Wiley-Interscience, New York, 1980.

6.J. Bigeleisen, Proceedings of the International Symposium on Isotope Separation, North-Holland, Amsterdam, 1958.

20. The synthesis and uses of amino and quaternary ammonium salts

947

7.J. Bigeleisen and M. Wolfsberg, Adv. Chem. Phys., 1, 15 (1958).

8.J. Bigeleisen, J. Chem. Phys., 17, 675 (1949).

9.S. Glasstone, K. J. Laidler and H. Eyring, The Theory of Rate Processes, McGraw-Hill, New York, 1941.

10.W. H. Saunders, Jr., Chem. Scr., 8, 27 (1975).

11.L. B. Sims, A. Fry, L. T. Netherton, J. C. Wilson, K. D. Reppond and W. S. Cook, J. Am. Chem. Soc., 94, 1364 (1972).

12.F. H. Westheimer, Chem. Rev., 61, 265 (1961).

13.R. A. More O’Ferrall, J. Chem. Soc. (B), 785 (1970).

14.A. Streitwieser, Jr., R. H. Jagow, R. C. Fahey and S. Suzuki, J. Am. Chem. Soc., 80, 2326 (1958).

15.K. C. Westaway and S. F. Ali, Can. J. Chem., 57, 1089 (1979).

16.S. R. Hartshorn and V. J. Shiner, Jr., J. Am. Chem. Soc., 94, 9002 (1972).

17.H. Humski, V. Sendijarevic and V. J. Shiner, Jr., J. Am. Chem. Soc., 96, 6187 (1974).

18.S. Wolfe and C. -K. Kim, J. Am. Chem. Soc., 113, 8056 (1991).

19.R. A. Poirier, Y. Wang and K. C. Westaway, J. Am. Chem. Soc., 116, 2526 (1994).

20.C. K. Ingold, E. D. Hughes and D. V. Banthorpe, J. Chem. Soc., 2864 (1964).

21.M. J. S. Dewar and A. Marchand, Annu. Rev. Phys. Chem., 16, 338 (1965).

22.H. J. Shine, H. Zmuda, K. H. Park, H. Kwart, A. G. Horgan and M. Brechbiel, J. Am. Chem. Soc., 104, 2501 (1982).

23.H. J. Shine, H. Zmuda, K. H. Park, H. Kwart, A. G. Horgan, C. Collins and B. E. Maxwell, J. Am. Chem. Soc., 103, 955 (1981).

24.H. J. Shine, G. N. Henderson, A. Cu and P. Schmid, J. Am. Chem. Soc., 99, 3719 (1977).

25.S. H. Korzeniowski, L. Blum and G. W. Gokel, J. Org. Chem., 42, 1469 (1977).

26.H. J. Shine, H. Zmuda, H. Kwart, A. G. Horgan and M. Brechbiel, J. Am. Chem. Soc., 104, 5181 (1982).

27.A. Heesing and U. Schinke, Chem. Ber., 105, 3838 (1972).

28.A. Heesing and U. Schinke, Chem. Ber., 110, 3819 (1977).

29.H. J. Shine, J. Habdas, H. Kwart, M. Brechbiel, A. G. Horgan and J. San Filippo, Jr., J. Am. Chem. Soc., 105, 2823 (1983).

30.G. S. Hammond and J. S. Clovis, J. Org. Chem., 28, 3283 (1963).

31.M. J. S. Dewar, The Electronic Theory of Organic Chemistry, Oxford University Press, Oxford, 1949, p. 239.

32.D. V. Banthorpe and J. G. Winter, J. Chem. Soc., Perkin Trans. 2, 868 (1972).

33.C. G. Swain, E. C. Stivers, J. F. Reuwer, Jr. and L. J. Schaad, J. Am. Chem. Soc., 80, 5885 (1958).

34.H. J. Shine, J. Zygmunt, M. L. Brownawell, and J. San Filippo, Jr., J. Am. Chem. Soc., 106, 3610 (1984).

35.J. H. Ridd and J. P. B. Sandall, J. Chem. Soc., Chem. Commun., 261, (1982).

36.H. J. Shine, K. H. Park, M. L. Brownawell and J. San Filippo, Jr., J. Am. Chem. Soc., 106, 7077 (1984).

37.H. J. Shine, E. Gruszecka, W. Subotkowski, M. Brownawell and J. San Filippo, Jr., J. Am. Chem. Soc., 107, 3218 (1985).

38.H. J. Shine, L. K. Subotkowski and W. Subotkowski, J. Am. Chem. Soc., 107, 6674 (1985).

39.E. S. Rhee and H. J. Shine, J. Am. Chem. Soc., 108, 1000 (1986).

40.H. J. Shine and E. S. Rhee, J. Labelled Compd. Radiopharm., 21, 569 (1984).

41.W. Subotkowski, L. K. Subotkowski and H. J. Shine, J. Am. Chem. Soc., 115, 5073 (1993).

42.B. Boduszek and H. J. Shine, J. Am. Chem. Soc., 110, 3247 (1988).

43.B. Miller, J. Am. Chem. Soc., 86, 1127 (1964).

44.B. S. Axelsson, B. Langstrom and O. Matsson, J. Am. Chem. Soc., 109, 7233 (1987).

45. B. Langstrom, G. Antoni, P. Gullberg, C. Halldin, P. Malmborg, K. Nagren, A. Rimland and

H. Svard, J. Nucl. Med., 28, 1037 (1987).

46.B. S. Axelsson, O. Matsson and B. Langstrom, J. Phys. Org. Chem., 4, 77 (1991).

47.T. Ando, T. Kimura and H. Yamataka, in Nucleophilicity (Eds. J. M. Harris and S. P. McManus) Chap. 7, American Chemical Society, Washington, DC, 1987, p. 108

48.J. L. Kurz, M. W. Daniels, K. S. Cook and M. M. Nasr, J. Phys. Chem., 90, 5357 (1986).

49.J. L. Kurz, J. E. Pantano, D. R. Wright and M. M. Nasr, J. Phys. Chem., 90, 5360 (1986).

50.T. Ando, H. Yamataka and E. Wada, Isr. J. Chem., 26, 354 (1985).

51.J. M. Harris, M. S. Paley and T. W. Prasthofer, J. Am. Chem. Soc., 103, 5915 (1981).

52.P. Paneth and M. H. O’Leary, J. Am. Chem. Soc., 113, 1691 (1991).

948	Kenneth C. Westaway

53.T. Ando, H. Tanabe and H. Yamataka, J. Am. Chem. Soc., 106, 2084 (1984).

54.I. Lee, H. J. Koh, B. -S. Lee, D. S. Sohn and B. C. Lee, J. Chem. Soc., Perkin Trans. 2, 1741 (1991).

55.J. Persson, U. Berg and O. Matsson, J. Org. Chem., 60, 5037 (1995).

56.W. J. Le Noble and A. R. Miller, J. Org. Chem., 44, 889 (1979).

57.C. G. Swain and N. D. Hershey, J. Am. Chem. Soc., 94, 1901 (1972).

58.V. T. Pham, M.Sc. Dissertation, Laurentian University, Sudbury, Ont., Canada, 1993.

59.A. Maccoll, Annu. Rep. A. Chem. Soc., (London), 71, 77 (1974).

60.K. C. Westaway and S. F. Ali, Can. J. Chem., 57, 1354 (1979).

61.K. C. Westaway, Can. J. Chem., 71, 2084 (1993).

62.Z. G. Lai and K. C. Westaway, Can. J. Chem., 67, 21 (1989).

63.K. C. Westaway and Z. G. Lai, Can. J. Chem., 66, 1263 (1988).

64.W. Jiang, M.Sc. Dissertation, Laurentian University, Sudbury, Ont., Canada, 1996.

65.E. R. Thornton, J. Am. Chem. Soc., 89, 2915 (1967).

66.R. A. More O’Ferrall, J. Chem. Soc. (B), 274 (1970).

67.W. P. Jencks, Chem. Rev., 72, 705 (1972).

68.A. Pross and S. S. Shaik, J. Am. Chem. Soc., 103, 3702 (1981).

69.M. J. Dewar and R. C. Dougherty, The PMO Theory of Organic Chemistry, Plenum Press, New York, 1975, pp. 219, 220.

70. V. J. Shiner, Jr., W. Dowd, R. D. Fisher, S. R. Hartshorn, M. A. Kessik, L. Milakofsky and

M. W. Rapp., J. Am. Chem. Soc., 91, 4838 (1969).

71.K. M. Koshy and R. E. Robertson, J. Am. Chem. Soc., 96, 914 (1974).